Stem cell therapy for chronic ischaemic heart disease and congestive heart failure

  • Review
  • Intervention

Authors


Abstract

Background

A promising approach to the treatment of chronic ischaemic heart disease (IHD) and heart failure is the use of stem cells. The last decade has seen a plethora of randomised controlled trials (RCTs) developed worldwide which have generated conflicting results.

Objectives

The critical evaluation of clinical evidence on the safety and efficacy of autologous adult bone marrow-derived stem cells (BMSC) as a treatment for chronic ischaemic heart disease (IHD) and heart failure.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 3), MEDLINE (from 1950), EMBASE (from 1974), CINAHL (from 1982) and the Transfusion Evidence Library (from 1980), together with ongoing trial databases, for relevant trials up to 31st March 2013.

Selection criteria

Eligible studies included RCTs comparing autologous adult stem/progenitor cells with no autologous stem/progenitor cells in participants with chronic IHD and heart failure. Co-interventions such as primary angioplasty, surgery or administration of stem cell mobilising agents, were included where administered to treatment and control arms equally.

Data collection and analysis

Two review authors independently screened all references for eligibility, assessed trial quality and extracted data. We undertook a quantitative evaluation of data using fixed-effect meta-analyses. We evaluated heterogeneity using the I² statistic; we explored considerable heterogeneity (I² > 75%) using a random-effects model and subgroup analyses.

Main results

We include 23 RCTs involving 1255 participants in this review. Risk of bias was generally low, with the majority of studies reporting appropriate methods of randomisation and blinding, Autologous bone marrow stem cell treatment reduced the incidence of mortality (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.14 to 0.53, P = 0.0001, 8 studies, 494 participants, low quality evidence) and rehospitalisation due to heart failure (RR 0.26, 95% CI 0.07 to 0.94, P = 0.04, 2 studies, 198 participants, low quality evidence) in the long term (≥12 months). The treatment had no clear effect on mortality (RR 0.68, 95% CI 0.32 to 1.41, P = 0.30, 21 studies, 1138 participants, low quality evidence) or rehospitalisation due to heart failure (RR 0.36, 95% CI 0.12 to 1.06, P = 0.06, 4 studies, 236 participants, low quality evidence) in the short term (< 12 months), which is compatible with benefit, no difference or harm. The treatment was also associated with a reduction in left ventricular end systolic volume (LVESV) (mean difference (MD) -14.64 ml, 95% CI -20.88 ml to -8.39 ml, P < 0.00001, 3 studies, 153 participants, moderate quality evidence) and stroke volume index (MD 6.52, 95% CI 1.51 to 11.54, P = 0.01, 2 studies, 62 participants, moderate quality evidence), and an improvement in left ventricular ejection fraction (LVEF) (MD 2.62%, 95% CI 0.50% to 4.73%, P = 0.02, 6 studies, 254 participants, moderate quality evidence), all at long-term follow-up. Overall, we observed a reduction in functional class (New York Heart Association (NYHA) class) in favour of BMSC treatment during short-term follow-up (MD -0.63, 95% CI -1.08 to -0.19, P = 0.005, 11 studies, 486 participants, moderate quality evidence) and long-term follow-up (MD -0.91, 95% CI -1.38 to -0.44, P = 0.0002, 4 studies, 196 participants, moderate quality evidence), as well as a difference in Canadian Cardiovascular Society score in favour of BMSC (MD -0.81, 95% CI -1.55 to -0.07, P = 0.03, 8 studies, 379 participants, moderate quality evidence). Of 19 trials in which adverse events were reported, adverse events relating to the BMSC treatment or procedure occurred in only four individuals. No long-term adverse events were reported. Subgroup analyses conducted for outcomes such as LVEF and NYHA class revealed that (i) route of administration, (ii) baseline LVEF, (iii) cell type, and (iv) clinical condition are important factors that may influence treatment effect.

Authors' conclusions

This systematic review and meta-analysis found moderate quality evidence that BMSC treatment improves LVEF. Unlike in trials where BMSC were administered following acute myocardial infarction (AMI), we found some evidence for a potential beneficial clinical effect in terms of mortality and performance status in the long term (after at least one year) in people who suffer from chronic IHD and heart failure, although the quality of evidence was low.

Résumé scientifique

Traitement à base de cellules souches pour la cardiopathie ischémique chronique et l'insuffisance cardiaque congestive

Contexte

Une approche prometteuse pour le traitement de la cardiopathie ischémique chronique (CIC) et de l'insuffisance cardiaque est l'utilisation de cellules souches. La dernière décennie a révélé une pléthore d'essais contrôlés randomisés (ECR) développés dans le monde qui ont généré des résultats contradictoires.

Objectifs

L'évaluation critique de preuve clinique sur l'innocuité et l'efficacité des cellules souches autologues dérivées de la moelle osseuse adulte (BMSC) comme traitement de la cardiopathie ischémique chronique (CIC) et de l'insuffisance cardiaque.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) ( La Bibliothèque Cochrane 2013, numéro 3), MEDLINE (depuis 1950), EMBASE (depuis 1974), CINAHL (depuis 1982) et Transfusion Evidence Library (depuis 1980), ainsi que dans les bases de données d'essais en cours, pour les essais pertinents jusqu'au 31 mars 2013.

Critères de sélection

Les études éligibles incluaient des ECR comparant les cellules souches /progénitrices autologues adultes avec aucune cellule souche /progénitrice autologue chez les participants atteints de CIC et d'insuffisance cardiaque. Les co-interventions, telles que l'angioplastie primaire, la chirurgie ou l'administration d'agents mobilisant les cellules souches, ont été incluses lorsqu'elles étaient administrées au traitement et aux groupes témoins de façon égale.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment examiné toutes les références pour l'éligibilité, évalué la qualité des essais et extrait les données. Nous avons entrepris une évaluation quantitative des données à l'aide des méta-analyses à effets fixes. Nous avons évalué l'hétérogénéité à l'aide des statistiques I²; nous avons exploré une hétérogénéité considérable (I² > 75 %) en utilisant un modèle à effets aléatoires et des analyses en sous-groupes.

Résultats principaux

Dans cette revue, nous avons inclus 23 ECR, impliquant 1 255 participants. Le risque de biais était généralement faible, avec la majorité des études rapportant des méthodes appropriées de randomisation et d'assignation en aveugle, le traitement à base de cellules souches autologues de la moelle osseuse réduisait l'incidence de la mortalité (risque relatif (RR) 0,28, intervalle de confiance à 95 % (IC) de 0,14 à 0,53, P = 0,0001, 8 études, 494 participants, preuves de faible qualité) et de la réadmission à l'hôpital en raison d'une insuffisance cardiaque (RR 0,26, IC à 95 % de 0,07 à 0,94, P = 0,04, 2 études, 198 participants, preuves de faible qualité) sur le long terme (?12 mois). Le traitement n'avait aucun effet évident sur la mortalité (RR 0,68, IC à 95 % de 0,32 à 1,41, P = 0,30, 21 études, 1 138 participants, preuves de faible qualité) ou sur la réadmission à l'hôpital en raison d'insuffisance cardiaque (RR 0,36, IC à 95 % de 0,12 à 1,06, P = 0,06, 4 études, 236 participants, preuves de faible qualité) sur le court terme (< 12 mois), ce qui est compatible avec un bénéfice, aucune différence ou un effet nocif. Le traitement était également associé à une diminution du volume systolique du ventricule gauche (LVESV) (différence moyenne (DM) -14,64 ml, IC à 95 % de -20,88 ml à -8,39 ml, P < 0,00001, 3 études, 153 participants, preuves de qualité modérée) et de l'indice de volume des AVC (DM 6,52, IC à 95 % de 1,51 à 11,54, P = 0,01, 2 études, 62 participants, preuves de qualité modérée), ainsi qu'une amélioration de la fraction d'éjection ventriculaire gauche (FEVG) (DM 2,62%, IC à 95 % de 0,50 % à 4,73%, P = 0,02, 6 études, 254 participants, preuves de qualité modérée), tous à un suivi à long terme. Dans l'ensemble, nous avons observé une réduction de la classification fonctionnelle (classification de New York Heart Association (NYHA)) en faveur du traitement des BMSC pendant le suivi à court terme (DM -0,63, IC à 95 % de -1,08 à -0,19, P = 0,005, 11 études, 486 participants, preuves de qualité modérée) et pendant le suivi à long terme (DM -0,91, IC à 95 % de -1,38 à -0,44, P = 0,0002, 4 études, 196 participants, preuves de qualité modérée), ainsi qu'une différence en termes de score de la Société Canadienne de Cardiologie en faveur des BMSC (DM -0,81, IC à 95 % -1,55 à -0,07, P = 0,03, 8 études, 379 participants, preuves de qualité modérée). Sur 19 essais dans lesquels les effets indésirables étaient rapportés, les effets indésirables liés au traitement ou à la procédure des BMSC sont survenus chez seulement quatre individus. Aucun effet indésirable à long terme n'a été rapporté. Les analyses en sous-groupe réalisées pour les critères de jugement, tels que la FEVG et la classification NYHA, révélaient que (i) la voie d'administration, (ii) le point de comparaison de la FEVG, (iii) le type cellulaire et (iv) l'état clinique sont des facteurs importants qui peuvent avoir une influence sur l'effet du traitement.

Conclusions des auteurs

Cette revue systématique et cette méta-analyse ont trouvé des preuves de qualité modérée indiquant que le traitement des BMSC améliore la FEVG. Contrairement aux essais dans lesquels les BMSC étaient administrés suite à un infarctus aigu du myocarde (IAM), nous avons trouvé certaines preuves d'un effet clinique potentiellement bénéfique en termes de mortalité et de performance sur le long terme (après au moins un an) chez les patients souffrant de CIC et d'insuffisance cardiaque, bien que la qualité des preuves soit faible.

摘要

慢性缺血性心臟病和充血性心臟衰竭的幹細胞療法

背景

對慢性缺血性心臟病 (ischaemic heart disease, IHD) 和心臟衰竭而言,使用幹細胞是前途看好的治療方法。近10年來全球已展開多血症 (plethora) 的隨機對照試驗 (randomized controlled trial, RCT),但卻得到相互矛盾的結果。

目的

針對成人使用自體骨髓幹細胞 (bone marrow-derived stem cell, BMSC) 移植,以治療慢性缺血性心臟病 (ischaemic heart disease, IHD) 和心臟衰竭 (heart failure) 的安全性和療效相關臨床證據,進行重要評估。

搜尋策略

我們搜尋考科藍對照試驗中央註冊 (Cochrane Central Register of Controlled Trials, CENTRAL) (考科藍圖書館,2013年第3次發行)、MEDLINE (自1950年起)、EMBASE (自1974年起)、CINAHL (自1982年起) 和Transfusion Evidence Library (自1980年起),以及進行中試驗的資料庫,找尋截至2013年3月31日為止的相關試驗。

選擇標準

符合本次文獻回顧納入條件的試驗為:比較自體移植成人幹細胞/前驅細胞 (progenitor cell) 和無自體移植幹細胞/前驅細胞之慢性IHD和心臟衰竭患者的RCT。亦納入治療組和對照組同樣使用的併用介入,例如初期血管成形術 (primary angioplasty)、外科手術或投予幹細胞驅動藥物 (mobilising agent)。

資料收集與分析

由2位文獻回顧作者獨立篩選所有參考文獻,找尋符合納入條件的試驗,並評估試驗品質及萃取資料。我們採用固定效果後設分析 (meta-analysis),進行資料的量化評估。²並使用I²統計量評估異質性;本次文獻回顧採用隨機效果模式 (random-effect model) 和子群體分析,探究重要的異質性 (I ²   > 75%)。

主要結果

本次文獻回顧納入23篇RCT,包含1255名受試者。偏差風險普遍偏低,大部分試驗皆通報適當的隨機分配和盲性處理方式。自體移植骨髓幹細胞治療,可降低長期 (≥ 12 個月) 因心臟衰竭導致的死亡率 (風險比 [RR] 為0.28,95%信賴區間 [CI] 為0.14至0.53,P = 0.0001,8篇試驗,494名受試者,證據品質低) 和再住院率 (RR為0.26,95% CI為0.07至0.94,P = 0.04,2篇試驗,198名受試者,證據品質低)。短期治療 (< 12 個月) 對因心臟衰竭導致的死亡率 (RR為0.68,95% CI為0.32至1.41,P = 0.30,21篇試驗,1138名受試者,證據品質低) 或再住院率 (RR為0.36,95% CI為0.12至1.06,P = 0.06,4篇試驗,236名受試者,證據品質低),並無明確影響,療效相當,傷害亦無差異。長期追蹤發現,此種治療亦可降低左心室收縮末期容積 (left ventricular end systolic volume, LVESV) (平均差 [MD] 為 -14.64ml,95% CI為 -20.88 ml至 -8.39 ml,P < 0.00001,3篇試驗,153名受試者,證據品質中等) 和心動搏出量指數 (stroke volume index) (MD為6.52,95% CI為1.51至11.54,P = 0.01,2篇試驗,62名受試者,證據品質中等),並改善左心室射出分率 (left ventricular ejection fraction, LVEF) (MD為2.62%,95% CI為0.50%至4.73%,P = 0.02,6篇試驗,254名受試者,證據品質中等)。整體而言,我們觀察到短期追蹤 (MD為 -0.63,95% CI為 -1.08至 -0.19,P = 0.005,11篇試驗,486名受試者,證據品質中等) 和長期追蹤 (MD為 -0.91,95% CI為 -1.38至 -0.44,P = 0.0002,4篇試驗,196名受試者,證據品質中等) 的結果均顯示,BMSC治療降低患者功能類別 (紐約心臟學會 [New York Heart Association, NYHA] 類別) 的療效較佳,此外加拿大心血管學會 (Canadian Cardiovascular Society) 分數差的結果,亦以BMSC治療為佳 (MD為 -0.81,95% CI為 -1.55至 -0.07,P = 0.03,8篇試驗,379名受試者,證據品質中等)。在19篇報告不良事件的試驗中,只有4名受試者發生BMSC治療或程序相關不良事件。並無長期不良事件報告。針對諸如LVEF和NYHA類別等結果所進行的子群體分析顯示,(i) 給藥途徑、(ii) 基準點LVEF、(iii) 細胞類型和 (iv) 臨床狀況,為影響治療效果的重要因素。

作者結論

本次系統性文獻回顧和後設分析發現,BMSC治療可改善LVEF (證據品質中等)。不同於在急性心肌梗塞 (acute myocardial infarction, AMI) 後才進行BMSC的試驗,我們發現雖然證據品質偏低,但有些證據顯示,對慢性IHD和心臟衰竭患者的長期 (至少1年後) 死亡率和體能狀態,可能具有有益的臨床療效。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Resumo

Terapia com células-tronco para cardiopatia isquêmica crônica e insuficiência cardíaca congestiva

Introdução

O uso de células-tronco é uma abordagem promissora para o tratamento da cardiopatia isquêmica crônica e da insuficiência cardíaca. Ao longo dos últimos 10 anos, foram publicados muitos ensaios clínicos randomizados (ECR) sobre isso, porém seus resultados são conflitantes.

Objetivos

Avaliar a evidência clínica existente sobre a segurança e eficácia da terapia com células-tronco autólogas derivadas da medula óssea de adultos (inglês: BMSC) para o tratamento de pacientes com cardiopatia isquêmica crônica e insuficiência cardíaca.

Métodos de busca

As buscas foram realizadas em 31 de março de 2013 nas seguintes bases de dados: Cochrane Central Register of Controled Trials (CENTRAL) (The Cochrane Library, 2013, volume 3), MEDLINE (desde 1950), Embase (desde 1974), CINAHL (desde 1982) e na Transfusion Evidence Library (desde 1980). Na mesma data, também fizemos buscas nas plataformas de registros de ensaios clínicos em andamento.

Critério de seleção

Incluímos ECRs que compararam grupos de pacientes com cardiopatia isquêmica crônica e insuficiência cardíaca tratados com e sem terapia com células-tronco/progenitoras autólogas de adultos. Os estudos que usaram intervenções adicionais, tais como a angioplastia primária, cirurgia ou uso de agentes de mobilização de células-tronco, foram incluídos contanto que essas intervenções fossem dadas a ambos os grupos (controle e intervenção).

Coleta dos dados e análises

Dois revisores selecionaram de maneira independente todas as referências elegíveis, extraíram os dados e fizeram a avaliação da qualidade dos estudos. Usamos o modelo de efeito fixo para as metanálises. Avaliamos a heterogeneidade, usando a estatística I². Em caso de alta heterogeneidade (I² > 75%), fizemos metanálises usando o modelo de efeitos aleatórios e análises de subgrupo.

Principais resultados

Incluímos 23 ECRs envolvendo 1.255 participantes. No geral, o risco de viés foi baixo, já que a maioria dos estudos usou métodos adequados de randomização e cegamento. O tratamento com células-tronco de medula óssea autóloga reduziu a incidência de mortalidade [risco relativo (RR) 0,28, intervalo de confiança de 95% (IC) 0,14 a 0,53, P = 0,0001, 8 estudos, 494 participantes,evidência de baixa qualidade] e a incidência de reinternação devido a insuficiência cardíaca (RR 0,26, 95% IC 0,07 a 0,94, P = 0,04, 2 estudos, 198 participantes, evidência de baixa qualidade) a longo prazo ( ≥ 12 meses). No curto prazo, a intervenção não teve um efeito consistente sobre a mortalidade (RR 0,68, IC 95% 0,32 a 1,41, P = 0,30, 21 estudos, 1.138 participantes, evidência de baixa qualidade) ou reinternação devido a insuficiência cardíaca (RR 0,36, 95% IC 0,12 a1,06, P = 0,06, 4 estudos, 236 participantes, evidência de baixa qualidade) a curto prazo (< 12 meses). O tratamento também reduziu o volume sistólico final do ventrículo esquerdo [diferença média (MD) -14.64 ml, IC 95% -20.88 ml a-8.39 ml, P < 0,00001 3 estudos, 153 participantes, evidência de qualidade moderada] e reduziu o índice de volume sistólico (MD 6,52, IC 95% 1,51 a 11,54, P = 0,01, 2 estudos, 62 participantes, evidência de qualidade moderada). A intervenção também melhorou a fração de ejeção do ventrículo esquerdo (MD 2,62% 95% CI 0,50% a 4,73%, P = 0,02, 6 estudos, 254 participantes, evidência de qualidade moderada) e o acompanhamento a longo prazo. A terapia também promoveu uma redução na classe funcional (New York Heart Association – NYHA), dos pacientes tanto a curto prazo (MD -0,63, IC 95% -1,08 a -0,19, P = 0,005, 11 estudos, 486 participantes, evidência de qualidade moderada) como a longo prazo (MD -0,91, IC 95% -1,38 a - 0,44, P = 0,0002, 4 estudos, 196 participantes, evidência de qualidade moderada). O tratamento também promoveu uma redução significativa da classificação dos pacientes na escala da Canadian Cardiovascular Society (MD -0,81 IC 95% -1,55 a -0,07, P = 0,03, 8 estudos, 379 participantes, evidência de qualidade moderada). Apenas 4 pessoas no grupo da terapia com células-tronco tiveram eventos adversos, nos 19 estudos que relataram esse desfecho. Nenhum efeito adverso a longo prazo foi relatado. As análises de subgrupo realizadas para os desfechos tais como fração de ejeção ventricular esquerda e classe da NYHA revelaram que (i) a via de administração, (ii) nível de base da fração de ejeção ventricular esquerda, (iii) o tipo de célula (iii) e (iv) a condição clínica do paciente são fatores importantes que podem influenciar o efeito do tratamento.

Conclusão dos autores

Esta revisão sistemática e metanálise encontraram evidências de qualidade moderada de que a terapia com células-tronco melhora a fração de ejeção do ventrículo esquerdo. Ao contrário dos estudos que usaram essa terapia após infarto agudo do miocárdio, existe evidência de que seu uso em pacientes com cardiopatia isquêmica crônica e insuficiência cardíaca pode ser benéfico em termos de mortalidade e desempenho cardíaco a longo prazo (após pelo menos um ano). Porém, a qualidade da evidência que apoia essa conclusão é baixa.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva). Contato: tradutores@centrocochranedobrasil.org.br

Plain language summary

Stem cell treatment for chronic ischaemic heart disease and congestive heart failure

Those suffering from heart disease and heart failure are currently treated with drugs and, when possible, the blood supply is restored in the heart (revascularisation) either by opening the arteries with a tiny balloon in a procedure called primary angioplasty (or percutaneous coronary intervention (PCI)) or by heart surgery (or coronary artery bypass graft (CABG)). Revascularisation has reduced the death rate associated with these conditions. In some people heart disease and heart failure symptoms persist even after revascularisation. Those people may not have other treatments available to them. Recently, bone marrow stem/progenitor cells have been investigated as a new treatment for people with heart disease and heart failure, whether they are also treated for revascularisation or not. Results from 23 randomised controlled trials, covering more than 1200 participants, to 2013 indicates that this new treatment leads to a reduction in deaths and readmission to hospital and improvements over standard treatment as measured by tests of heart function. At present, these results provide some evidence that stem cell treatment may be of benefit in people both with chronic ischaemic heart disease and with heart failure. Adverse events are rare, with no long-term adverse events reported. However, the quality of the evidence is relatively low because there were few deaths and hospital readmissions in the studies, and individual study results varied. Further research involving a large number of participants is required to confirm these results.

Laički sažetak

Terapija matičnim stanicama za kroničnu ishemijsku bolest srca i kongestivno zatajenje srca

Osobe koje pate od srčanih bolesti i zatajenja srca trenutno se liječe lijekovima a, kad je to
moguće, dotok krvi u srce popravlja se (revaskularizacija) invazivnim zahvatima u kojima se
arterije otvaraju malim balonom u zahvatu koji se naziva angioplastika (ili perkutana
koronarna intervencija – PCI) ili kirurgijom srca (bajpas srčanih arterija). Revaskularizacija je
smanjila smrtnost povezanu s tim bolestima. U nekih osoba simptomi srčane bolesti i
zatajenja srca i dalje postoje nakon što se obavi revaskularizacija. Za te ljude možda nema
drugih mogućnosti liječenja. Nedavno su se počele istraživati matične stanice iz koštane
srži/progenitorske stanice kao novi oblik liječenja za osobe sa srčanom bolesti i zatajenjem
srca, bez obzira na to jesu li već liječeni postupcima za revaskularizaciju ili ne. Cochrane
sustavni pregled pronašao je 23 randomizirana klinička pokusa, s ukupno više od 1200
ispitanika, objavljenih do 2013. godine, koji pokazuju da ta nova terapija smanjuje smrtnost i
broj primitaka u bolnicu te da omogućuje poboljšanja u odnosu na standardnu terapiju, što je
izmjereno testovima funkcije srca. Trenutno ti rezultati pokazuju da postoje dokazi za korist
od terapije matičnim stanicama u osoba s kroničnim ishemijskim bolestima i zatajenjem srca.
Nuspojave su rijetke i nisu opisani dugoročni štetni učinci. Međutim, kvaliteta dokaza bila je
relativno niska; opisan je mali broj smrtnih slučajeva i ponovnih primitaka u bolnicu. Osim
toga rezultati pojedinih studija pokazali su odstupanja. Potrebna su daljnja istraživanja na
većem broju ispitanika da bi se potvrdili ti rezultati.

Bilješke prijevoda

Prevoditelj:: Croatian Branch of the Italian Cochrane Centre

Résumé simplifié

Traitement à base de cellules souches pour la cardiopathie ischémique chronique et l'insuffisance cardiaque congestive

Les patients souffrant de cardiopathie et d'insuffisance cardiaque sont actuellement traités avec des médicaments et, lorsque cela est possible, l'approvisionnement en sang est restauré dans le cœur (la revascularisation) soit en ouvrant les artères avec un ballonnet lors d'une procédure appelée angioplastie primaire (ou une intervention coronarienne percutanée (ICP)), soit par une chirurgie cardiaque (ou une intervention de pontage aorto-coronarien (PAC)). La revascularisation a réduit le taux de mortalité associé à ces conditions. Chez certains patients, les symptômes de la cardiopathie et de l'insuffisance cardiaque persistent même après une revascularisation. Les patients peuvent ne pas avoir d'autres traitements qui leur soient disponibles. Les cellules souches /progénitrices de la moelle osseuse ont récemment été étudiées dans un nouveau traitement chez les patients souffrant d'une cardiopathie et d'insuffisance cardiaque, qu'ils soient également traités pour la revascularisation ou non. Les résultats de 23 essais contrôlés randomisés, portant sur plus de 1 200 participants jusqu'en 2013, indiquent que ce nouveau traitement conduit à une réduction des décès et des réadmissions à l'hôpital, ainsi qu'à des améliorations par rapport au traitement standard, comme mesurées par des tests de la fonction cardiaque. À l'heure actuelle, ces résultats apportent certaines preuves indiquant que le traitement à base de cellules souches peut être bénéfique chez les patients atteints d'une cardiopathie ischémique chronique et d'une insuffisance cardiaque. Les effets indésirables sont rares et aucun effet indésirable n'a été rapporté à long terme. Cependant, la qualité des preuves est relativement faible puisque les études comportaient peu de décès et peu de réadmissions à l'hôpital, et les résultats des études individuelles variaient. D'autres recherches portant sur un grand nombre de participants sont nécessaires pour confirmer ces résultats.

Notes de traduction

Traduit par: French Cochrane Centre 6th August, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

淺顯易懂的口語結論

慢性缺血性心臟病和充血性心臟衰竭的幹細胞療法

目前的心臟疾病和心臟衰竭治療包括藥物和進行初期血管成形術 [或稱為經皮冠狀動脈介入 (percutaneous coronary intervention, PCI)] ( 這種手術利用1個小氣球使動脈恢復暢通),或心臟手術 [又稱為冠狀動脈繞道手術 (coronary artery bypass graft, CABG)]),若任一手術可行,將恢復心臟血液供應 [又稱血管再造 (revascularisation)]。血管再造可降低這些疾病的死亡率,不過有些患者即使接受血管再造,心臟病和心臟衰竭的症狀仍然持續存在,這些患者可能並無其他療法可用。近年來已針對無論是否也接受血管再造治療的患者,研究以骨髓幹細胞/前驅細胞作為心臟病和心臟衰竭的新療法。依據截至2013年為止的23篇隨機對照試驗結果 (涵蓋超過1200名受試者) 顯示,這項新療法可降低患者的死亡率和再住院率,且心臟功能檢驗測得的改善效果,也優於標準治療。目前這些結果提供的部分證據顯示,幹細胞治療可能對慢性缺血性心臟病和心臟衰竭患者有益。不良事件很罕見,也未通報發生長期不良事件。無論如何證據品質相當低,因為試驗只有少數死亡和再住院病例,而且個別試驗的結果也有相當大的歧異。未來必須進行收錄大量受試者的試驗,以確認上述結果。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Laienverständliche Zusammenfassung

Stammzellbehandlung bei chronisch ischämischer Herzkrankheit und kongestiver Herzinsuffizienz

Menschen, die an einer Herzerkrankung oder einer Herzinsuffizienz leiden werden derzeit mit Medikamenten behandelt und, wenn möglich wird der Blutfluss ins Herz wiederhergestellt (Revaskularisation). Dies geschieht entweder durch eine Öffnung der Arterien mit einem kleinen Ballon, auch primäre Angioplastie (oder perkutane Koronarintervention (PCI)) genannt oder durch eine Herzoperation (oder Bypass der Koronararterie (CABG)). Revaskularisation hat die Todesrate dieser Erkrankungen gesenkt. Bei manchen Menschen bleiben die Symptome der Herzkrankheit und der Herzinsuffizienz selbst nach der Revaskularisation bestehen. Diesen Menschen stehen möglicherweise keine anderen Behandlungen zur Verfügung. Kürzlich wurden Knochenmark-Stammzellen/ Progenitorzellen als neue Behandlungsmöglichkeit für Menschen mit Herzkrankheit und Herzinsuffizienz mit oder ohne Revaskularisations-Behandlung erforscht. Ergebnisse aus 23 randomisierten kontrollierten Studien, die mehr als 1200 Teilnehmer einschlossen, zeigten, dass diese neue Behandlung zu einer Reduktion der Sterberaten und Wiederaufnahmen ins Krankenhaus sowie zu einer Verbesserung gegenüber der Standardbehandlung, gemessen durch Herzfunktionstests, führt. Derzeit liefern diese Ergebnisse einige Evidenz dafür, dass Stammzelltherapie sowohl bei Menschen mit chronisch ischämischer Herzerkrankung als auch Herzinsuffizienz von Nutzen sein könnte. Unerwünschte Ereignisse sind selten und keine langfristigen unerwünschten Ereignisse wurden berichtet. Jedoch ist die Qualität der Evidenz aufgrund der geringen Anzahl der Todesfälle und Wiederaufnahmen ins Krankenhaus und der Unterschiede der Ergebnisse zwischen den einzelnen Studien relativ niedrig. Weitere Forschung, die eine große Anzahl an Teilnehmern einschließt wird benötigt, um die Ergebnisse zu bestätigen.

Anmerkungen zur Übersetzung

I. Töws und K. Kunzweiler, Koordination durch Cochrane Schweiz.

Resumo para leigos

Tratamento com células-tronco para pessoas com cardiopatia isquêmica crônica e insuficiência cardíaca congestiva

As pessoas que sofrem de doenças cardíacas e insuficiência cardíaca são atualmente tratadas com remédios e, quando possível, passam por um procedimento de desobstrução das artérias do coração (revascularização). Esse procedimento pode ser feito usando um balãozinho, que é introduzido através de uma veia na perna e é empurrado até as artérias do coração (coronárias), e dilata esses vasos (angioplastia primária), ou por cirurgia cardíaca, que desvia o sangue para as artérias coronárias. A revascularização reduziu a mortalidade associada a essas condições. Em algumas pessoas, os sintomas de doença cardíaca e de insuficiência cardíaca persistem mesmo após a revascularização. Não existiam outros tratamentos para essas condições. Recentemente, pesquisadores no mundo todo começaram a testar a terapia com células-tronco/progenitoras provenientes de medula óssea como um possível novo tratamento para as pessoas com doenças cardíacas e insuficiência cardíaca, com e sem revascularização. Os resultados de 23 ensaios clínicos randomizados realizados até 2013 e que incluíram mais de 1.200 participantes, indicam que esse novo tratamento (comparado ao tratamento habitual) diminui o risco de morrer e de reinternação no hospital, além de melhorar a função do coração avaliada por testes específicos. Atualmente, esses resultados fornecem algumas evidências de que o tratamento com células-tronco pode ser benéfico para pessoas com cardiopatia isquêmica crônica e com insuficiência cardíaca. Os efeitos adversos são raros, e nenhum deles foi relatado no longo prazo. No entanto, a qualidade das evidências é relativamente baixa, porque houve poucas mortes e reinternações nos estudos, e os resultados de estudos individuais variaram. Mais pesquisas envolvendo um grande número de participantes sãonecessárias para confirmar esses resultados.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva). Contato: tradutores@centrocochranedobrasil.org.br

Summary of findings(Explanation)

Summary of findings for the main comparison. 
Bone marrow stem cells (BMSC) (intervention) compared with control (no intervention) for chronic ischaemic heart disease and congestive heart failure

Patient or population: People with chronic ischaemic heart disease and congestive heart failure

Settings: [setting]

Intervention: Bone marrow stem cells

Comparison: Control (no cells)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlBMSC
Mortality - Short-term follow-up (< 12 months) 25 per 1000 14 per 1000
(9 to 35)
RR 0.68 (0.32 to 1.41)1138 participants
(21 studies)
⊕⊕⊝⊝
low
A combination of low events and discordant results from one study leads to low confidence in the estimate of the effect. This is likely to change with further research.
Mortality - Long-term follow-up (≥ 12 months) 148 per 1000 27 per 1000
(8 to 78)
RR 0.28 (0.14 to 0.53)494 participants
(8 studies)
⊕⊕⊝⊝
low
As above.
Rehospitalisation due to heart failure- Short-term follow-up (< 12 months) 95 per 1000 33 per 1000
(5 to 101)
RR 0.36 (0.12 to 1.06)236 participants
(4 studies)
⊕⊕⊝⊝
low
As above.
Rehospitalisation due to heart failure- Long-term follow-up (≥ 12 months) 92 per 1000 23 per 1000
( 3 to 86)
RR 0.26 (0.07 to 0.94)198 participants
(2 studies)
⊕⊕⊝⊝
low
As above.
LVEF (%): mean change from baseline to end of study (< 12 months)See commentsSee comments MD 4.22% (3.47 to 4.97)746 participants
(18 studies)
⊕⊕⊕⊝
moderate

LVEF measurements are given in percentage.

There is lack of appropriate blinding in a number of studies, which increases the risk of bias and moderate statistical heterogeneity.

LVEF (%): mean change from baseline to end of study (≥12 months)See commentsSee comments MD 2.62% (0.50 to 4.73)254 participants
(6 studies)
⊕⊕⊕⊝
moderate

LVEF measurements are given in percentage.

There is lack of appropriate blinding in a number of studies, which increases the risk of bias and moderate statistical heterogeneity.

NYHA classification: mean value at end of study -

Class I to IV (< 12 months)

See commentsSee comments MD -0.63 (-1.08 to -0.19)486 participants
(11 studies)
⊕⊕⊕⊝
moderate

NYHA Class I (1), II (2), III (3) and IV (4).

There is lack of appropriate blinding in a number of studies which increases the risk of bias, and high statistical heterogeneity.

NYHA classification: mean value at end of study -

Class I to IV (≥ 12 months)

See commentsSee comments MD -0.91 (-1.38 to -0.44)196 participants
(4 studies)
⊕⊕⊕⊝
moderate

NYHA Class I (1), II (2), III (3) and IV (4).

There is lack of appropriate blinding in a number of studies which increases the risk of bias, and high statistical heterogeneity.

*The assumed risk is provided as the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk Ratio; MD: Mean Difference.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Ischaemic heart disease (IHD) is a major cause of mortality and morbidity and the main cause of congestive heart failure (CHF) in Western societies (BHF 2008). Despite current therapies having increased the short-term survival of people suffering from myocardial infarction (MI), the number of people with CHF is rapidly increasing. In IHD, although some of the myocardium has been replaced by scar tissue, the heart may prevent the death of cardiomyocytes by reducing the energy demands of contraction. This results in non-contracting or hibernating, but viable, myocardium. This is a physiological response to chronic hypoxic stress, which is identifiable by electromechanical dissociation, and potentially reversible by revascularisation of the hibernating myocardium in order to restore cardiac function.

As with acute MI (AMI), pharmacological therapy, angioplasty and bypass surgery are the standard treatments offered to those suffering from CHF. In the acute setting, angioplasty restores the normal flow in infarct-related arteries in more than 90% of those who have suffered MI (Grines 1999; Stone 1998). This early revascularisation of the occluded artery after AMI has improved the prognosis, although a significant number of people still develop CHF. Preventing the progression of IHD and the development of CHF therefore remains a challenge. In some cases, people who have already received angioplasty or bypass surgery are treated with maximal medical therapy, but they still present symptoms of chronic myocardial ischaemia, sometimes with refractory angina.

Alternative therapies for CHF, such as stem/progenitor cell transplantation, are being investigated to complement current pharmacological therapies, primary angioplasty and cardiac surgery. This approach to the treatment of CHF developed from the observation in animal models that mononuclear cells from bone marrow or mobilised peripheral blood were effective in cardiac repair (Deb 2003; Orlic 2001a; Orlic 2001b; Yoon 2005). Later, it was demonstrated in the first non-randomised trials that cardiac function was improved when bone marrow stem/progenitor cells were transplanted into the infarcted myocardium (Assmus 2002; Strauer 2002). Although the stem cell type contributing to the repair of damaged tissue was not well defined, a study by Stamm 2003 indicated that the delivery of CD133⁺ progenitor cells from haematopoietic tissues (e.g. bone marrow and blood) into the ischaemic cardiac muscle could improve revascularisation. This has resulted in a number of larger randomised controlled trials (RCTs) worldwide, for AMI (Janssens 2006; Lunde 2006; Meyer 2006; Schächinger 2006) and chronic heart failure (Assmuss 2006; Erbs 2005; Hendrikx 2006; Patel 2006; Stamm 2007).

Description of the intervention

The procedure is currently as follows: either the bone marrow is harvested from the recipient or stem/progenitor cells are mobilised into circulation by a growth factor stimulant (most commonly granulocyte colony-stimulating factor (G-CSF)). In the first procedure, cells are usually collected (sometimes under general anaesthesia) from the pelvic bone, using large suction needles. Thereafter, the cells are separated from other bone marrow cells in sterile conditions. The bone marrow harvest and separation of stem cells may take several hours. In the G-CSF mobilisation procedure, stem/progenitor cells are collected as a blood sample and then separated from other blood cells in sterile conditions. In both procedures, the stem/progenitor cells are infused directly into the recipient's coronary arteries or heart. The first procedure delivers the cells to the coronary arteries via a special balloon-catheter during angioplasty (e.g. percutaneous coronary intervention (PCI)) using a stop-flow technique. The second procedure administers the cells into the heart muscle during an angioplasty-like procedure using electromechanical mapping and direct intramyocardial injection (e.g. NOGA system) or during cardiac surgery (e.g. coronary artery bypass grafting (CABG)). The interval between the collection of the stem cells and their reinfusion varies, but as the stem cells are used fresh the time cannot be too long unless they undergo some form of culture and expansion ex vivo.

The collection of the stem cells is most probably undertaken by a haematologist. A specialised technician or scientist undertakes the separation of the stem/progenitor cells from the other bone marrow cells and the cardiologist or cardiac surgeon undertakes the infusion or intramyocardial injection of the cells.

There are no adverse effects associated with the administration of stem cells as a treatment for people with chronic IHD or heart failure. In those trials where G-CSF has been administered prior to the stem cell harvest, transient complications arising from the G-CSF treatment have been described. However, no long-term adverse effects have been reported.

This treatment is currently only available in research-associated facilities, but it is conceivable that, if long-term effectiveness is confirmed, this procedure may be available to some or all people with chronic heart disease, since bone marrow harvest is a standard procedure used in bone marrow transplantation. The most effective results so far have been found in recipients with low left ventricular ejection fraction (LVEF) and heart failure symptoms (Pokushalov 2010).

The costs may be high, depending on the procedures used, and currently relate to the costs of the stem/progenitor cell procedure (stem cell harvest) and to the costs of the collection of the stem/progenitor cells (approximately a tenth of the overall cost of the trial). The potential for a large, funded clinical trial is limited, as there are no intellectual property rights associated with this procedure in its current form, rendering it unattractive to private company funding.

How the intervention might work

The mechanisms of the beneficial effects of bone marrow-derived stem cells (BMSC) remain unclear, and clinical trials in which BMSC have been administered to participants with acute myocardial infarction (AMI) and chronic myocardial ischaemia have produced divergent results. The type of stem cell contributing to the repair of the damaged tissue or the amelioration of tissue damage is still not well defined and the mechanism of action is not yet fully understood. Bone marrow-, cord blood- or peripheral blood-derived stem cells may exert their effects on cardiac function by increasing vascularity via endothelial progenitor cell incorporation into the ischaemic tissue, by generating cardiomyocytes, by modulating cardiac remodelling and/or, in a paracrine fashion, by producing cytokines or other factors that may help to promote cardiac repair and limit fibrosis in the affected area (Beltrami 2003; Carr 2008; Martin-Rendon 2008a; Mathur 2004; Stuckey 2006; Yoon 2005).

Why it is important to do this review

Stem cell therapy represents an exciting new form of treatment for many diseases. Heart disease is one of the clinical settings in which to address this new form of therapy, although the exact clinical role for stem cell therapy remains to be defined. A recent systematic review (Martin-Rendon 2008b; Martin-Rendon 2008c) of stem cell treatment for AMI found that stem cell treatment may lead to some improvements over conventional therapy as measured by surrogate tests of heart function, although further trials are required to confirm that these changes translate into improvements in long-term survival and are not accompanied by side effects. A number of RCTs have been undertaken and published exploring a clinical role for stem cell treatment in people with chronic IHD and heart failure. This is a clinical group with defined treatment options and problems sufficiently different from those who have suffered an AMI to indicate the need for a new systematic review. In addition, several RCTs have generated contradictory results.

Since the use of stem/progenitor cells for cardiac tissue repair is such a recent intervention in clinical practice, it is important that a systematic review is undertaken at an early stage to assess the safety and efficacy of this intervention. We define safety as the absence of adverse events (e.g. increased mortality and morbidity, increased risk of infarction, restenosis and arrhythmias), and efficacy as a significant improvement in cardiac function, clinical outcomes and quality of life.

Objectives

The critical evaluation of clinical evidence on the safety and efficacy of autologous adult bone marrow-derived stem cells (BMSC) as a treatment for chronic ischaemic heart disease (IHD) and heart failure.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs).

Types of participants

Anyone with a clinical diagnosis of IHD or congestive heart failure (CHF), excluding people with acute myocardial infarction (AMI).

Types of interventions

Studies involving the administration of autologous adult stem cells on their own or in combination with co-interventions, such as cardiac surgery, as treatment for IHD or CHF.

Participants in the comparator treatment arm of the trial received either no intervention or a placebo (e.g. the medium in which the stem cells were suspended or plasma). Trials where co-interventions (e.g. coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), granulocyte colony-stimulating factor (G-CSF), extracorporal shockwave therapy) were additionally administered were eligible as long as the co-interventions were equal in both arms and administered to an equivalent proportion of participants.

In summary:

  1. Any autologous human adult stem cells

  2. Any single dose

  3. Any method of stem cell isolation

  4. Any route of administration

  5. Any co-intervention

  6. Repeated intervention or multiple doses.

Types of outcome measures

We divided beneficial outcomes into clinically-based and surrogate endpoints. At the protocol stage of this review, we had intended to consider clinical and surrogate endpoint data at 30 days, six months and 12 months after baseline; however, this was not possible due to the variation in follow-up periods reported in individual studies. We therefore stratified outcome data into short-term (up to 12 months) and long-term (12 months or longer) follow-up.

Primary outcomes
Clinical

Mortality.

Surrogate endpoints

Left ventricular ejection fraction (LVEF).

Adverse events

Secondary outcomes
Clinical
  1. Morbidity (infarction, heart failure, arrhythmias);

  2. Composite outcome of morbidity and infarction;

  3. Health-related quality of life;

  4. Performance status;

Surrogate endpoints
  1. Engraftment and survival of the infused stem cells;

  2. End-systolic volume;

  3. End-diastolic volume;

  4. Wall motion score;

  5. Stroke volume index.

Search methods for identification of studies

Electronic searches

We identified relevant studies from searches of the Cochrane Central Register of Controlled trials (CENTRAL) on The Cochrane Library 2013, Issue 3, and the Cochrane Heart Group’s Trials Register, MEDLINE (1948 to 31 March 2013), PubMed (epublications only, 31 March 2013), EMBASE (1974 to 31 March 2013) and CINAHL (1982 to 31 March 2013). We combined the MEDLINE search with RCT search filters based on the validated Cochrane MEDLINE filter according to the current version of the Cochrane Handbook for Systematic Reviews of Interventions, section 6.4.11.1 (Higgins 2011). We also searched the databases LILACS, KoreaMed, IndMed, PakMediNet and the Transfusion Evidence Library on 31 March 2013, using a selection of keywords. See Appendix 1 for details of the search strategies.

Searching other resources

We searched the following trial registers for ongoing trials on 31 March 2013: Current Controlled Trials (ISRCTN), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), UMIN-CTR (Japanese Clinical Trials Registry) and the Hong Kong Clinical Trials Register.

We checked the reference lists of all identified eligible papers and relevant narrative reviews. We applied no language or date restrictions to any of the searches.

Data collection and analysis

Selection of studies

The information specialist (CD) conducted the electronic search for potentially relevant papers and removed references that were duplicates, clearly irrelevant and/or included in previous search results. Two review authors (SAF, EMR) screened all titles and abstracts identified by the review search strategy for relevance to the review question. We excluded only studies that were clearly irrelevant at this stage, and assessed all other studies as full-text articles for inclusion or exclusion using the criteria indicated above (type of studies, participants, interventions and outcome measures). At this point, two review authors (SAF, EMR) independently assessed eligibility using ad hoc eligibility forms, and resolving disagreements between them by discussion.

Data extraction and management

We extracted data onto tailored data extraction forms which were created and piloted specifically for this review. Two review authors (EMR, SAF) undertook data extraction for all eligible studies independently.

Aside from details relating to the quality of included studies, we extracted the following two groups of data:

(1) Study characteristics: place of publication, date of publication, population characteristics, setting, detailed nature of intervention, detailed nature of comparator, detailed nature of outcomes. A key purpose of these data was to explain clinical heterogeneity between included studies independently from analysis of the results;

(2) Results of included studies for each of the main outcomes indicated in the review question. For dichotomous outcomes we recorded the numbers of outcomes in treatment and control groups. For continuous outcomes, we recorded the mean and standard deviation.

We resolved data extraction disagreements by consensus between the review authors. When disagreements regarding any of the above were unclear, we attempted to contact authors of the original trials to provide further details. One review author (SAF) then transcribed the data into the systematic review computer software Review Manager 5 (Review Manager 2012).

Assessment of risk of bias in included studies

The two review authors (SAF, EMR) undertaking the data extraction independently assessed the risk of bias for each trial using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and resolving any disagreements by discussion. We assessed the design, conduct and analysis of the trial using a three-point scale: low, high or unclear risk of bias. To assess risks of bias, the authors included the following questions in the 'Risk of bias' table for each included study:

  1. Was the allocation sequence adequately generated?

  2. Was allocation adequately concealed?

  3. Was knowledge of the allocated intervention adequately prevented (i.e. blinded) throughout the study?

  4. Were incomplete outcome data adequately addressed for every outcome?

  5. Were reports of the study free of selective outcome reporting?

  6. Was the study apparently free of other problems that could put it at risk of bias?

With reference to (1) to (6) above, the review authors assessed the likely magnitude and direction of the bias and whether they considered it likely to impact on the findings.

Measures of treatment effect

We expressed dichotomous data for each arm in a particular study as a proportion or risk and the treatment effect as a risk ratio (RR) with 95% confidence intervals (CIs). We expressed continuous data for each arm in a particular study as a mean and standard deviation, and the treatment effect as the mean difference (MD) if outcomes were measured in the same way across trials. For outcomes measured using different methods, we combined the treatment effect data and analysed them using the standardised mean difference (SMD). We used fixed-effect models in the first instance, but random-effects models in the presence of considerable heterogeneity (I² greater than 75%) or for outcomes which were measured using different methods across studies.

Although we intended to analyse continuous outcomes as mean change from baseline, several studies only reported baseline and endpoint data. Where possible, we calculated the standard deviation of the mean change from baseline based on reported confidence intervals or P values, and we used these values in the analysis. However, for several studies, insufficient information was reported to calculate the standard deviation. Since the mean difference based on the change from baseline can be assumed to address the same underlying intervention effects as an analysis based on final measures (i.e. the differences in mean final values will on average be the same as the differences in mean change scores), we combined studies reporting mean change from baseline values with those reporting endpoint values, but presented mean change and endpoint values separately as well as in combined analyses for clarity.

We did not conduct this pooling of studies by method of reporting of continuous measures for analyses of exercise capacity, since the assumption of consistent underlying effects does not hold for standardised mean differences.

Several studies reported surrogate endpoints (left ventricular end systolic volume (LVESV), left ventricular end diastolic volume (LVEDV), stroke volume, left ventricular ejection fraction (LVEF)), using different measures (magnetic resonance imaging (MRI), echocardiography, single-photon emission computed tomography (SPECT), left ventricular angiography) and in some cases, results from several different methods were reported within a single study. In this case, we used MRI data as the preferred measure followed by left ventricular angiography, SPECT and echocardiography.

Unit of analysis issues

In studies in which there were multiple interventions in the same trial, we combined the intervention trial arms for a single comparison with the comparator (control) arm to avoid double counting of participants and potential correlation of results. However, for subgroup and sensitivity analyses, where the two intervention arms were classified into different categories (for example, type of cell, cell dose, route of administration of cells), we included results for each treatment arm in the corresponding group, with the control group included in both groups. In order to avoid unit of analysis issues, we treated cross-over trials as parallel trials and included them in the review up to the point of cross-over, i.e. first phase data only.

Dealing with missing data

We attempted to contact the authors of 15 studies by email for clarification of methods (randomisation, allocation concealment and blinding), potential overlapping of studies and/or requests for additional data. In five cases we failed to make contact with the authors by email. Of the remaining 10 studies, we received replies from three study authors who provided additional data. In one study (Assmus 2006), results were reported for a pooled randomised cohort and a non-randomised pilot study cohort; the authors of this study provided full clinical and surrogate endpoint data for the randomised cohort alone, as well as details of the method of randomisation. The authors of a second study (Hendrikx 2006) provided LVESV and LVEDV data (as only LVESV/LVEDV index values were reported). For a third study (Hu 2011), authors provided mean change from baseline data for surrogate endpoint measures.

Assessment of reporting biases

Although we believe that we made every effort to identify unpublished studies, we assessed publication bias using a funnel plot for the primary outcome of mortality. We accept that asymmetry, of which publication bias may be one cause, is difficult to detect with the small numbers of studies (i.e. fewer than 10) often encountered in systematic reviews.

Data synthesis

We undertook meta-analyses using the Review Manager 5 software (Review Manager 2012), where there were sufficient data of suitable type. We used a fixed-effect model to combine data in the first instance. Where we detected considerable heterogeneity (I² greater than 75%) using a fixed-effect model, we repeated the analysis using a random-effects model.

Although quantitative synthesis was the main method of analysis, we incorporated insights from a qualitative evaluation of studies for an overall interpretation of the data. We based conclusions on patterns of results identified across clearly-tabulated results of included studies as well as summary measures, taking both direction and magnitude of any effect into account.

Subgroup analysis and investigation of heterogeneity

We examined statistical heterogeneity using the I² statistic (Higgins 2003) and by visual inspection of forest plots. We rated values of I² greater than 75% as indicating a considerable level of heterogeneity at which summary estimates should be explored and results interpreted with caution. We explored potential reasons for observed heterogeneity in comparisons with at least 10 studies and statistical significance in the observed effect (P < 0.05). We placed particular emphasis on study population, treatment, outcome measurements and study quality differences between the included studies. We assessed clinical heterogeneity based on the data extracted on the characteristics of the included studies.

We planned subgroup analysis for mortality and LVEF (primary clinical and surrogate endpoint outcomes) as well as for outcomes which met the above conditions for further exploration of heterogeneity. Subgroup analysis considered the following factors:

  1. Dose of stem cells administered;

  2. Route of cell administration;

  3. Baseline cardiac function;

  4. Type of cell administered (mononuclear cells; circulating progenitor cells; haematopoietic progenitor cells; and mesenchymal stem cells);

  5. Participant diagnosis (chronic IHD; heart failure (secondary to IHD); intractable/refractory angina);

  6. Eligibility for revascularisation.

We regard the latter three subgroup comparisons listed above as hypothesis-generating.

Sensitivity analysis

We assessed the robustness of the overall results for the primary outcome of LVEF for sensitivity to the following factors:

  1. Risk of bias (selection bias; performance bias; detection bias; attrition bias);

  2. Co-intervention or comparator;

  3. Method of measurement (MRI, left ventricular angiography, SPECT, echocardiography).

Differences in methods of reporting for continuous outcomes across trials led us to combine mean change from baseline and endpoint data for several outcomes (LVESV, LVEDV, stroke volume index, LVEF) (see Measures of treatment effect above). We present results separately as well as in combination to assess the sensitivity of the results to the method of reporting.

Results

Description of studies

Results of the search

Given that a wide variety of products and terms have been used in the comparator arms of the included studies, for ease of reference we use the term 'control' throughout this review to refer to the comparator treatment arm.

We identified 7704 references from electronic database searches. De-duplication and removal of all clearly irrelevant references by the Information Specialist (CD) excluded 5370 references. Initial screening of the remaining 2334 citations against inclusion criteria excluded a further 2225 references. Of the remaining 109 citations, we subsequently excluded 25 references (describing 21 independent studies), as they did not fully meet the inclusion criteria (see Excluded studies). Eight further references described six independent study protocols (see Ongoing studies). Nine studies (14 references) were published in abstract form only and although they appeared to meet the inclusion criteria, did not contain sufficient data for inclusion; these have been identified as Studies awaiting classification. The remaining 62 citations describe a total of 23 independent RCTs (see Included studies). A summary of study classification is displayed in a PRISMA flow diagram (Figure 1).

Figure 1.

PRISMA flow diagram.

Searching of ongoing trial databases identified 837 trial records. De-duplication and removal of clearly irrelevant trials by the Information Specialist (CD) excluded 651 records. Of the remaining 186 records, 25 ongoing trials met the eligibility criteria and are shown in Ongoing studies.

Included studies

Twenty-three studies met the inclusion criteria for this review and included a total of 1137 participants (659 bone marrow-derived stem cells (BMSC) and 478 control) who were assessed for the primary outcomes of the study. The mean age of participants ranged from 53.4 years to 69.8 years and the proportion of men ranged from 50% to 100%. All trials were presented as full journal articles with the exception of one trial (Assmus 2012) which was published in the form of a conference abstract. Five studies (Losordo 2007; Losordo 2011; Perin 2011; Perin 2012a; Tse 2007) were multicentre trials. Studies were based worldwide, including China (Chen 2006; Hu 2011; Wang 2009; Wang 2010; Yao 2008; Zhao 2008), Germany (Assmus 2006; Assmus 2012; Erbs 2005; Honold 2012; Turan 2011), the United States (Losordo 2007; Losordo 2011; Perin 2011; Perin 2012a; Perin 2012b), United Kingdom (Ang 2008), Belgium (Hendrikx 2006), The Netherlands (Van Ramshorst 2009), Russia (Pokushalov 2010), Hong Kong/Australia (Tse 2007), Korea (Kang 2006) and Argentina (Patel 2005). Two studies included publications in Chinese (Hu 2011; Wang 2009); these studies was translated into English for this review.

Ten studies included participants with chronic ischaemic heart disease (IHD) (Ang 2008; Assmus 2006; Assmus 2012; Chen 2006; Erbs 2005; Hendrikx 2006; Honold 2012; Kang 2006; Turan 2011; Yao 2008), normally defined as multivessel disease with persistent ischaemia and at least 30 days from the last myocardial infarction (MI), with the exception of one study that defines 'old MI' as only 14 days post-infarction (Kang 2006). Seven studies included people with congestive heart failure (CHF), defined as severe ischaemic heart failure and post-infarction heart failure (secondary to IHD) (Hu 2011; Patel 2005; Perin 2011; Perin 2012a; Perin 2012b; Pokushalov 2010; Zhao 2008) and six studies were of people with intractable or refractory angina (Losordo 2007; Losordo 2011; Tse 2007; Van Ramshorst 2009; Wang 2009; Wang 2010). All trials maintained the participants with a standard set of drugs including aspirin, clopidogrel, heparin, blockers, statins, angiotensin converting enzyme (ACE) inhibitors, nitrates and/or diuretics.

Duration of follow-up ranged from three months (Assmus 2006), four months (Assmus 2012; Hendrikx 2006), six months (Ang 2008; Hu 2011; Kang 2006; Losordo 2007; Patel 2005; Perin 2011; Perin 2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; Wang 2009; Wang 2010; Yao 2008; Zhao 2008), 12 months (Chen 2006; Losordo 2011; Pokushalov 2010; Turan 2011), 15 months (Erbs 2005) and five years (Honold 2012).

Eighteen trials isolated the stem cells by bone marrow aspiration and further separation of the mononuclear cells using ficoll gradient centrifugation (Ang 2008; Assmus 2006; Assmus 2012; Chen 2006; Hendrikx 2006; Hu 2011; Patel 2005; Perin 2011; Perin 2012a; Perin 2012b; Pokushalov 2010; Tse 2007; Turan 2011; Van Ramshorst 2009; Wang 2009; Wang 2010; Yao 2008; Zhao 2008). Three of these trials enriched the stem cell fraction in CD34-positive haematopoietic progenitors by magnetic separation (Patel 2005; Wang 2009; Wang 2010), whilst one trial enriched the stem cell fraction in aldehyde dehydrogenase (ALDH)-positive haematopoietic progenitors (Perin 2012b), and one trial cultured the mononuclear cell population from bone marrow ex vivo to enrich in mesenchymal progenitors (Chen 2006). In one three-arm trial (Assmus 2006), bone marrow mononuclear cells were compared with circulating progenitor cells (CPCs), and with mononuclear cells isolated from venous peripheral blood. In the CPC arm, cells were isolated from peripheral blood by leukapheresis. In the remaining five trials, bone marrow stem cells were mobilised into circulation with granulocyte colony-stimulating factor (G-CSF) and subsequently isolated from blood via leukapheresis (Erbs 2005; Honold 2012; Kang 2006; Losordo 2007; Losordo 2011). Whilst previous trials reported severe but transient complications associated with G-CSF treatment (Kang 2006), the most recent pilot study by Honold 2012 demonstrated that G-CSF can be safely administered to people suffering from IHD since none of the participants included in this trial developed the type of adverse events previously associated with G-CSF treatment. Two of these trials further enriched the stem cell population in CD34-positive progenitors by magnetic separation (Losordo 2007; Losordo 2011).

The dose of bone marrow mononuclear cells administered varied between 2 x 10⁶ cells (Perin 2011) and 2 x 10⁸ cells (Assmus 2006), whilst the dose of CD34-positive cells varied between 1 x 10⁶ cells (Wang 2009) to 5.6 x 10⁸ cells (Losordo 2011). The doses of ALDH-positive cells (Perin 2012b) and mesenchymal progenitors (Chen 2006) administered averaged 2.96 x 10⁶ cells and 5 x 10⁶ cells respectively. In the trial where bone marrow mononuclear cells were compared to CPCs, the dose of CPCs administered was 2.2 x 10⁷ cells (Assmus 2006). Eleven trials administered the treatment via a coronary artery (intracoronarily (IC)) (Assmus 2006; Assmus 2012; Chen 2006; Erbs 2005; Honold 2012; Hu 2011; Kang 2006; Turan 2011; Wang 2009; Wang 2010; Yao 2008), whilst 11 trials delivered the treatment intramyocardially (IM) (Hendrikx 2006; Losordo 2007; Losordo 2011; Patel 2005; Perin 2011; Perin 2012a; Perin 2012b; Pokushalov 2010; Tse 2007; Van Ramshorst 2009; Zhao 2008). Nine out of these 11 trials aided their delivery into the heart muscle using electromechanical mapping of the heart. The other two (Hendrikx 2006; Zhao 2008) did not report whether the IM delivery of stem cells was aided in any other way. Only one trial had three arms comparing IC and IM delivery of stem cells with control (Ang 2008).

Thirteen studies (Assmus 2012; Erbs 2005; Hendrikx 2006; Hu 2011; Losordo 2007; Losordo 2011; Perin 2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; Wang 2010; Yao 2008; Zhao 2008) compared stem cell therapy with administration of a placebo that consisted of a cell-free solution, either a heparin saline solution or a saline solution containing the participant's own serum; one further study (Perin 2011) used a simulated mock injection procedure for participants in the control arm, but without administering a placebo solution. The remaining nine trials compared treatment to no treatment (Ang 2008; Assmus 2006; Chen 2006; Honold 2012; Kang 2006; Patel 2005; Pokushalov 2010; Turan 2011; Wang 2009).

Three studies included a three-way comparison involving two interventions, including intracoronary versus intramyocardial cell administration (Ang 2008), mononuclear cells versus circulating progenitor cells (Assmus 2006) and high versus low cell dose (Losordo 2011). Data for both intervention arms were combined for the main analyses, although we used individual intervention trial arms for subgroup analyses where applicable. A fourth study (Assmus 2012) which involved a co-intervention of shockwave therapy also included an additional trial arm involving BMSC treatment, but since the co-intervention was not administered in this treatment arm, we include only the first two treatment arms in this review. One three-arm trial was also a cross-over study (Assmus 2006); we include only data up to the point of cross-over (three months) in this review.

One study described aortic cross-clamping during surgery with clamp times exceeding 25 - 30 minutes (Hendrikx 2006). Aortic cross-clamping isolates the systemic circulation during surgery but causes ischaemia. Although increasing times of aortic cross-clamping has been identified as a predictor of mortality, the effect of cross-clamping in this study was not as strong as might be expected. This may be due to the fact that the cause of cardiac damage is multifactorial, including coronary lesions.

The majority of included studies reported the primary outcomes of this review, i.e. mortality, LVEF and adverse events. One study which was published only in abstract form (Assmus 2012) did not report mortality, and all but four studies (Losordo 2007; Losordo 2011; Wang 2009; Wang 2010) reported LVEF.

For a summary details of the included studies, see the Characteristics of included studies tables.

Excluded studies

We excluded 21 studies (described by 25 references) from the review following full-text assessment against the eligibility criteria (see Characteristics of excluded studies tables).

In summary, the reasons for exclusion were as follows: 14 studies were not RCTs, four studies included participants with AMI, one trial included participants with idiopathic dilated cardiomyopathy, one trial provided a review of imaging techniques for cardiac stem cell therapy, and one trial described outcomes not included in the protocol of this review.

Risk of bias in included studies

See the Characteristics of included studies tables for details of our assessment of risk of bias for each study; a summary of risk of bias is shown in Figure 2.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

All trial comparisons randomised the participants. However, nine of them (Ang 2008; Assmus 2012; Chen 2006; Erbs 2005; Honold 2012; Turan 2011; Wang 2009; Wang 2010; Yao 2008) did not report the randomisation method used. In the 14 trials which reported their randomisation methods, these included the use of sequentially-numbered sealed envelopes, computer-generated randomisation tables using a block size of six or nine, and telephone call-in followed by an interactive voice-response system.

Allocation

Seven of the 23 comparisons included here described appropriate methods of allocation concealment (Hendrikx 2006; Losordo 2011; Perin 2011; Perin 2012a; Perin 2012b; Van Ramshorst 2009; Tse 2007), while the remaining 16 trials did not report the method of allocation concealment. Methods of allocation concealment included sequentially-numbered sealed envelopes, telephone call-in followed by an interactive voice-response system and masking treatment assignment to all but one designated cell processing team member at each centre not involved in participant care in the case of a multicentre trial (Perin 2012a).

Blinding

Twelve studies blinded their participants (Erbs 2005; Hendrikx 2006; Hu 2011; Losordo 2007; Losordo 2011; Patel 2005; Perin 2011; Perin 2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; Wang 2010) by treating all the participants with G-CSF, where this was part of the trial protocol, obtaining bone marrow aspirates from all participants or/and administering placebo to those participants in the control arm, or in some instances giving a mock injection. Four studies did not blind their participants (Ang 2008; Chen 2006; Kang 2006; Turan 2011) while the remaining seven studies did not report the blinding status of their participants.

In one study (Wang 2009) outcome assessors were not blinded; a further four studies (Assmus 2006; Chen 2006; Honold 2012; Kang 2006) did not report blinding of outcome assessors. Outcome assessors were blinded in all remaining studies.

Incomplete outcome data

One trial published in abstract form (Assmus 2012) did not report the number of individuals randomised to each treatment arm and in this study the attrition rate could not be evaluated. In all other trials, withdrawals and loss to follow-up were similar in both treatment arms.

Selective reporting

No trial reported deviations from the trial protocol, although selective reporting of outcomes would be difficult to rule out.

A funnel plot for the primary outcome of mortality at short-term follow-up was symmetrical (Figure 3). However, given the very small size of the included studies, a funnel plot is uninformative to detect small study bias. Furthermore, 12 ongoing studies were completed or due to be completed in advance of our search date but we identified but no publications for them. We therefore cannot rule out the possibility of publication bias.

Figure 3.

Funnel plot of comparison: 1 Stem cells versus no stem cells, outcome: 1.1 Mortality.

Other potential sources of bias

Fourteen studies (Ang 2008; Assmus 2006; Erbs 2005; Hu 2011; Kang 2006; Losordo 2007; Losordo 2011; Perin 2011; Perin 2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; Yao 2008; Zhao 2008) provided details of study funding or sponsorship. The majority of these were funded entirely by academic and/or healthcare research grants and received no commercial sponsorship. Two studies acknowledged provision of equipment (Losordo 2007; Perin 2012a) and one study acknowledged receipt of consultant fees from Biosense-Webster (Tse 2007). Full commercial sponsorship was declared in two studies: from Baxter Heathcare (Losordo 2011) and from Aldagen Inc. (Perin 2012b). A further study declared partial commercial funding from Baxter Heathcare (Losordo 2007).

We identified no other sources of bias, although other potential sources of bias cannot be completely ruled out.

Effects of interventions

See: Summary of findings for the main comparison

An overview of results for the main outcomes (mortality, incidence of heart failure, LVEF and NYHA class) is given in the 'Summary of findings' table.

In one study (Yao 2008), continuous measures were reported as mean +/- standard deviation. However, visual inspection of the data revealed that the standard deviations were considerably lower than might be expected for all continuous outcomes. This study also reported P values for statistical comparisons between the baseline and follow-up data using paired t-tests. However, we could not identify the reported significance values, either using the standard deviations provided, or based on an assumption that the values were in fact standard errors. We therefore could not verify or include continuous data from this study. Only five studies (Ang 2008; Assmus 2006; Hu 2011; Kang 2006; Perin 2012a) reported loss to follow-up, which was low and comparable between different treatment arms.

Primary outcomes

Mortality

Mortality was included as an outcome in all except one study (Assmus 2012), which was published in abstract form only. Of 22 studies which reported mortality rates during short-term follow-up (< 12 months), deaths were reported in nine trials (Ang 2008; Assmus 2006; Hendrikx 2006; Hu 2011; Kang 2006; Perin 2012a; Pokushalov 2010; Van Ramshorst 2009; Zhao 2008). The remaining 13 trials reported no deaths. A total of nine deaths (2.9%) were reported in 311 participants who received BMSC therapy compared with 12 deaths (5.3%) in 226 participants who received no stem cell therapy (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.32 to 1.41, P = 0.30; 21 trials, 1138 participants) (Analysis 1.1.1).

Five studies reported reasons for short-term mortality. Causes of death in participants who received BMSC included perforated oesophageal ulcer complicated by mediastinitis seven days postoperatively (Hendrikx 2006), panperitonitis two months after enrolment (Kang 2006), pump failure leading to death on day 29 after therapy (Perin 2012a), myocardial ischaemia leading to acute heart failure at 2½ months (Van Ramshorst 2009), ventricular fibrillation five hours postoperatively leading to death on day three (Zhao 2008), and cerebral vessel accident during six-month follow-up (Zhao 2008). One cause of death was reported in a participant who did not receive stem cell therapy, i.e. multiple organ failure secondary to low cardiac output syndrome (Hendrikx 2006). The remaining four studies did not report cause of mortality.

Eight studies (Chen 2006; Erbs 2005; Honold 2012; Losordo 2007; Losordo 2011; Pokushalov 2010; Tse 2007; Turan 2011) with long-term follow-up (≥ 12 months) reported mortality as an outcome. Deaths were reported in six studies (Chen 2006; Erbs 2005; Honold 2012; Losordo 2011; Pokushalov 2010; Tse 2007) with a total of eight deaths (3.3%) in 241 participants who received BMSC therapy compared with 30 deaths (18.5%) in 162 participants who received no stem cell therapy; the risk of mortality over long-term follow-up was significantly lower for those who received BMSC therapy (RR 0.28, 95% CI 0.14 to 0.53, P = 0.0001; 8 trials, 494 participants) (Analysis 1.1.2).

Reasons for mortality at long-term follow-up were reported in four studies. Two sudden deaths were reported in participants who received stem cell therapy (Chen 2006). This study also reported four deaths in participants who did not receive stem cell therapy, due to ventricular fibrillation, sudden death, and heart failure (two people). Other reported deaths in participants in the control arm were angina followed by sudden death secondary to AMI (Erbs 2005), progressive heart failure (Honold 2012) and AMI (Tse 2007).

Left ventricular ejection fraction (LVEF)

LVEF was measured in 19 studies (Ang 2008; Assmus 2006; Assmus 2012; Chen 2006; Erbs 2005; Hendrikx 2006; Honold 2012; Hu 2011; Kang 2006; Patel 2005; Perin 2011; Perin 2012a; Perin 2012b; Pokushalov 2010; Tse 2007; Turan 2011; Van Ramshorst 2009; Yao 2008; Zhao 2008) with one study (Yao 2008) excluded due to data inconsistencies as described above.

Measurement methods included MRI (Ang 2008; Assmus 2006; Erbs 2005; Hendrikx 2006; Honold 2012; Hu 2011; Kang 2006; Tse 2007; Van Ramshorst 2009), left ventricular angiography (Assmus 2006; Honold 2012; Perin 2011; Perin 2012b; Turan 2011), single-photon emission computed tomography (SPECT) (Chen 2006; Perin 2011; Van Ramshorst 2009) and echocardiography (Perin 2011; Perin 2012a; Perin 2012b; Pokushalov 2010; Van Ramshorst 2009; Zhao 2008). One study (Assmus 2012) did not report the method of LVEF measurement and in another study (Patel 2005) LVEF appeared to be measured by either SPECT or echocardiography.

Mean change from baseline at short-term follow-up was reported in 10 studies (Ang 2008; Assmus 2006; Assmus 2012; Erbs 2005; Hendrikx 2006; Hu 2011; Perin 2011; Perin 2012a; Tse 2007; Van Ramshorst 2009); the remaining eight studies (Chen 2006; Honold 2012; Kang 2006; Patel 2005; Perin 2012b; Pokushalov 2010; Turan 2011; Zhao 2008) reported baseline and endpoint data only with insufficient data to calculate the standard deviation of the mean difference. Combined evidence across all 18 studies showed a significant mean difference in LVEF in participants who received BMSC compared with those who did not receive stem cell therapy (mean difference (MD) 4.22%, 95% CI 3.47% to 4.95%, P < 0.00001; 18 trials, 746 participants). There was moderate heterogeneity between studies (I² = 53%) (Analysis 1.2).

In six studies which reported LVEF at long-term follow-up, three (Erbs 2005; Pokushalov 2010; Van Ramshorst 2009) reported mean change from baseline and three (Chen 2006; Honold 2012; Turan 2011) reported baseline and endpoint values. The significant mean difference in LVEF in participants who received BMSC was maintained at long-term follow-up (MD 2.62%, 95% CI 0.50% to 4.73%, P = 0.02; 6 trials, 254 participants), with moderate heterogeneity between studies (I² = 32%) (Analysis 1.3).

Adverse events

Nineteen trials (947 participants) reported adverse events as an outcome, although one trial (Assmus 2012) reported adverse events pooled across treatment arms; only four trials did not give any information about adverse events(Hendrikx 2006; Losordo 2011; Perin 2012a; Turan 2011). Adverse events were not related to the BMSC treatment or procedure, with the exception of one trial which reported one case of haematoma during bone marrow harvest in the BMSC treatment arm (Patel 2005), and one trial which reported pulmonary oedema during injection of BMSC in three cases in the treatment arm (Chen 2006). Three trials that administered G-CSF prior to BMSC enrichment (Erbs 2005; Honold 2012; Kang 2006) reported transient complications arising from the G-CSF treatment, as described previously in AMI trials (Clifford 2012a; Clifford 2012b). Additionally, in one trial (Perin 2011) there was one case in the treatment arm and one in the control arm of periprocedural transient bundle-brance block and one post-procedural non-significant pericardial effusion in the treatment arm. A variety of definitions was used to record adverse events across the studies and some trials reported adverse events combined over both treatment arms rather than separately. No long-term adverse events were reported. Adverse events reported over short-term and long-term follow-up are presented as forest plots (Analysis 1.4).

Secondary outcomes

Morbidity
(a) Incidence of infarction

Sixteen studies (Ang 2008; Assmus 2006; Erbs 2005; Honold 2012; Hu 2011; Kang 2006; Losordo 2007; Perin 2011; Perin 2012a; Perin 2012b; Tse 2007; Van Ramshorst 2009; Wang 2009; Wang 2010; Yao 2008; Zhao 2008) reported infarction as an outcome at short-term follow-up. In seven studies (Assmus 2006; Erbs 2005; Honold 2012; Perin 2012a; Perin 2012b; Tse 2007; Yao 2008) which reported participants with infarction, three cases of infarction were reported in participants who received BMSC compared with four cases in those who received no stem cell therapy (RR 0.57, 95% CI 0.20 to 1.59, P = 0.28; 16 trials, 737 participants) (Analysis 1.5.1).

Of three studies (Honold 2012; Losordo 2007; Losordo 2011) which reported infarction as an outcome at long-term follow-up, only two (Honold 2012; Losordo 2011) reported participants with infarction; these occurred in both treatment arms (RR 0.48, 95% CI 0.19 to 1.22, P = 0.12; 3 trials, 221 participants) (Analysis 1.5.2).

(b) Rehospitalisation due to heart failure

Five studies (Assmus 2006; Honold 2012; Losordo 2011; Perin 2012a; Yao 2008) reported rehospitalisation due to heart failure as an outcome. In four studies (Assmus 2006; Honold 2012; Perin 2012a; Yao 2008) which reported rehospitalisation at short-term follow-up, eight participants (9.5%) in the control arm were rehospitalised, compared with five participants (3.3%) in the BMSC arm, but combined evidence from meta-analysis did not show a significant difference between trial arms (RR 0.36, 95% CI 0.12 to 1.06, P = 0.06; 4 trials, 236 participants) (Analysis 1.6.1).

However, at long-term follow-up, evidence from two studies (Honold 2012; Losordo 2011) showed a significant reduction in the risk of rehospitalisation due to heart failure in participants who had received stem cell therapy compared with those who had not (RR 0.26, 95% CI 0.07 to 0.94, P = 0.04; 2 trials, 198 participants) (Analysis 1.6.2).

(c) Incidence of arrhythmias

Incidence of arrhythmias was reported as an outcome in 15 studies (Ang 2008; Assmus 2006; Chen 2006; Hu 2011; Losordo 2007; Patel 2005; Perin 2011; Perin 2012b; Pokushalov 2010; Tse 2007; Van Ramshorst 2009; Wang 2009; Wang 2010; Yao 2008; Zhao 2008), although the majority of these studies reported no incidence of arrhythmias during follow-up in either treatment arm. Four studies (Assmus 2006; Perin 2012b; Zhao 2008; Wang 2010) observed participants with arrhythmia during follow-up, although in one study (Wang 2010), the total number of participants with arrhythmia was unclear. In the remaining three trials, only four cases of arrhythmia were observed: three in participants who received BMSC and one in a control participant.

Quality of life
(a) Angina frequency

Five studies measured angina frequency: one study (Wang 2009) reported mean change in number of angina episodes per week and the remaining four studies (Losordo 2007; Losordo 2011; Pokushalov 2010; Wang 2010) reported angina frequency at short-term follow-up. Combined evidence from all five studies showed a significant mean difference in angina frequency between treatment arms in favour of BMSC (MD -4.64, 95% CI -7.06 to -2.23, P = 0.0002; 5 trials, 429 participants), with low levels of heterogeneity between studies (I² = 26%) (Analysis 1.7).

(b) Other quality of life measures

Other measures of quality of life include assessments based on the Seattle Angina Questionnaire (Losordo 2007; Losordo 2011; Van Ramshorst 2009), Minnesota Living with Heart Failure (MLHF) (Perin 2011; Pokushalov 2010) and the SF-36 (Perin 2011). However, in the majority of cases, results were presented descriptively without mean change from baseline or mean at follow-up data for both treatment arms and this, together with differences in data representation (scales, summary measures), prevented any formal comparison of results.

Performance status
(a) NYHA classification

Thirteen studies measured New York Heart Association (NYHA) classification, although one study (Ang 2008) only reported the number of participants in class III/IV and a second study (Perin 2012a) did not report standard deviations for the mean NYHA class. The absence of NYHA classification at baseline in several studies prevented a comparison of mean change from baseline between groups; we therefore compared NYHA class between groups at follow-up. In the remaining 11 studies (Assmus 2006; Assmus 2012; Chen 2006; Honold 2012; Patel 2005; Perin 2011; Perin 2012b; Pokushalov 2010; Tse 2007; Turan 2011; Zhao 2008), the mean NYHA class at short-term follow-up was significantly different between treatment arms, favouring BMSC therapy (MD -1.27, 95% CI -1.33 to 1.22, P < 0.00001; 11 trials, 486 participants). We noted considerable heterogeneity between studies (I² = 97%); the significantly lower NYHA class in participants who received BMSC compared with those who received no stem cell therapy remained when we used a random-effects model (MD -0.63, 95% CI -1.08 to -0.19, P = 0.005) (Analysis 1.8).

Meta-analysis of four studies (Chen 2006; Honold 2012; Pokushalov 2010; Turan 2011) using a random-effects model showed that the significant improvement in NYHA class was maintained over long-term follow-up (MD -0.91, 95% CI -1.38 to -0.44, P = 0.0002; 4 trials, 196 participants), although considerable heterogeneity (I² = 89%) remained across studies (Analysis 1.9) .

(b) Canadian Cardiovascular Society (CCS) angina class

Eleven studies measured CCS angina classification, although three studies did not report sufficient data to be included in a meta-analysis: one study (Ang 2008) only reported the number of participants in class 2 and above, a second study (Perin 2012a) reported that there was no significant difference in change in CCS class between the treatment groups, and a third study (Losordo 2011) only reported the percentage who changed angina class in each group. At short-term follow-up, four studies (Losordo 2007; Perin 2011; Wang 2009; Wang 2010) reported mean change in CCS class from baseline, whilst four studies (Perin 2012b; Pokushalov 2010; Tse 2007; Zhao 2008) only reported CCS class at follow-up. Combined evidence from all eight studies incorporating both mean change from baseline and endpoint data showed a significant mean difference between treatment arms in favour of BMSC (MD -0.85, 95% CI -1.00 to -0.71, P < 0.00001; 8 trials, 379 participants). There was considerable heterogeneity between studies (I² = 96%). The mean difference between treatment arms remained significant under a random-effects model (MD -0.81, 95% CI -1.55 to -0.07, P = 0.03) (Analysis 1.10).

(c) Exercise capacity

Exercise capacity was reported in 11 trials. Measures of exercise capacity included an exercise tolerance test measured as metabolic equivalents (Chen 2006) or as time in minutes (Losordo 2007; Wang 2009; Wang 2010), seconds (Losordo 2011), or log seconds (Tse 2007); a bicycle test measured as maximum O₂ update (Erbs 2005; Honold 2012) or by workload (Van Ramshorst 2009); and by a six-minute walk test measured as distance in minutes (Hu 2011; Pokushalov 2010).

Mean change from baseline was reported (or could be calculated) in seven studies (Hu 2011; Losordo 2007; Losordo 2011; Tse 2007; Van Ramshorst 2009; Wang 2009; Wang 2010). The remaining four studies (Chen 2006; Erbs 2005; Honold 2012; Pokushalov 2010) only reported baseline and endpoint data, and we could not calculate standard deviations. Results are described using the standardised mean difference with a random-effects model, allowing outcomes of different measurement scales to be combined in a meta-analysis. This method of analysis does not allow mean change from baseline and endpoint data to be combined and we therefore present separate analyses of mean change from baseline and endpoint data.

At short-term follow-up, there was no evidence for a difference in mean change in exercise capacity from baseline between treatment arms (SMD 0.22, 95% CI -0.13 to 0.58, P = 0.22; 7 trials, 464 participants) (Analysis 1.11.1). However, in eight studies which reported endpoint values (Chen 2006; Erbs 2005; Honold 2012; Hu 2011; Pokushalov 2010; Tse 2007; Van Ramshorst 2009; Wang 2010), we observed a significant difference between treatment arms in favour of BMSC (SMD 0.58, 95% CI 0.15 to 1.02, P = 0.008; 8 trials, 429 participants) (Analysis 1.11.2). There was considerable heterogeneity across studies (I² = 76%), although all eight studies reported some degree of increased exercise performance in participants who received BMSC compared with those who received no stem cell therapy.

At long-term follow-up, one study which reported mean change from baseline showed a significant difference in exercise capacity in favour of BMSC (SMD 0.39, 95% CI 0.05 to 0.73, P = 0.02; 1 trial, 156 participants) (Analysis 1.12.1). However, this significant effect was not demonstrated in four studies which reported the mean value at endpoint (SMD 0.97, 95% CI -0.33 to 2.27, P = 0.14; 4 trials, 158 participants) (Analysis 1.12.2).

Surrogate endpoints
Left ventricular end-systolic volume (LVESV)

LVESV was measured in 16 studies. Of these, two studies (Yao 2008; Zhao 2008) reported LVESV diameter, while two further studies (Hendrikx 2006; Perin 2012a) reported LVESV index values (i.e. scaled by body surface area), although the authors of the Hendrikx 2006 study kindly supplied LVESV data upon request. One study (Honold 2012) additionally reported LVESV index values in a subset of measures. Methods of LVESV measurement included MRI (Ang 2008; Erbs 2005; Hendrikx 2006; Honold 2012; Hu 2011; Kang 2006; Tse 2007; Van Ramshorst 2009), left ventricular angiography (Assmus 2006; Honold 2012; Turan 2011) and echocardiography (Perin 2012a; Perin 2012b; Pokushalov 2010; Van Ramshorst 2009; Yao 2008; Zhao 2008). One study (Perin 2011) did not report the method of measurement.

Mean change from baseline data was reported in eight studies (Ang 2008; Assmus 2006; Erbs 2005; Hendrikx 2006; Hu 2011; Kang 2006; Tse 2007; Van Ramshorst 2009); the remaining five studies (Honold 2012; Perin 2011; Perin 2012b; Pokushalov 2010; Turan 2011) only reported baseline and endpoint data (with insufficient information to calculate standard deviations for the mean change from baseline). Combined evidence across all studies showed a significant difference in mean LVESV between treatment arms at short-term follow-up in favour of BMSC (MD -5.47 ml, 95% CI -8.81 to -2.14, P = 0.001; 13 trials, 470 participants) (Analysis 1.13). We observed moderate heterogeneity between studies (I² = 50%). Evidence from three studies (Erbs 2005; Pokushalov 2010; Turan 2011) demonstrated that the significant improvement in LVESV in participants who received BMSC was maintained over long-term follow-up (MD -14.64 ml, 95% CI -20.88 to -8.39, P < 0.00001; 3 trials, 153 participants) (Analysis 1.14). We noted considerable heterogeneity across three studies at long-term follow-up of LVESV (I² = 84%). Visual inspection of the forest plots revealed a strong and highly significant effect of the Pokushalov 2010 study of people with chronic IHD and end-stage chronic heart failure.

Left ventricular end-diastolic volume (LVEDV)

Seventeen studies measured LVEDV, with two studies (Yao 2008; Zhao 2008) reporting LVEDV diameter and two further studies (Hendrikx 2006; Perin 2012a) reporting LVEDV index values (although LVEDV values were made available by Hendrikx 2006 as noted above). Methods of LVEDV measurement included MRI, left ventricular angiography, and echocardiography as detailed above. In one study (Patel 2005) which reported LVEDV (but not LVESV), LVEDV appeared to be measured by either SPECT or echocardiography.

Mean change from baseline data was reported in eight studies (Ang 2008; Assmus 2006; Erbs 2005; Hendrikx 2006; Hu 2011; Kang 2006; Tse 2007; Van Ramshorst 2009); the remaining six studies (Honold 2012; Patel 2005; Perin 2011; Perin 2012b; Pokushalov 2010; Turan 2011) only reported baseline and endpoint data (with insufficient information to calculated standard deviations for the mean change from baseline). The combined evidence across all studies showed no difference IN LVEDV between treatment arms at short-term follow-up (MD 2.00 ml, 95% CI -2.21 to 6.21, P = 0.35; 14 trials, 490 participants) (Analysis 1.15) or at long-term follow-up (MD -3.30 ml, 95% CI -13.11 to 6.51, P = 0.51; 3 trials, 170 participants) (Analysis 1.16).

Stroke volume index

Four studies (Ang 2008; Assmus 2006; Honold 2012; Turan 2011) reported stroke volume index (ml/m²); two studies (Ang 2008; Assmus 2006) reported mean change from baseline values while the remaining two studies (Honold 2012; Turan 2011) only reported baseline and endpoint values. An additional three studies (Hu 2011; Perin 2012a; Van Ramshorst 2009) reported only stroke volume, i.e. uncorrected for body mass index. Combined evidence across all studies showed a significant improvement in stroke volume index between treatment arms at short-term follow-up (MD 3.84, 95% CI 0.95 to 6.73, P = 0.009; 4 trials, 148 participants) (Analysis 1.17). Evidence from two studies (Honold 2012; Turan 2011) showed that this significant effect in favour of stem cell therapy was maintained at long-term follow-up (MD 6.52, 95% CI 1.51 to 11.54, P = 0.01: 2 trials, 62 participants) (Analysis 1.18).

Engraftment and survival of the infused stem/progenitor cells

No studies reported engraftment and/or survival of the infused cells as an outcome.

Subgroup analysis and investigation of heterogeneity

Mortality

We found no evidence of heterogeneity between studies for mortality (I² = 0% for both short- and long-term outcomes). Subgroup analysis was precluded due to the low number of studies reporting the incidence of death in either treatment arm.

LVEF

We explored the moderate heterogeneity between studies measuring LVEF at short-term follow-up using subgroup analysis (see Table 1 for a summary of results). We found no significant differences between studies grouped according to cell dose (Analysis 2.1; 16 trials, 747 participants) or baseline cardiac function (Analysis 3.1; 17 trials, 677 participants). However, the mean difference in LVEF in favour of BMSC, although significant both in studies with intracoronary administration of cells (MD 3.19%, 95% CI 2.19 to 4.19, P < 0.00001; 9 trials, 365 participants) and studies in which cells were administered directly into the myocardium (MD 5.30%, 95% CI 4.21 to 6.40, P < 0.00001; 10 trials, 388 participants), was significantly better when cells were administered intramyocardially (test for subgroup differences: P = 0.005) (Analysis 4.1).

Table 1. LVEF and NYHA class: subgroup analysis
  1. CIHD: chronic ischaemic heart disease; CPC: circulating progenitor cells; HF: heart failure (secondary to ischaemic heart disease); HSC: haematopoietic stem cells; IC: intracoronary; IM: intramyocardial; IRA: intractable/refractory angina; MNC: mononuclear cells; MSC: mesenchymal stem cells.

Factor Subgroup LVEF NYHA
  

No.

studies

MD (95% CI) P I²

No.

studies

MD (95% CI) P I²
Cell dose< 10⁷35.48 (2.74, 8.23)< 0.00010%3-0.53 (-1.20, 0.14)0.1293%
10⁷ - 10⁸114.12 (3.22, 5.01)< 0.0000173%6-0.74 (-1.40, -0.07)0.0396%
> 10⁸53.38 (2.00, 4.77)< 0.000010%2-0.49 (-1.15, 0.18)0.1580%
Test for subgroup differences: P = 0.38 P = 0.86
Route of administrationIC93.19 (2.19, 4.19)< 0.0000143%5-0.40 (-0.85, 0.04)0.0882%
IM105.30 (4.21, 6.40)< 0.0000152%6-0.83 (-1.43, -0.23)0.00797%
    Test for subgroup differences: P = 0.005 P = 0.26
Baseline cardiac function (LVEF)< 30%45.40 (3.81, 6.99)< 0.0000144%2-1.41 (-1.68, -1.14)<0.0000157%
30% - 50%114.36 (3.28, 5.45)< 0.0000156%8-0.48 (-0.82, -0.14)0.00585%
> 50%24.65 (2.47, 6.84)< 0.00017% NA  
    Test for subgroup differences: P = 0.57 P < 0.0001
Cell typeMNC133.77 (2.91, 4.63)< 0.0000119%7-0.60 (-1.12, -0.08)0.0297%
CPC31.58 (-0.01, 3.17)0.0567%2-0.02 (-0.40 to 0.36)0.920%
HSC28.44 (6.11, 10.78)< 0.0000152%2-0.88 (-3.04, 1.27)0.4297%
MSC16.00 (3.08, 8.92)< 0.0001NA1-1.20 (-1.58, -0.82)<0.00001NA
    Test for subgroup differences: P < 0.0001 P = 0.0004
Participant diagnosisCIHD93.20 (2.20, 4.20)< 0.0000121%5-0.40 (-0.85, 0.04)0.0883%
HF75.95 (4.67, 7.23)< 0.0000161%5-0.92 (-1.57, -0.26)0.00697%
IRA24.02 (1.72, 6.31)0.00060%1-0.38 (-1.16, -0.25)0.05NA
Test for subgroup differences: P = 0.0009 P = 0.35

We also found significant differences in the effect of BMSC on LVEF at short-term follow-up by type of cells administered (test for subgroup differences: P < 0.0001) (Analysis 5.1). In particular, in two studies which administered circulating progenitor cells (mononuclear cells isolated from venous peripheral blood, not from bone marrow aspiration), the effect of BMSC on LVEF was only marginally statistically significant (MD 1.58%, 95% CI -0.01 to 3.17, P = 0.05; 3 trials, 73 participants). A comparison of studies using mononuclear cells with those using haematopoietic stem cells (e.g. CD34⁺ and ALDH⁺ cells isolated from bone marrow) showed that the mean difference in LVEF was significantly better when haematopoietic stem cells were administered (MD 8.44%, 95% CI 6.11 to 10.78, P < 0.00001; 2 trials, 40 participants) than mononuclear cells (MD 3.77%, 95% CI 2.91 to 4.63, P < 0.00001; 13 trials, 606 participants) (test for subgroup differences: P = 0.0002).

Finally, subgroup analysis of studies categorised by participant diagnosis at baseline (chronic IHD, heart failure secondary to IHD, and intractable/refractory angina) showed significant differences in the effect of stem cell therapy on LVEF at short-term follow-up (test for subgroup differences: P = 0.004; 18 trials, 746 participants) (Analysis 6.1). Although the mean difference in LVEF between treatment arms was significant for all groups of participants, we observed a significantly greater mean difference in LVEF between treatment arms in favour of stem cell therapy in studies of people with heart failure (MD 5.95%, 95% CI 4.67% to 7.23%, P < 0.00001; 7 trials, 344 participants) than in studies of people with chronic IHD (MD 3.20%, 95% CI 2.20% to 4.20%, P < 0.00001; 9 trials, 336 participants ) (test for subgroup differences: P = 0.0009).

NYHA classification

In view of the high level of heterogeneity across studies measuring NYHA class at short-term follow-up, we conducted subgroup analyses (see Table 1 for a summary of results of subgroup analyses). There were no differences in the effect of BMSC on NYHA class between studies grouped according to different cell doses (Analysis 2.2; 10 trials, 435 participants), routes of administration (Analysis 4.2; 11 trials, 486 participants) or participant diagnosis at baseline (Analysis 6.2; 11 trials, 486 participants). However, we note a significantly greater mean difference in NYHA class between treatment arms in participants with lower baseline cardiac function (LVEF < 30%) (MD -1.41, 95% CI -1.68 to -1.14, P < 0.00001; 2 trials, 144 participants) than in participants with a baseline LVEF > 30% (MD -0.48, 95% CI -0.82 to -0.14, P = 0.005; 8 trials, 273 participants) (test for subgroup differences: P < 0.0001), although heterogeneity between studies remained high in both comparisons (Analysis 3.2; 17 trials, 677 participants).

A comparison of the mean difference in NYHA class according to cell type also revealed significant differences (test for subgroup differences: P = 0.0004) (Analysis 5.2). In particular, we observed the greatest mean difference in NYHA class between treatment arms in one study using mesenchymal stem cells (Chen 2006) (MD -1.20, 95% CI -1.58 to -0.82; 45 participants). The effect size for this study was significantly different from that in two studies using circulating progenitor cells (Assmus 2006; Honold 2012; 68 participants) (MD -0.02, 95% CI -0.40 to 0.36) (test for subgroup differences: P < 0.0001), in which there was no evidence of heterogeneity (I² = 0%).

Sensitivity analysis

Mortality

One study (Pokushalov 2010) reported a high rate of deaths (BMSC: 6/55; no BMSC: 21/54). Although cause of death was not reported, participants in this study had chronic IHD and end-stage chronic heart failure. A sensitivity analysis of the risk of long-term mortality showed that the significantly lower risk of mortality associated with BMSC therapy remained even when this study was excluded from the analysis (RR 0.27, 95% CI 0.10 to 0.79, P = 0.02).

LVEF

A sensitivity analysis of LVEF according to the method of measurement was carried out, since the limitations of some of the methods used to assess LVEF are well known (Arnesen 2007). We observed a significant effect of BMSC on LVEF at short-term follow-up in all methods of measurement with overlapping confidence intervals for all analyses (MRI: MD 3.35%, 95% CI 2.17 to 4.53, P < 0.00001 (9 trials, 298 participants); left ventricular angiography: MD 2.91%, 95% CI 1.35 to 4.47, P = 0.0003 (5 trials, 185 participants); SPECT: MD 5.47%, 95% CI 2.80 to 8.14, P < 0.0001 (3 trials, 124 participants); echocardiography: MD 4.78%, 95% CI 3.36 to 6.21, P < 0.00001 (6 trials, 314 participants)) (Analysis 7.1).

We also conducted a sensitivity analysis of the effect of studies at high or unclear risk of bias (see Figure 2 for a summary of the risk of bias in individual studies). A significant mean difference in LVEF at short-term follow-up remained when we restricted studies to those with a low risk of selection bias (MD 3.27%, 95% CI 1.69 to 4.84, P < 0.0001; 6 trials, 218 participants), a low risk of performance bias (MD 5.11%, 95% CI 3.89 to 6.33, P < 0.00001; 9 trials, 320 participants) and a low risk of detection bias (MD 4.58%, 95% CI 3.71 to 5.45, P < 0.00001; 14 trials, 588 participants) (Analysis 8.1).

Differences between studies included the type of comparator (placebo versus no placebo) and co-intervention (no co-intervention, coronary artery bypass graft (CABG)) used (see Table 2 for a summary of placebo and co-intervention use in individual studies). The significant mean difference in LVEF in favour of stem cell therapy at short-term follow-up was also robust to the type of comparator (placebo: MD 3.33%, 95% CI 2.25 to 4.41, P < 0.00001, 9 trials, 373 participants; no placebo: MD 5.05%, 95% CI 4.02 to 6.09, P < 0.00001; 8 trials, 343 participants) and to the presence or absence of a co-intervention (no co-intervention: MD 4.31%, 95% CI 2.97 to 5.64, P < 0.00001; 6 trials, 297 participants; CABG: MD 6.51%, 95% CI 4.76 to 8.26, P < 0.00001, 5 trials, 158 participants; PCI: MD 3.35%, 95% CI 2.30 to 4.40, P < 0.00001; 7 trials, 291 participants) (Analysis 9.1)

Table 2. Summary characteristics of studies
  1. BM: bone marrow; BMMNC: bone marrow mononuclear cell(s); CABG: coronary artery bypass graft; CCS: Canadian Cardiolovascular Society functional classification of angina; CPC: circulating progenitor cells; Echo: echocardiography; EMM: ElectroMechanical Maping, usually using the commercially available NOGA™ system; EPC: endothelial progenitor cells; G-CSF: granulocyte colony stimulating factor; HSA: human serum albumin; IC: intracoronary; IM: intramyocardial; LVA: left ventricular angiography; LVEF: left ventricular ejection fraction; MACS: magnetic activated cell sorting; MRI: magnetic resonance imaging; MSC: mesenchymal stem cells; NR: Not reported; NYHA: New York Heart Association functional classification of heart failure; PCI: percutaneous coronary intervention; SC: stem cells; SD: standard deviation; SPECT: single-photon emission computed tomography; SW: shock wave. 
    (*): BM aspiration: bone marrow was harvested by aspiration and mononuclear cells were isolated by Ficoll density gradient centrifugation;
    (†): in the meta-analysis, controls from the Losordo 2011 trial were divided into 2 equal groups to enable separate analysis of each of the BMSC treatment groups.
    (ǂ) LVEF was measured by ECHO, SPECT and LVA or ECHO and LVA. Results from ECHO are reported here.

 

 

 

Trial

 

 

 

Co- intervention

 

 

 

Type of stem cell

 

 

Mean dose (SD) of cells

 

Method of stem cell isolation and route of delivery

 

 

 

 

Comparator arm

 

Number of participants assessed for primary outcome

 

 

Baseline functional Class

 

Baseline LVEF (%)

Mean (SD)

 

Method(s) used to measure  LVEF

 

 

 

Duration of trial (months)

 

SC arm

Control arm

 

SC arm

Control arm SC arm Control arm
Ang 2008 ICMedical therapy and CABGBMMNC115 (73) x 10⁶ cells

BM aspiration*,

IC

CABG87

NYHA: NR

CCS:

2.3

NYHA: NR

CCS:

2.7

28.5 (6.5)20.9 (8.9)MRI6
Ang 2008 IMMedical therapy and CABGBMMNC84 (56) x 10⁶ cells

BM aspiration*,

IM

CABG107

NYHA: NR

CCS:

2.7

NYHA: NR

CCS:

2.7

25.4 (8.1)20.9 (8.9)MRI6
Assmus 2006 BMSCMedical therapy and PCIBMMNC2.05 (1.1) x 10⁸ cells

BM aspiration*,

IC

PCI in a proportion of participants2418

NYHA: 2.2 (0.6)

CCS:

NR

NYHA: 1.91 (0.7)

CCS:

NR

41 (11)43 (13)LVA3
Assmus 2006 CPCMedical therapy and PCICPC2.2 (1.1) x 10⁷ cells

Leukapheresis,

IC

PCI in a proportion of participants1918

NYHA: 2.2 (0.8)

CCS:

NR

NYHA: 1.91 (0.7)

CCS:

NR

39 (10)43 (13)LVA3
Assmus 2012Medical therapy + PCI + SWNRNRBM aspiration*, ICPCI + SW + placebo3732

NYHA: 2.3 (0.6)

CCS:

NR

NYHA: 2.1 (0.3)

CCS:

NR

NRNRMRI4
Chen 2006Medical therapy + PCIMSC5 x 10⁶ cellsBM aspiration*, ICPCI, no placebo22 at 6 months, 20 at 12 months23 at 6 months, 19 at 12 months

NYHA: 2.7 (0.8)

CCS:

NR

NYHA: 2.9 (0.6)

CCS:

NR

26 (6)23 (8)SPECT12
Erbs 2005Medical therapy, PCI and G-CSFCPC69 (14) x 10⁶ cells

Leukapheresis, IC

 

PCI + G-CSF + infusion of cell-free serum12 at 3 months; 12 at 15 months11 at 3 months; 10 at 15 months

NYHA: NR

CCS:

NR

NYHA: NR

CCS:

NR

51.0 (12.1)55.8 (12.4)MRI15
Hendrikx 2006Medical therapy and CABGBMMNC62.25 (31.35) x 10⁶ cellsBM aspiration*, IMCABG + saline1010

NYHA: NR

CCS:

NR

NYHA: NR

CCS:

NR

42.9 (10.3)39.5 (5.5.)MRI4
Honold 2012Medical therapy + G-CSF + PCIEPC29 (12) x 10⁶ cellsLeukapheresis, culture ex vivo, ICG-CSF + PCI, no placebo94

NYHA: 1.9 (0.7)

CCS:

NR

NYHA: 2.0 (0.7)

CCS:

NR

33.4 (12.7)23.3 (7.2)MRI60
Hu 2011Medical therapy and CABGBMMNC13.17 (10.66) x 10⁷ cellsBM aspiration*, ICCABG + placebo (0.8 saline + 0.2 participant’s own serum)3128

NYHA: NR

CCS:

NR

NYHA: NR

CCS:

NR

22.7824.95MRI6
Kang 2006Medical therapy, PCI and G-CSFBMMNCNR

Leukapheresis, IC

 

PCI, no G-CSF,

no placebo

1516

NYHA: NR

CCS:

NR

NYHA: NR

CCS:

NR

48.5 (12.9)45.1 (10.2)MRI6
Losordo 2007

Medical therapy

+

G-CSF

CD34+ cells2.2 (2.5) x 10⁵ CD34+ cells/kg

Leukapheresis and selection of CD34 by MACS,

IM (EMM)

G-CSF+  injection of saline with 5% autologous plasma

18

 

6

 

NYHA: NR

CCS:

NR

NYHA:

NR

CCS:

NR

NRNR-6
Losordo 2011 LD

Medical therapy

+

G-CSF

CD34+ cells1 x 10⁶ CD34+ cells/kg

Leukapheresis and selection of CD34 by MACS,

IM (EMM)

 G-CSF + injection of saline with 5% autologous plasma54 at 6 months; 53 at 12 months53 at 6 months; 50 at 12 months†

NYHA: NR

CCS:

NR

NYHA:

NR

CCS:

NR

58.9 (14.2)59.8 (14.5)Echo or SPECT12
Losordo 2011 HD

Medical therapy

+

G-CSF

CD34+ cells5 x 10⁶ CD34+ cells/kg

Leukapheresis and selection of CD34 by MACS,

IM (EMM)

 B-CSF + injection of saline with 5% autologous plasma55 at 6 months; 53 at 12 months53 at 6 months; 50 at 12 months†

NYHA: NR

CCS:

NR

NYHA:

NR

CCS:

NR

60.6 (13.3)59.8 (14.5)Echo or SPECT12
Patel 2005Medical therapy and CABGCD34+ cells22 x 10⁶ CD34 cells

BM aspiration* and selection of CD34 by MACS,

IM (EMM)

CABG, no placebo1010

NYHA: 3.5

CCS:

NR

NYHA: 3.4

CCS:

NR

29.4 (3.6)30.7 (2.5)

SPECT

Echo

6
Perin 2011Medical therapyBMMNC2 x 10⁶ BMMNCBM aspiration*, IM (EMM)

Mock injection

but no placebo administered

2010

NYHA: 2.3 (0.2)

CCS:

3.0 (0.2)

NYHA:

2.6 (0.3)

CCS:

3.0 (0.3)

37.0 (10.6)39,0 (9.1)Echo (ǂ)6
Perin 2012aMedical therapyBMMNC

100 x 10⁶

BMMNC

BM aspiration*, IM (EMM)Injection of saline with 5% HSA5428

NYHA: NR

CCS:

NR

NYHA:

NR

CCS:

NR

34.7 (8.8)32.2 (8.6)Echo6
Perin 2012bMedical therapy

ALDH+

cells         

2.94 (1.58) x 10⁶ ALDH+ cells

BM aspiration*, selection of ALDH+ cells by cell sorting

IM (EMM)

Injection of saline with 5% HSA1010

NYHA: 2.5 (0.5)

CCS:

2.0 (0.5)

NYHA:

2.6 (0.5)

CCS:

2.5 (0.5)

36.1 (10.9)32.1 (10.6)Echo (ǂ)6
Pokushalov 2010Medical therapyBMMNC41 (16) x 10⁶ BMMNCBM aspiration*, IM (EMM)No additional therapy53 at 6 months, 49 at 12 months46 at 6 months, 33 at 12 months

NYHA: 3.3 (0.2)

CCS:

3.1 (0.4)

NYHA:

3.5 (0.1)

CCS: 3.5 (0.5)

27.8 (3.4)26.8 (3.8)Echo12
Tse 2007Medical therapyBMMNC10 - 20 x 10⁶ BMMNCBM aspiration*, IM (EMM)Injection of saline with 10% HSA199

NYHA: 2.8 (0.8)

CCS:

3.3 (0.5)

NYHA:

2.8 (0.4)

CCS: 3.1 (0.3)

51.9 (8.5)45.3 (8.3)MRI6
Turan 2011Medical therapy and PCIBMMNC99 (25) x 10⁶ cellsBM aspiration*, ICPCI, no placebo3316

NYHA: 2.4 (0.4)

CCS: NR

 

NYHA: 2.5 (0.9)

CCS: NR

 

46 (10)46 (10)LVA12
Van Ramshorst 2009Medical therapyBMMNC98 (6) x 10⁶ BMMNCBM aspiration*, IM (EMM)Injection of saline with 0. 5% HSA2425

NYHA: NR

CCS:

3.0 (0.6)

NYHA:

NR

CCS: 2.9 (0.7)

56.0

(12.0)

54.0

(10.0)

MRI6
Wang 2009

Medical therapy + PCI

 

 

CD34+ cells1.0 - 6.1 x 10⁶ CD34 cellsBM aspiration* and selection of CD34 by MACS, ICPCI, no placebo1616

NYHA: NR

CSS: NR

 

NYHA: NR

CSS: NR

NRNR-6m
Wang 2010

Medical therapy

 

 

CD34+ cells5.6 (2.3) x 10⁷ CD34 cells+BM aspiration* and selection of CD34 by MACS, ICInjection of saline with HSA5656

NYHA: NR

CSS:

3.3 (24.7)

NYHA:

NR

CSS:

3.5 (26.2)

NRNR-6
Yao 2008Medical therapy and PCIBMMNC7.2 x 10⁷ cellsBM aspiration* , ICPCI in a proportion of participants + injection of 0.9% saline and heparin2426

NYHA: NR

CSS:NR

 

NYHA: NR

CSS:NR

 

44.4 (5.5)42.5 (7.3)

MRI

Echo

6
Zhao 2008Medical therapy and CABGBMMNC6.59 (5.12) x 10⁸ cellsBM aspiration* , IMCABG + injection of 0.9% saline and heparin1618

NYHA: 3.33 (0.48)

CSS:3.22 (0.43)

 

NYHA: 3.40 (0.50)

CSS:3.30 (0.46)

 

35.8 (7.3)36.7 (9.2)Echo6

Discussion

The incidence of heart failure secondary to ischaemic heart disease (IHD) is increasing exponentially worldwide as a consequence of improved standard clinical care and improved long-term survival following myocardial infarction (MI). During the last 12 years, stem cell therapies have emerged as a new treatment for IHD and numerous randomised controlled trials (RCTs) have been developed to treat people with left ventricular dysfunction following myocardial infarction and people with chronic ischaemia (Clifford 2012a; Clifford 2012b; Fisher 2013; Jeevanantham 2012). Overall, treatment has been shown to be safe and to have no adverse effects. However, the clinical efficacy of this new treatment is still debated (Clifford 2012a; Jeevanantham 2012), as a reduction in mortality has been reported in only a handful of trials (Grajek 2010; Schächinger 2006; Pokushalov 2010). We have previously evaluated the effect of stem cells as treatment for acute myocardial infarction (AMI) (Clifford 2012a; Clifford 2012b; Martin-Rendon 2008b; Martin-Rendon 2008c). Here we present data on the safety and efficacy of autologous bone marrow-derived stem cells (BMSC) administered to people with chronic IHD and heart failure.  

Twenty-three RCTs were eligible for inclusion in this review. All trials compared the effect of BMSC treatment to no treatment or to control. Generally, standard primary intervention included medical therapy only, or medical therapy and revascularisation using primary angioplasty (e.g. percutaneous coronary intervention (PCI)) or surgery (e.g. coronary artery bypass graft (CABG)). Participants were diagnosed with chronic IHD, generally including chronic symptoms of ischaemia that persisted for at least 30 days since the last MI, heart failure secondary to IHD or refractory angina. The type of cells, route of administration and dose are detailed in Table 2. All trials reported short-term follow-up data to 12 months, and seven studies had long-term follow-up for 12 months and longer. In this review, we defined mortality and left ventricular ejection fraction (LVEF) as primary outcomes for comparison with previous meta-analyses and because they are the most common primary outcomes defined by the majority of included studies. We also included adverse events as a primary outcome for this systematic review.

The main findings of the review are:

  • BMSC treatment significantly reduced both mortality (RR 0.28, 95% CI 0.14 to 0.53, P = 0.02, 8 studies, 494 participants, low quality evidence) and rehospitalisation due to heart failure (RR 0.26, 95% CI 0.07 to 0.94, P = 0.04, 2 studies, 198 participants, low quality evidence) at long-term follow-up.

  • The treatment was also associated with a significant reduction in heart failure symptoms (measured by New York Heart Association (NYHA) functional class) in favour of BMSC treatment at short-term (MD -0.63, 95% CI -1.08 to -0.19, P = 0.005, 11 studies, 486 participants, moderate quality evidence) and long-term follow-up (MD -0.91, 95% CI -1.38 to -0.44, P = 0.0002, 4 studies, 196 participants, moderate quality evidence), as well as a reduction in angina symptoms (measured by Canadian Cardiovascular Society (CCS) score) in favour of BMSC (MD -0.81, 95% CI -1.55 to -0.07, P = 0.03, 8 studies, 379 participants, moderate quality evidence) at short-term follow-up.

  • There was a significant reduction in left ventricular end systolic volume (LVESV) at short-term (MD -5.47 ml, 95% CI -8.81 ml to -2.14 ml, P = 0.001, 13 studies, 470 participants, moderate quality evidence) and long-term follow-up (MD -14.64 ml, 95% CI -20.88 ml to -8.39 ml, P < 0.00001, 3 studies, 153 participants, moderate quality evidence), but not left ventricular end diastolic volume (LVEDV), in favour of BMSC treatment.

  • Stroke volume index was significantly improved by BMSC treatment at short-term (MD 3.84, 95% CI 0.95 to 6.73, P = 0.009, 4 studies, 148 participants, moderate quality evidence) and long-term follow-up (MD 6.52, 95% CI 1.51 to 11.54, P = 0.01, 2 studies, 62 participants, moderate quality evidence).

  • BMSC treatment improved LVEF significantly at short-term (MD 4.22%, 95% CI 3.47% to 4.97%, P < 0.00001, 18 studies, 746 participants, moderate quality evidence) and long-term follow-up (MD 2.62%, 95% CI 0.50% to 4.73%, P = 0.02, 6 studies, 254 participants, moderate quality evidence).

  • Unlike previous reviews and meta-analyses, statistical heterogeneity was generally low or negligible for all outcomes, with the exception of NYHA class (I² = 97%), CCS class (I² = 94%) and exercise capacity (I² = 76%), for which results remained significant with a random-effects model.

  • Results were robust to all sensitivity analyses.

There are a number of important limitations to the strength of the conclusions derived from this review and meta-analysis.

Firstly, the included studies are very small. Only four included studies randomised more than 50 participants to treatment in each trial arm and the majority of studies included substantially fewer participants; there is therefore a risk of small study bias, leading to spuriously inflated effect sizes. Secondly, whilst the number of ongoing randomised trials in this field is encouraging, several of these appear to have been completed prior to the date of our search, but we have been unable to identify any publications associated with them. We therefore cannot rule out the possibility of publication bias. Thirdly, the number of outcomes assessed in this systematic review leads us to the possibility of multiple testing and hence of false positive results. Our results should therefore be interpreted with some caution. There is a clear need for large-scale, adequately-powered studies with well-defined participant cohorts and long-term follow-up to confirm the beneficial effects of BMSC in terms of reduced mortality and rehospitalisation, and improved cardiac function.

Additional limitations include the low number of studies with long-term follow-up, and a lack of standardisation of outcome assessment methods. These limitations do not differ from those found in our previous systematic review of BMSC treatment in AMI trials (Clifford 2012a; Clifford 2012b).

Surprisingly, what differs from our previous review of BMSC treatment for AMI is the significant reduction in mortality at long-term follow-up observed in this review. This reduction in mortality may be due to the cohort of participants included here, diagnosed in some cases with refractory angina (Losordo 2011) or with advanced heart failure (Pokushalov 2010). As stand-alone therapy administered to people with IHD and no option of revascularisation, BMSC treatment has been shown to be efficacious and it appears to reduce the incidence of mortality and improve angina symptoms as well as NYHA class (Fisher 2013). This reduction in mortality has been demonstrated in very few trials and never in a meta-analysis of AMI studies (Clifford 2012a; Clifford 2012b; Martin-Rendon 2008b; Martin-Rendon 2008c). However, it should be noted that the Pokushalov 2010 study of people with end-stage heart failure reported a particularly high number of deaths. Although a statistically significant beneficial effect of BMSC on mortality remained in a sensitivity analysis after exclusion of this study, the number of observed deaths when the Pokushalov 2010 study was excluded was very small, leaving the clinical significance of this finding unclear.

Our previous Cochrane review evaluated stem cell treatment in people who suffered from AMI in 33 trials and of 1765 participants (Clifford 2012a; Clifford 2012b). Even with the relatively large number of trials and participants included, there was insufficient evidence to conclude that this new treatment reduces the incidence of mortality when administered following AMI. To this end, a European Phase III multicentre RCT (the BAMI trial) has been designed to test the clinical efficacy of BMSC therapy for AMI.

In agreement with previous studies, we observed a moderate improvement in LVEF in favour of BMSC treatment in this review. However, the improvement in LVEF does not adequately define the clinical efficacy of BMSC treatment. Although global LVEF has been used as the gold-standard surrogate to measure heart function, especially in large trials in cardiology such as the CADILLAC trial (Stone 2002; Cox 2003), its use in cell therapy trials is controversial (Traverse 2011). LVEF is a powerful predictor of mortality in people with LV dysfunction (Solomon 2005), the typical cohort of participants included in BMSC trials following AMI (Clifford 2012a; Clifford 2012b). However, in the trials included in this review, where many of the participants have normal LVEF at baseline, primary endpoints defined in individuals studies include safety, mortality, incidence of heart failure, rehospitalisation due to heart failure, NYHA functional class, angina episodes or angina symptoms, exercise tolerance and quality of life.

The observed risk ratio reduction in long-term mortality of 72% represents evidence from only 39% of all included studies. In contrast, an improvement in LVEF of 2.62% comes from a much larger proportion of the included trials. This moderate improvement in LVEF is very unlikely to explain the differential survival, and hence the above results should be interpreted with caution.  

Incidence of mortality should be the primary endpoint of future clinical trials to confirm the clinical efficacy of this treatment. Additionally, and depending on the clinical diagnosis, incidence of rehospitalisation due to heart failure together with NYHA class should be used as surrogate measures of disease progression in people with heart failure, whereas frequency of angina episodes and CCS angina class should be measured for people with refractory angina.

We conducted subgroup analyses for the outcomes of LEVF and NYHA class, as LVEF was measured by a high proportion of the trials, and we noted a high degree of statistical heterogeneity for NYHA class. Variables included cell dosing, route of cell administration or delivery, baseline cardiac function measured by LVEF, participant clinical diagnosis, cell type injected and method of measurement of heart function. In summary, the results of these subgroup analyses suggest that cell dose does not seem to have a significant effect on LVEF or NYHA classification, whereas intramyocardial injection of BMSC seems to increase the treatment effect for LVEF and NYHA class, and participants with lower LVEF at baseline (LVEF below 30%) or diagnosed with congestive heart failure (CHF) seem to benefit more from treatment than those with LVEF above 30% or diagnosed with chronic IHD (and not symptomatic of heart failure). The majority of trials administered bone marrow-derived mononuclear cells; few studies administered other more enriched populations of cells such as mesenchymal progenitors, haemopoietic progenitor cells or circulating progenitor cells, and hence we could only make limited comparisons between cell types. Finally, the significant improvement in LVEF in BMSC-treated participants over control appears to be robust to the different methods used to measure this outcome (e.g. magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), LV angiography and echocardiography).

In summary, the results of this review may be clinically relevant, but the evidence for the reduction in the number of deaths with BMSC treatment relative to controls is of low quality. Although BMSC treatment has the potential to be used in clinical practice for people with heart failure and for those with no other treatment option, the results of this review warrant larger clinical trials to confirm the present findings. To this end, the first Phase II/III and Phase III clinical trials for severe IHD (NCT01727063; NCT00362388; NCT00747708), heart failure (NCT01768702) and refractory angina (NCT01508910) have been designed and are currently ongoing. Research should also focus on a better understanding of the best types of cells to use and why some people respond to treatment whereas others do not.  

Authors' conclusions

Implications for practice

This review and meta-analysis show some evidence of a reduction in mortality and rehospitalisation due to heart failure at long-term follow-up (12 months and over) when BMSC treatment is administered to people suffering from chronic IHD and congestive heart failure. These results should be confirmed in larger appropriately powered clinical trials before developing BMSC treatment for these patients as clinical practice. 

Implications for research

The results of this systematic review should be confirmed in large, adequately-powered trials assessing the clinical relevance of the treatment. With a potential clinical effect such as a reduction in mortality and rehospitalisation due to heart failure in this cohort of participants, future research should also focus on a better understanding of the cell therapies used (e.g. mononuclear cells, circulating progenitor cells, mesenchymal stem cells or haematopoietic progenitor cells) and their mechanism of action. Additionally, patient-dependent outcomes need to be more thoroughly investigated, to ascertain and distinguish between responders and non-responders, and to be able to tailor autologous, allogeneic or modified cell therapies to each patient group.

Acknowledgements

We are in debt to Mr HJ Zhang, University of Oxford, UK, for the translation of papers from Mandarin to English; and to Dr Brigitt Assmus, University of Frankfurt, Germany, Dr Marc Hendrikx, Virga Jesse Hospital, Belgium, and Dr Sheng Liu, Fuwai Hospital, China for their generosity and time spent clarifying data for this review. We would also like to thank Professors M Murphy, Suzanne M Watt and D Roberts, NHS Blood and Transplant, for their continuous support and encouragement.

Data and analyses

Download statistical data

Comparison 1. Stem cells versus no stem cells
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality (any)22 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Short-term follow-up (< 12 months)211138Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.32, 1.41]
1.2 Long-term follow-up (≥ 12 months)8494Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.14, 0.53]
2 LVEF (%): Short-term follow-up (< 12 months)18 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 Mean change from baseline10435Mean Difference (IV, Fixed, 95% CI)2.93 [2.02, 3.83]
2.2 Mean at endpoint8311Mean Difference (IV, Fixed, 95% CI)7.03 [5.70, 8.36]
2.3 Combined18746Mean Difference (IV, Fixed, 95% CI)4.22 [3.47, 4.97]
3 LVEF (%): Long-term follow-up (≥ 12 months)6 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Mean change from baseline3153Mean Difference (IV, Fixed, 95% CI)5.68 [1.65, 9.71]
3.2 Mean at endpoint3101Mean Difference (IV, Fixed, 95% CI)1.45 [-1.04, 3.94]
3.3 Combined6254Mean Difference (IV, Fixed, 95% CI)2.62 [0.50, 4.73]
4 Adverse effects18999Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.67, 1.44]
4.1 Short-term follow-up (< 12 months)18830Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.67, 1.44]
4.2 Long-term follow-up (≥ 12 months)3169Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Infarction17 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Short-term follow-up (< 12 months)16737Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.20, 1.59]
5.2 Long-term follow-up (≥ 12 months)3221Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.19, 1.22]
6 Rehospitalisation due to heart failure5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Short-term follow-up (< 12 months)4236Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.12, 1.06]
6.2 Long-term follow-up (≥ 12 months)2198Risk Ratio (M-H, Fixed, 95% CI)0.26 [0.07, 0.94]
7 Angina episodes per week: short term follow-up (<12 months)5 Mean Difference (IV, Fixed, 95% CI)Subtotals only
7.1 Mean change from baseline132Mean Difference (IV, Fixed, 95% CI)-3.60 [-12.80, 5.60]
7.2 Mean value at endpoint4397Mean Difference (IV, Fixed, 95% CI)-4.72 [-7.22, -2.22]
7.3 Combined5429Mean Difference (IV, Fixed, 95% CI)-4.64 [-7.06, -2.23]
8 NYHA Classification: short-term follow-up (< 12 months)11 Mean Difference (IV, Random, 95% CI)Subtotals only
8.1 Mean value at endpoint11486Mean Difference (IV, Random, 95% CI)-0.63 [-1.08, -0.19]
9 NYHA Classification: long-term follow-up (≥ 12 months)4 Mean Difference (IV, Random, 95% CI)Subtotals only
9.1 Mean value at endpoint4196Mean Difference (IV, Random, 95% CI)-0.91 [-1.38, -0.44]
10 CCS class: short-term follow-up (< 12 months)8 Mean Difference (IV, Random, 95% CI)Subtotals only
10.1 Mean change from baseline4198Mean Difference (IV, Random, 95% CI)-1.26 [-2.06, -0.46]
10.2 Mean value at endpoint4181Mean Difference (IV, Random, 95% CI)-0.55 [-1.54, 0.45]
10.3 Combined8379Mean Difference (IV, Random, 95% CI)-0.81 [-1.55, -0.07]
11 Exercise capacity: short-term follow-up (< 12 months)11 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
11.1 Mean change from baseline7464Std. Mean Difference (IV, Random, 95% CI)0.22 [-0.13, 0.58]
11.2 Mean value at endpoint8429Std. Mean Difference (IV, Random, 95% CI)0.58 [0.15, 1.02]
12 Exercise capacity: long-term follow-up (≥ 12 months)5 Std. Mean Difference (IV, Random, 95% CI)Subtotals only
12.1 Mean change from baseline1156Std. Mean Difference (IV, Random, 95% CI)0.39 [0.05, 0.73]
12.2 Mean value at endpoint4158Std. Mean Difference (IV, Random, 95% CI)0.97 [-0.33, 2.27]
13 LVESV (ml): short-term follow-up (< 12 months)13 Mean Difference (IV, Fixed, 95% CI)Subtotals only
13.1 Mean change from baseline8246Mean Difference (IV, Fixed, 95% CI)-2.81 [-6.64, 1.02]
13.2 Mean at endpoint5224Mean Difference (IV, Fixed, 95% CI)-13.72 [-20.46, -6.97]
13.3 Combined13470Mean Difference (IV, Fixed, 95% CI)-5.47 [-8.81, -2.14]
14 LVESV (ml): long-term follow-up (≥ 12 months)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
14.1 Mean change from baseline122Mean Difference (IV, Fixed, 95% CI)-8.2 [-19.81, 3.41]
14.2 Mean at endpoint2131Mean Difference (IV, Fixed, 95% CI)-17.25 [-24.66, -9.85]
14.3 Combined3153Mean Difference (IV, Fixed, 95% CI)-14.64 [-20.88, -8.39]
15 LVEDV (ml): short-term follow-up (< 12 months)14 Mean Difference (IV, Fixed, 95% CI)Subtotals only
15.1 Mean change from baseline8246Mean Difference (IV, Fixed, 95% CI)3.45 [-1.30, 8.19]
15.2 Mean at endpoint6244Mean Difference (IV, Fixed, 95% CI)-3.36 [-12.49, 5.77]
15.3 Combined14490Mean Difference (IV, Fixed, 95% CI)2.00 [-2.21, 6.21]
16 LVEDV (ml): long-term follow-up (≥ 12 months)3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
16.1 Mean change from baseline122Mean Difference (IV, Fixed, 95% CI)-2.0 [-19.61, 15.61]
16.2 Mean at endpoint2148Mean Difference (IV, Fixed, 95% CI)-3.88 [-15.70, 7.93]
16.3 Combined3170Mean Difference (IV, Fixed, 95% CI)-3.30 [-13.11, 6.51]
17 Stroke volume index: short term follow-up (<12 months)4 Mean Difference (IV, Fixed, 95% CI)Subtotals only
17.1 Mean change from baseline286Mean Difference (IV, Fixed, 95% CI)2.33 [-1.26, 5.92]
17.2 Mean at endpoint262Mean Difference (IV, Fixed, 95% CI)6.64 [1.75, 11.53]
17.3 Combined4148Mean Difference (IV, Fixed, 95% CI)3.84 [0.95, 6.73]
18 Stroke volume index: long term follow-up (≥12 months)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
18.1 Mean at endpoint262Mean Difference (IV, Fixed, 95% CI)6.52 [1.51, 11.54]
Analysis 1.1.

Comparison 1 Stem cells versus no stem cells, Outcome 1 Mortality (any).

Analysis 1.2.

Comparison 1 Stem cells versus no stem cells, Outcome 2 LVEF (%): Short-term follow-up (< 12 months).

Analysis 1.3.

Comparison 1 Stem cells versus no stem cells, Outcome 3 LVEF (%): Long-term follow-up (≥ 12 months).

Analysis 1.4.

Comparison 1 Stem cells versus no stem cells, Outcome 4 Adverse effects.

Analysis 1.5.

Comparison 1 Stem cells versus no stem cells, Outcome 5 Infarction.

Analysis 1.6.

Comparison 1 Stem cells versus no stem cells, Outcome 6 Rehospitalisation due to heart failure.

Analysis 1.7.

Comparison 1 Stem cells versus no stem cells, Outcome 7 Angina episodes per week: short term follow-up (<12 months).

Analysis 1.8.

Comparison 1 Stem cells versus no stem cells, Outcome 8 NYHA Classification: short-term follow-up (< 12 months).

Analysis 1.9.

Comparison 1 Stem cells versus no stem cells, Outcome 9 NYHA Classification: long-term follow-up (≥ 12 months).

Analysis 1.10.

Comparison 1 Stem cells versus no stem cells, Outcome 10 CCS class: short-term follow-up (< 12 months).

Analysis 1.11.

Comparison 1 Stem cells versus no stem cells, Outcome 11 Exercise capacity: short-term follow-up (< 12 months).

Analysis 1.12.

Comparison 1 Stem cells versus no stem cells, Outcome 12 Exercise capacity: long-term follow-up (≥ 12 months).

Analysis 1.13.

Comparison 1 Stem cells versus no stem cells, Outcome 13 LVESV (ml): short-term follow-up (< 12 months).

Analysis 1.14.

Comparison 1 Stem cells versus no stem cells, Outcome 14 LVESV (ml): long-term follow-up (≥ 12 months).

Analysis 1.15.

Comparison 1 Stem cells versus no stem cells, Outcome 15 LVEDV (ml): short-term follow-up (< 12 months).

Analysis 1.16.

Comparison 1 Stem cells versus no stem cells, Outcome 16 LVEDV (ml): long-term follow-up (≥ 12 months).

Analysis 1.17.

Comparison 1 Stem cells versus no stem cells, Outcome 17 Stroke volume index: short term follow-up (<12 months).

Analysis 1.18.

Comparison 1 Stem cells versus no stem cells, Outcome 18 Stroke volume index: long term follow-up (≥12 months).

Comparison 2. Cell dose: subgroup analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)16747Mean Difference (IV, Fixed, 95% CI)4.01 [3.28, 4.74]
1.1 Dose < 10⁷395Mean Difference (IV, Fixed, 95% CI)5.48 [2.74, 8.23]
1.2 Dose 10⁷ to 10⁸11426Mean Difference (IV, Fixed, 95% CI)4.12 [3.22, 5.01]
1.3 Dose 10⁸ to 10⁹5226Mean Difference (IV, Fixed, 95% CI)3.38 [2.00, 4.77]
2 NYHA Classification: short-term follow-up (< 12 months)10435Mean Difference (IV, Random, 95% CI)-0.63 [-1.08, -0.19]
2.1 Dose < 10⁷395Mean Difference (IV, Random, 95% CI)-0.53 [-1.20, 0.14]
2.2 Dose 10⁷ to 10⁸6264Mean Difference (IV, Random, 95% CI)-0.74 [-1.40, -0.07]
2.3 Dose 10⁸ to 10⁹276Mean Difference (IV, Random, 95% CI)-0.49 [-1.15, 0.18]
Analysis 2.1.

Comparison 2 Cell dose: subgroup analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Analysis 2.2.

Comparison 2 Cell dose: subgroup analysis, Outcome 2 NYHA Classification: short-term follow-up (< 12 months).

Comparison 3. Baseline cardiac function: subgroup analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)17677Mean Difference (IV, Fixed, 95% CI)4.69 [3.86, 5.52]
1.1 Baseline LVEF <30%4228Mean Difference (IV, Fixed, 95% CI)5.40 [3.81, 6.99]
1.2 Baseline LVEF 30-50%11386Mean Difference (IV, Fixed, 95% CI)4.36 [3.28, 5.45]
1.3 Baseline LVEF >50%263Mean Difference (IV, Fixed, 95% CI)4.65 [2.47, 6.84]
2 NYHA Classification: short-term follow-up (< 12 months)10417Mean Difference (IV, Random, 95% CI)-0.68 [-1.14, -0.22]
2.1 Baseline LVEF < 30%2144Mean Difference (IV, Random, 95% CI)-1.41 [-1.68, -1.14]
2.2 Baseline LVEF 30 - 50%8273Mean Difference (IV, Random, 95% CI)-0.48 [-0.82, -0.14]
Analysis 3.1.

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Analysis 3.2.

Comparison 3 Baseline cardiac function: subgroup analysis, Outcome 2 NYHA Classification: short-term follow-up (< 12 months).

Comparison 4. Route of cell administration: subgroup analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)18753Mean Difference (IV, Fixed, 95% CI)4.15 [3.41, 4.88]
1.1 Intracoronary9365Mean Difference (IV, Fixed, 95% CI)3.19 [2.19, 4.19]
1.2 Intramyocardial10388Mean Difference (IV, Fixed, 95% CI)5.30 [4.21, 6.40]
2 NYHA Classification: short-term follow-up (< 12 months)11486Mean Difference (IV, Random, 95% CI)-0.63 [-1.08, -0.19]
2.1 Intracoronary5255Mean Difference (IV, Random, 95% CI)-0.40 [-0.85, 0.04]
2.2 Intramyocardial6231Mean Difference (IV, Random, 95% CI)-0.83 [-1.43, -0.23]
Analysis 4.1.

Comparison 4 Route of cell administration: subgroup analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Analysis 4.2.

Comparison 4 Route of cell administration: subgroup analysis, Outcome 2 NYHA Classification: short-term follow-up (< 12 months).

Comparison 5. Cell type: subgroup analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)18764Mean Difference (IV, Fixed, 95% CI)3.89 [3.19, 4.59]
1.1 Mononuclear cells13606Mean Difference (IV, Fixed, 95% CI)3.77 [2.91, 4.63]
1.2 Circulating progenitor cells373Mean Difference (IV, Fixed, 95% CI)1.58 [-0.01, 3.17]
1.3 Haematopoietic progenitor cells240Mean Difference (IV, Fixed, 95% CI)8.44 [6.11, 10.78]
1.4 Mesenchymal stem cells145Mean Difference (IV, Fixed, 95% CI)6.0 [3.08, 8.92]
2 NYHA Classification: short-term follow-up (< 12 months)11504Mean Difference (IV, Random, 95% CI)-0.59 [-1.03, -0.16]
2.1 Mononuclear cells7351Mean Difference (IV, Random, 95% CI)-0.60 [-1.12, -0.08]
2.2 Circulating progenitor cells268Mean Difference (IV, Random, 95% CI)-0.02 [-0.40, 0.36]
2.3 Haematopoietic stem cells240Mean Difference (IV, Random, 95% CI)-0.88 [-3.04, 1.27]
2.4 Mesenchymal stem cells145Mean Difference (IV, Random, 95% CI)-1.2 [-1.58, -0.82]
Analysis 5.1.

Comparison 5 Cell type: subgroup analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Analysis 5.2.

Comparison 5 Cell type: subgroup analysis, Outcome 2 NYHA Classification: short-term follow-up (< 12 months).

Comparison 6. Participant diagnosis: subgroup analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)18746Mean Difference (IV, Fixed, 95% CI)4.22 [3.47, 4.97]
1.1 Chronic ischaemic heart disease9336Mean Difference (IV, Fixed, 95% CI)3.20 [2.20, 4.20]
1.2 Heart failure (secondary to ischaemic heart disease)7344Mean Difference (IV, Fixed, 95% CI)5.95 [4.67, 7.23]
1.3 Intractable/refractory angina266Mean Difference (IV, Fixed, 95% CI)4.02 [1.72, 6.31]
2 NYHA Classification: short-term follow-up (< 12 months)11486Mean Difference (IV, Random, 95% CI)-0.63 [-1.08, -0.19]
2.1 Chronic ischaemic heart disease5255Mean Difference (IV, Random, 95% CI)-0.40 [-0.85, 0.04]
2.2 Heart failure (secondary to ischaemic heart disease)5203Mean Difference (IV, Random, 95% CI)-0.92 [-1.57, -0.26]
2.3 Intractable/refractory angina128Mean Difference (IV, Random, 95% CI)-0.38 [-0.75, -0.01]
Analysis 6.1.

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Analysis 6.2.

Comparison 6 Participant diagnosis: subgroup analysis, Outcome 2 NYHA Classification: short-term follow-up (< 12 months).

Comparison 7. Method of measurement: sensitivity analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)16 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Measured by MRI9298Mean Difference (IV, Fixed, 95% CI)3.35 [2.17, 4.53]
1.2 Measured by left ventricular angiography5186Mean Difference (IV, Fixed, 95% CI)2.91 [1.35, 4.47]
1.3 Measured by SPECT3124Mean Difference (IV, Fixed, 95% CI)5.47 [2.80, 8.14]
1.4 Measured by echocardiography6314Mean Difference (IV, Fixed, 95% CI)4.78 [3.36, 6.21]
Analysis 7.1.

Comparison 7 Method of measurement: sensitivity analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Comparison 8. Risk of bias: sensitivity analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)14 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Low risk of selection bias6218Mean Difference (IV, Fixed, 95% CI)3.27 [1.69, 4.84]
1.2 Low risk of performance bias9320Mean Difference (IV, Fixed, 95% CI)5.11 [3.89, 6.33]
1.3 Low risk of detection bias14588Mean Difference (IV, Fixed, 95% CI)4.58 [3.71, 5.45]
Analysis 8.1.

Comparison 8 Risk of bias: sensitivity analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Comparison 9. Co-intervention/comparator sensitivity analysis
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 LVEF (%): short-term follow-up (< 12 months)18 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Placebo9373Mean Difference (IV, Fixed, 95% CI)3.33 [2.25, 4.41]
1.2 No placebo8343Mean Difference (IV, Fixed, 95% CI)5.05 [4.02, 6.09]
1.3 No co-intervention received6297Mean Difference (IV, Fixed, 95% CI)4.31 [2.97, 5.64]
1.4 Co-intervention: CABG5158Mean Difference (IV, Fixed, 95% CI)6.51 [4.76, 8.26]
1.5 Co-intervention: PCI7291Mean Difference (IV, Fixed, 95% CI)3.35 [2.30, 4.40]
Analysis 9.1.

Comparison 9 Co-intervention/comparator sensitivity analysis, Outcome 1 LVEF (%): short-term follow-up (< 12 months).

Appendices

Appendix 1. Search strategies

THE COCHRANE LIBRARY

#1 STEM CELL TRANSPLANTATION explode all trees (MeSH)
#2 HEMATOPOIETIC STEM CELL MOBILIZATION single term (MeSH)
#3 STEM CELLS explode all trees (MeSH)
#4 CELL TRANSPLANTATION single term (MeSH)
#5 haematopoietic or hematopoietic or haematopoetic or hematopoetic or hemopoietic or haemopoietic or marrow NEAR cell* or stem cell* or progenitor cell* or precursor cell* or cell* therapy
#6 ((myoblast* or cell*) NEAR (transplant* or graft* or implant*))
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 MYOCARDIAL ISCHEMIA explode all trees (MeSH)
#9 HEART FAILURE explode all trees (MeSH)
#10 HEART DISEASES single term (MeSH)
#11 (myocardial or myocardium or subendocardial or transmural or cardiac or cardial or coronary or heart) NEAR (infarct* or postinfarct* or hypoxi* or anoxi* or failure* or decompensation or insufficien*)
#12 heart disease* or coronary disease* or IHD or CIHD
#13 chronic myocardial dysfunction or angina or stenocardia
#14 (ischemi* or ischaemi*) NEAR (myocardium or myocardial or heart or coronary or cardiac or cardial or subendocardial or cardiomyopath*)
#15 (artery occlusion* or artery disease* or arterioscleros* or atheroscleros*) NEAR coronary
#16 (heart or cardiac or cardial or myocardium or myocardial) NEAR (repair* or reparation or improve* or regenerat*)
#17 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16
#18 #7 AND #17
#19 (cellular NEXT cardiomyoplast*) or (cardiomyocyte* NEAR transplant*) or (intramyocardial* NEAR (transplant* or stem or bone marrow)) or (transendocardial* NEAR stem NEXT cell*) or (intracoronary NEAR progenitor NEXT cell*) or (transcoronary NEAR transplant*)
#20 #18 or #19 

MEDLINE (Ovid)

1. CELL TRANSPLANTATION/
2. exp STEM CELL TRANSPLANTATION/
3. BONE MARROW TRANSPLANTATION//
4. exp STEM CELLS/
5. (haematopoietic or hematopoietic or haematopoetic or hematopoetic or hemopoietic or haemopoietic or (marrow adj2 cell*) or stem cell* or progenitor cell* or precursor cell* or cell* therapy or bone marrow).ti,ab.
6. ((mesenchymal or stromal) AND marrow).ti,ab.
7. (cell*) adj3 (transplant* or graft* or implant*)).ti,ab
8. cell transplantation.jn. or cell stem cell.jn. or stem cell reviews.jn. or bone marrow transplantation.jn.
9. or/1-8
10. exp MYOCARDIAL ISCHEMIA/
11. exp HEART FAILURE/
12. HEART DISEASES/
13. ((myocardial or myocardium or subendocardial or transmural or cardiac or cardial or coronary or heart) adj2 (infarct* or postinfarct* or hypoxi* or anoxi* or failure* or decompensation or insufficien*)).ti,ab.
14. (heart disease* or coronary disease* or IHD or CIHD).ti,ab.
15. (myocardial dysfunction or angina or stenocardia).ti,ab.
16. ((ischemi* or ischaemi*) adj2 (myocardium or myocardial or heart or coronary or cardiac or cardial or subendocardial or cardiomyopath*)).ti,ab.
17. ((end stage or endstage) adj cardiomyopath*).ti,ab.
18. ((artery occlusion* or artery disease* or arterioscleros* or atheroscleros*) adj2 coronary).ti,ab.
19. ((heart or cardiac or cardial or myocardium or myocardial) adj3 (repair* or reparation or improve* or regenerat*)).ti,ab.
20. or/10-19
21. 9 and 20
22. ((cellular adj cardiomyoplast*) or (cardiomyocyte* adj5 transplant*) or (intramyocardial* adj6 (transplant* or stem or bone marrow)) or (transendocardial* adj5 stem adj cell*) or (intracoronary adj5 progenitor adj cell*) or (transcoronary adj3 transplant*)).mp.
23. 21 or 22 

EMBASE (Ovid)

1. exp CELL THERAPY/
2. exp STEM CELL/
3. BONE MARROW CELL/
4. ((mesenchymal or stromal) AND marrow).ti,ab.
5. (haematopoietic or hematopoietic or haematopoetic or hematopoetic or hemopoietic or haemopoietic or marrow adj2 cell* or stem cell* or progenitor cell* or precursor cell* or cell* therapy or bone marrow).ti,ab.
6. (cell* adj3 (transplant* or graft* or implant*)).ti,ab.
7. cell transplantation.jn. or cell stem cell.jn. or stem cell reviews.jn.
8. or/1-7
9. exp ISCHEMIC HEART DISEASE/
10. exp HEART FAILURE/
11. exp MYOCARDIAL DISEASE/
12. ((myocardial or myocardium or subendocardial or transmural or cardiac or cardial or coronary or heart) adj2 (infarct* or postinfarct* or hypoxi* or anoxi* or failure* or decompensation or insufficien*).ti,ab.
13. (heart disease* or coronary disease* or IHD or CIHD).ti,ab.
14. (chronic myocardial dysfunction or angina or stenocardia).ti,ab.
15. ((ischemi* or ischaemi*) adj2 (myocardium or myocardial or heart or coronary or cardiac or cardial or subendocardial or cardiomyopath*)).ti,ab.
16. ((artery occlusion* or artery disease* or arterioscleros* or atheroscleros*) adj2 coronary).ti,ab.
17. ((end stage or endstage) adj cardiomyopath*).ti,ab.
18. ((heart or cardiac or cardial or myocardium or myocardial) adj3 (repair* or reparation or improve* or regenerat*)).ti,ab.
19. or/9-18
20. 8 AND 19
21. ((cellular adj cardiomyoplast*) or (cardiomyocyte* adj5 transplant*) or (intramyocardial adj6 (transplant* or stem or bone marrow)) or (transendocardial adj5 stem adj cell*) or (intracoronary adj5 progenitor adj cell*) or (transcoronary adj3 transplant*)).mp.
22. 20 or 21 

CINAHL (EBSCOhost)

S1 (MH "Cell Transplantation+")
S2 (MH "Stem Cells+")
S3 TI ( (haematopoietic OR hematopoietic OR haematopoetic OR hematopoetic OR hemopoietic OR haemopoietic OR (marrow N2 cell*) OR "stem cell*" OR "progenitor cell*" OR "precursor cell*" OR "cell* therapy" OR "bone marrow") ) OR AB ( (haematopoietic OR hematopoietic OR haematopoetic OR hematopoetic OR hemopoietic OR haemopoietic OR (marrow N2 cell*) OR "stem cell*" OR "progenitor cell*" OR "precursor cell*" OR "cell* therapy" OR "bone marrow") )
S4 TX ((mesenchymal or stromal) AND marrow)
S5 TI ( ((cell* N3 transplant*) OR (cell* N3 graft*) OR (cell* N3 implant*)) ) OR AB ( ((cell* N3 transplant*) OR (cell* N3 graft*) OR (cell* N3 implant*)) )
S6 S1 OR S2 OR S3 OR S4 OR S5
S7 (MH "Heart Diseases") OR (MH "Heart Failure+") OR (MH "Heart Valve Diseases+") OR (MH "Myocardial Diseases+") OR (MH "Myocardial Ischemia+")
S8 TI ( (myocardial or myocardium or subendocardial or transmural or cardiac or cardial or coronary or heart) N6 (infarct* or postinfarct* or hypoxi* or anoxi* or failure* or decompensation or insufficien*) ) OR AB ( (myocardial or myocardium or subendocardial or transmural or cardiac or cardial or coronary or heart) N6 (infarct* or postinfarct* or hypoxi* or anoxi* or failure* or decompensation or insufficien*) )
S9 TI ( ("heart disease*" or "coronary disease*" or IHD or CIHD) ) AND AB ( ("heart disease*" or "coronary disease*" or IHD or CIHD) )
S10 TI ( ("chronic myocardial dysfunction" OR angina OR stenocardia) ) OR AB ( ("chronic myocardial dysfunction" OR angina OR stenocardia) )
S11 TI ( ((ischemi* or ischaemi*) N5 (myocardium or myocardial or heart or coronary or cardiac or cardial or subendocardial or cardiomyopath*)) ) OR AB ( ((ischemi* or ischaemi*) N5 (myocardium or myocardial or heart or coronary or cardiac or cardial or subendocardial or cardiomyopath*)) )
S12 TI ( ((chronic or artery occlusion* or artery disease* or arterioscleros* or atheroscleros*) AND coronary) ) OR AB ( ((chronic or artery occlusion* or artery disease* or arterioscleros* or atheroscleros*) AND coronary) )
S13 TI ( ((heart or cardiac or cardial or myocardium or myocardial) AND (repair* or reparation or improve* or regenerat*)) ) OR AB ( ((heart or cardiac or cardial or myocardium or myocardial) AND (repair* or reparation or improve* or regenerat*)) )
S14 S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13
S15 S6 AND S14
S16 TX (transplant* N5 (cardiomyocyte* or transcoronary)) or (cellular N2 cardiomyoplast*) or (intramyocardial* N6 (transplant* or stem or marrow)) or (transendocardial* N5 stem cell*) or (intracoronary N5 progenitor cell*)
S17 S15 OR S16

TRANSFUSION EVIDENCE LIBRARY (www.transfusionevidencelibrary.com)

("marrow cell*" OR "stem cell*" OR "progenitor cell*" OR "precursor cell*") AND (infarct* OR coronar* OR myocard* OR heart OR cardiac* OR cardiomyo* OR intramyocardial* OR ischemi* OR ischaemi* OR angina)

PubMed (epublications only)

(stem[TI] OR marrow[TI] OR progenitor[TI] OR precursor[TI] OR cell[TI] OR cells[TI]) AND (infarct*[TI] OR coronar*[TI] OR heart*[TI] OR myocard*[TI] OR cardial[TI] OR cardiac[TI] OR transmural*[TI] OR ischemia[TI] OR ischemic[TI] OR subendocardial[TI] OR cardiomyopath*[TI] OR angina[TI]) AND (random* OR blind* OR control group* OR controlled OR placebo OR trial) AND (publisher[sb] NOT pubstatusnihms)

LILACS

("marrow cell$" OR "stem cell$" OR "progenitor cell$" OR "precursor cell$") AND (infarct$ OR coronar$ OR myocard$ OR heart OR cardiac$ OR cardiomyo$ OR intramyocardial$ OR ischemi$ OR ischaemi$ OR angina) AND (random$ OR blind$ OR control$ OR placebo$ OR trial)

KoreaMed & PakMediNet

(stem or marrow or progenitor or precursor or cell or cells) AND random*

IndMed

((marrow OR stem OR progenitor OR precursor) AND (infarct$ OR coronar$ OR myocard$ OR heart OR cardiac$ OR cardiomyo$ OR intramyocardial$ OR ischemi$ OR ischaemi$) AND (random$ OR blind$ OR control$ OR placebo$ OR trial))

ISRCTN Register (Current Controlled Trials)

("stem cells" or "stem cell" or marrow or "progenitor cells" or "precursor cells") and (infarction or infarct or coronary or myocardial or heart or myocardium or cardial or transmural or ischemia or ischemic or subendocardial or cardiomyopathy OR angina)

ClinicalTrials.gov

Study Type: Intervention Studies
Conditions: heart failure
Search Terms: marrow OR stem OR progenitor OR precursor OR myoblast OR myocell OR mesenchymal OR stromal

WHO ICTRP

Title: marrow OR stem OR progenitor OR precursor OR myoblast OR myocell OR mesenchymal OR stromal
Condition: heart OR cardiac OR myocardial
Recruitment Status: ALL

Contributions of authors

Sheila Fisher: methodology expert, eligibility screening, data extraction and quality assessment, data analysis and preparation of the final report.

Carolyn Doree: information specialist, design and implementation of search strategies, initial eligibility screening and data verification, comments on the final report.

Susan Brunskill: methodology expert, development of the protocol, comments on the final report.

Anthony Mathur: clinical content expert (clinical cardiology), preparation of the final report.

David P Taggart: clinical content expert (cardiac surgery), comments on the final report.

Enca Martin-Rendon: scientific content expert, eligibility screening, data extraction and quality assessment, preparation of the final report. Corresponding author who takes the global responsibility of this review.

Declarations of interest

Professor Anthony Mathur is the lead investigator of the ongoing BAMI trial. Dr Martin-Rendon works at the Stem Cell Research Laboratory, NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.

Sources of support

Internal sources

  • NHS Blood and Transplant, Research and Development., UK.

  • William Harvey Research Institute, UK.

External sources

  • NIHR, UK.

    National Institute for Health Research (NIHR) under its Programme Grant Scheme (RP-PG-0310-1001, EMR).

  • Oxford BRC, UK.

    Oxford Biomedical Research Centre Programme (SAF, CD and SJB).

Differences between protocol and review

Several outcomes listed in the protocol for this review were based on those of a previous review of AMI (Clifford 2012a) and were not as relevant for IHD and congestive heart failure. Secondary outcomes were therefore restricted to those most relevant to this review. In particular, we considered re-operation, length of hospital stay, restenosis, target vessel revascularisation and wall motion score index to be less relevant to the current review; they were rarely reported in individual studies and were not included in this review.

Difference in time points for the outcomes  - new stratifications used for the outcomes (as detailed in the Types of outcome measures section).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ang 2008

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: British Heart Foundation (grant PG04050).

Study setting: Leicester, UK.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: 21 intramyocardial (IM) 21 intracoronary (IC), 21 Control (C).
Number (N) of participants analysed (primary outcome) in each arm: 17 IM, 16 IC, 15 C.

Participants

Description: Hospitalised participants undergoing elective cardiac surgery with at least 1 myocardial scar.
Age distribution (SD) in each arm: 64.7 (8.7) years IM, 62.1 (8.7) years IC, 61.3 (8.3) years C.
Sex (% male) in each arm: 71.4% IM, 90.5% IC, 90% C.

Number of diseased vessels: multivessel.
Time from symptom onset to initial treatment: At least 6 weeks.
Statistically significant baseline imbalances between the groups? No

Interventions

Intervention arms: IM and IC.
Type of stem cells: BMSC (mononuclear fraction)
Summary of stem cell isolation and type and route of delivery: Bone marrow aspiration followed by density gradient centrifugation to enrich in mononuclear cells, infused via the coronary artery (IC) or injected into the myocardium (IM).
Dose of stem cells: 86 (56) x 10⁶ cells IM and 115 (73) x 10⁶ cells IC.
Timing of stem cell procedure: Concomitant to CABG

G-CSF details: Not applicable

Comparator arm: Control, no placebo

Outcomes Primary outcomes: Improvement in systolic function of scar segments 6 mths after treatment. 
Secondary outcomes: Reductions in infarct size, global end-diastolic volume and end-systolic volume, and improvement in stroke volume and LVEF.  Postoperative complications, troponin I levels within 24 hours of surgery and clinical evaluation (assessment of functional status and adverse events).
Outcome assessment points: Baselina and 6 months
Method(s) of outcome measurement: MRI
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and clinicians were not blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcomes assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with attrition rates similar in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Assmus 2006

Methods

Type of study: Cross-over RCT with 3 arms.
Type of publication: Full paper
Source of funding:Supported by the Deutsche Forschungsgemeinschaft (FOR 501-1: WA 146/2-1) The Foundation Leducq Transatlantic Network of excellence for Cardiac Regeneration, The European Union European Vascular Genomics Network (LSHM-CT-2003-503254) and the Alfried Krupp Stiftung. 

Study setting:Frankfurt, Germany
Number of centres: One
Length of follow-up: 3 months
Number (N) of participants randomised to each arm: 28 in BMSC arm; 24 in CPC arm and 23 in control arm.
Number (N) of participants analysed (primary outcome) in each arm: 24 in BMSC arm; 19 in CPC arm and 18 in control arm.

Participants

Description: Hospitalised participants who have suffered from MI at least 3 months previously.
Age distribution in each arm: 59 ± 12 years old in BMSC arm; 54 ± 12 years old in CPC arm and 61 ± 9 years old in control arm
Sex (% male) in each arm: 89% in BMSC arm; 79% in CPC arm and 100% in control arm.

Number of diseased vessels: 1 (n = 7), 2 (n = 13), 3 (n = 8) in BMSC arm; 1 (n = 7), 2 (n = 4), 3 (n = 12) in CPC arm and 1 (n = 2), 2 (n = 9), 3 (n = 12) in control arm
Time from symptom onset to initial treatment: Previous MI at least 3 months earlier. 100% participants with previous MI.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC and CPCs
Type of stem cells: BMSC, bone marrow mononuclear cells; CPCs, circulating progenitor cells.
Summary of stem cell isolation and type and route of delivery: BMSC arm: 50 ml of bone marrow aspirate was obtained under local anaesthesia on the morning of cell transplantation. Mononuclear cells were isolated by Ficoll-gradient centrifugation. CPC arm: Mononuclear cell fraction was isolated by Ficoll-gradient centrifugation of 270 mL of venous blood and cultured for 3 days ex vivo. In both arms of the trial cells were delivered intracoronarily.
Dose of stem cells: BMSC arm: 2.05 ± 1.1 x 10⁸ mononuclear cells. On average less than 1% were CD34-positive cells. CPC arm: 2.2 ± 1.1 x 10⁷ mononuclear cells. No measure of CD34-positive cells in this fraction.
Timing of stem cell procedure: At least 3 months after last MI. In some cases concomitant PCI.

G-CSF details: No G-CSF administered.

Comparator arm: No cell infusion.

Outcomes Primary outcomes: Absolute change in global LVEF as measured by quantitative LV angiography 3 months after cell infusion.
Secondary outcomes: 1. Quantitative variables relating to the regional LV function of the target area, as well as LV volumes derived from serial LV angiograms.
2. Functional status assessed by NYHA classification.
3. Event-free survival defined as freedom from death, MI, stroke or rehospitalisation for worsening heart failure.
4. Causes of rehospitalisation.
Outcome assessment points: Baseline and 3 months.
Method(s) of outcome measurement: LV angiography and MRI.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was performed using computerised simple random allocation with known N. No blockwise randomisation was performed.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
High riskClinicians were not blinded. Blinding of participants was not reported.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuantitative analysis of angiograms was performed by an investigator who was blinded to the individual participant's treatment.  The same for the MRI analysis.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Assmus 2012

Methods

Type of study: Parallel RCT.
Type of publication: Abstract.
Source of funding: Not reported.

Study setting: Germany.
Number of centres: One.
Length of follow-up: 4 months.
Number (N) of participants randomised to each arm: Not reported.
Number (N) of participants analysed (primary outcome) in each arm: 37 in BMSC arm; 32 in control arm.

Participants

Description: Hospitalised participants presenting post-infarction heart failure.
Age distribution in each arm: Not reported.
Sex (% male) in each arm: Not reported.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: Not reported.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC and shock wave.
Type of stem cells: Not reported.
Dose of stem cells: BMSC arm: Not reported.
Timing of stem cell procedure: 24 hours following shock wave.

G-CSF details: No G-CSF administered.

Comparator arm: No cell infusion, only shock wave.

Outcomes Primary outcomes: None reported/
Secondary outcomes: LVEF, NYHA, AE, extent of myocardial scar tissue, systolic wall thickening, mortality, hospitalisation.
Outcome assessment points: Baseline and 4 months.
Method(s) of outcome measurement: MRI for LVEF.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskThe trial was reported as "double-blind" but it was unclear whether this included clinicians and/or participants.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskThe trial was reported as "double-blind" but it was unclear whether this included clinicians and/or participants.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe number randomised to each treatment arm was not stated and attrition rates could not be determined.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Chen 2006

Methods

Type of study: Parallel RCT.

Type of publication: Full paper.
Source of funding: Not reported.

Study setting: China.
Number of centres: One.
Length of follow-up: 12 months.
Number (N) of participants randomised to each arm: 24 in BMSC arm and 24 in control arm.
Number (N) of participants analysed (primary outcome) in each arm: 22 in BMSC arm; 23 in control arm.

Participants

Description: Hospitalised participants with severe ischaemic heart failure due to an isolated chronic occluded left anterior descending artery.
Age distribution in each arm: 59.3 ± 6.8 years old in BMSC arm; 57.8 ± 7.2 years old in control arm.
Sex (% male) in each arm: 88% in BMSC arm; 92% in control arm.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: 14 days following successful PCI.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC and control.
Type of stem cells: Mesenchymal stem cells. 60 ml of autologous bone marrow were aspirated under local anaesthesia from the ilium of all participants during the morning of the 8th day after the PCI procedure and were then cultured for 7 days. BM mesenchymal stem cells were harvested and washed three to four times with heparinised saline. 2 hours before transplantation, the stem cell suspension was mixed with heparin, filtered and prepared for implantation. Cell viability was > 92%.
Dose of stem cells: BMSC arm: 5 x 10⁶ cells
Timing of stem cell procedure: 14 days following successful PCI and 7 days after bone marrow aspiration.

G-CSF details: No G-CSF administered.

Comparator arm: Not described.

Outcomes Primary outcomes: None reported
Secondary outcomes: reversible defects, metabolic equivalents, exercise, LVEF, NYHA, mortality.
Outcome assessment points: Baseline and 12 months.
Method(s) of outcome measurement: SPECT.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
High riskParticipants and clinicians were not blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Erbs 2005

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Supported by Heart Center Leipzig GmbH, University of Leipzig.

Study setting: Leizpig, Germany.
Number of centres: One.
Length of follow-up: 15 months.
Number (N) of participants randomised to each arm: BMSC arm: 14; Control arm: 14.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 12; Control arm: 11.

Participants

Description: Participants with chronic total artery occlusion with clinical signs of myocardial ischaemia and local wall motion abnormalities.
Age distribution in each arm: BMSC arm: 63 ± 7 years old; Control arm: 61 ± 9 years old.
Sex (% male) in each arm: BMSC arm: 71%; Control arm: 86%.

Number of diseased vessels: BMSC arm: 1 (n = 8), 2 (n = 4), 3 (n = 2); Control arm: 1 (n = 6), 2 (n = 5), 3 (n = 3).
Time from symptom onset to initial treatment: Complete total obstruction - defined as an obstruction of a native coronary artery for more than 30 days with no luminal continuity and with TIMI flow grade 0 or 1.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: mobilised bone marrow mononuclear cells.
Summary of stem cell isolation and type and route of delivery: All participants subcutaneously injected twice a day with filgrastin (G-CSF, 300 microg) over 4 days in order to increase the amount of CPCs in the blood. At day 4, 400 ml of venous blood were collected from all participants, MNC were purified and ex vivo-cultured for 4 days in endothelial-specific medium to  select CPCs. MNCs were isolated from 400 ml of venous blood by density gradient centrifugation (Histopaque-1077). Immediately after isolation, total MNC were plated on gelatine-coated cell culture flasks with a cell density of 1 x 10⁶ cells/cm². Cells were maintained for 4 days in endothelial basal medium supplemented with EGM SingleQuots and 10% human serum, collected from each individual participant.  Additionally the cell culture medium was supplemented with ascorbic acid (final concentration 75 ng/mL) and hydrocortisone (0.2 microg/mL). After 4 days of culture nonadherent cells were removed by a thorough washing with PBS and the adherent cells were detached with trypsin/EDTA. The collected cells were washed twice with PBS containing 2 mmol/L EDTA and resuspended in a final volume of 20 ml physiological NaCl supplemented with 10% autologous participant serum. Cells were administered intracoronarily.
Dose of stem cells: 69 ± 14 x 10⁶ CPCs (range 22 x 10⁶ to 200 x 10⁶).
Timing of stem cell procedure: 10 ± 1 days following successful recanalisation.

G-CSF details: 300mg of G-CSF administered for 4 days to all participants.

Comparator arm: Placebo, cell-free serum solution.

Outcomes Primary outcomes: LV function
Secondary outcomes: Assessment of coronary endothelial function, myocardial viability (number of myocardial segments with hybernation), regional wall motion, LV mass (myocardial mass; infarct size). Clinical outcomes, restenosis, coronary endothelium function, myocardial viability, number of hibernating segments in myocardium.
Outcome assessment points: Baseline, 3 and 15 months.
Method(s) of outcome measurement: MRI.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskNeither the interventionalist nor the clinical investigator were aware of whether participants received CPCs or serum. All participants received G-SCF and cells were isolated from all participants.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskImage analysis assessors remained blinded after the results at 3 months follow-up.  Other assessors were blinded to 3 months only.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Hendrikx 2006

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Not reported.

Study setting: Hasselt, Belgium.
Number of centres: One.
Length of follow-up: 4 months.
Number (N) of participants randomised to each arm: BMSC arm: 11; Control arm: 12.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 10; Control arm: 10.

Participants

Description: Elective CABG surgery; transmural myocardial infarction on ECG and akinesia or dyskinesia in part of the left ventricle as shown by angiography.
Age distribution in each arm: BMSC arm: 63.2 ± 8.5 years old; Control arm: 66.8 ± 9.2 years old.
Sex (% male) in each arm: BMSC arm: 100%; Control arm: 70%.

Number of diseased vessels: BMSC arm: 1 (n = 0), 2 (n = 2), 3 (n = 8); Control arm: 1 (n = 1), 2 (n = 2), 3 (n = 7).
Time from symptom onset to initial treatment: BMSC arm: 217 (162) days and control arm: 213 (145) days between occurrence of MI and time of CABG (and treatment).
Statistically significant baseline imbalances between the groups? No.

Interventions

articipanIntervention arm: BMSC.
Type of stem cells: BMSC, bone marrow mononuclear cells.
Summary of stem cell isolation and type and route of delivery: 40 mL of bone marrow was aspirated under local anaesthesia from the participant's iliac crest, the day before surgery. BMSC were immediately isolated by density gradient centrifugation using Lymphoprep. Isolated cells were washed twice with saline and subsequently resuspended in X-Vivo 15 medium (Cambrex) supplemented with 2% autologous serum. This cell suspension was transferred to Teflon bags at a concentration of approximately 1 x 10⁶ cells/mL for overnight cultivation. The next day, cells were harvested and washed 3 times before finally being suspended in 10 mL heparinised saline. 10 mL of cell suspension were injected into the border zone of the infarct with 29-gauge myoinjector syringes containing 0.5 mL of cell suspension. Multiple punctures were performed with prevent needles to make injections parallel to the epicardium and avoid delivery of cells into the ventricular cavity. 
Dose of stem cells: 60.25 (31.35) x 10⁶ cells with > 95% viability and over 73% recovery. Containing 1.42 (0.99)% CD34-positive cells and 76.37 (44.47) CFU-GM/ 10⁵ mononuclear cells.
Timing of stem cell procedure: Approximately 24 hours following bone marrow aspiration; 217 (162) days post-AMI.

G-CSF details: None.

Comparator arm: Placebo; a similar volume of heparinised saline was injected in the control group.

Outcomes Primary outcomes: global LVEF change and regional wall thickening changes in the infarct area.
Secondary outcomes:Changes in metabolic activity measured by thallium scintigraphy.
Outcome assessment points: Baseline and 4 months.
Method(s) of outcome measurement: MRI.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk1:1 randomisation was carried out using sequentially-numbered sealed envelopes.
Allocation concealment (selection bias)Low riskSealed envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Both groups had bone marrow aspirated. The BM group had bone marrow isolated the day before surgery from the iliac crest. The control group had bone marrow aspirated from the sternum during the operation.

The surgeon conducting surgery was unaware whether cells or only saline was injected.

Blinding of outcome assessment (detection bias)
All outcomes
Low riskCardiac MR images were analysed by an investigator blinded to treatment assignment. For Thallium Scintigraphy, 2 investigators independently analysed data, and were blinded to treatment assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Honold 2012

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Not reported.

Study setting: Germany.
Number of centres: One.
Length of follow-up: 60 months.
Number (N) of participants randomised to each arm: BMSC arm: 23; Control arm: 10.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 23; Control arm: 9.

Participants

Description: Hospitalised participants with CAD and a previous MI at least 3 months prior to cell therapy with a well demarcated LV regional wall motion abnormality.
Age distribution in each arm: BMSC arm: 53.4 ± 12.3 years old; Control arm: 58.8 ± 7.3 years old.
Sex (% male) in each arm: BMSC arm: 82%; Control arm: 100%.

Number of diseased vessels: BMSC arm: 1 (n = 10), 2 (n = 6), 3 (n = 6); Control arm: 1 (n = 4), 2 (n = 2), 3 (n = 4).
Time from symptom onset to initial treatment: At least 3 months from previous MI. 
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC
Type of stem cells: EPC from bone marrow aspirates.
Summary of stem cell isolation and type and route of delivery: G-CSF was administered to the participants for 5 days. 270 ml of peripheral blood was drawn. Mononuclear cells were isolated using a Ficoll gradient centrifugation and cells were resuspended in X-vivo 15 medium with 1 ng/ml carrier-free human recombinant VEGF, atorvastin and 20% human serum drawn from each individual participant. Cells were cultured ex vivo for 4 days to enrich in endothelial progenitor cells (uptake of LDL).
Dose of stem cells: 29 ± 12 x 10⁶.
Timing of stem cell procedure: % days following G-SCF administration and 4 days following bone marrow aspiration and cell culture.

G-CSF details: Yes, 5 days prior to cell isolation.

Comparator arm: no placebo.

Outcomes Primary outcomes: Safety and efficacy.
Secondary outcomes: Global and regional LV function and volumes after 3 months, determined by both LV angiography and MRI. Clinical parameters like functional NYHA class, cardiopulmonary exercise testing, and N-terming aprohormone of BNP serum levels were obtained during a 5-year follow-up period.
Outcome assessment points: Baseline and 60 months.
Method(s) of outcome measurement: MRI.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of clinicians and participants was not reported.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskMRI independent observers were blinded; blinding was not reported for other outcomes.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Hu 2011

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Key project in the National Science and Technology Pilar programme during the Eleventh 5-year plan period (2006BAJ01A09), Basic scientific research fund of the National Scientific Institute 2009-2011.

Study setting: Beijing, China.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 31; Control arm: 29.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 31; Control arm: 28.

Participants

Description: People between 18 and 75 years of age, suitable for CABG with CHF due to severe ischaemic cardiomyopathy.
Age distribution in each arm: BMSC arm: 56.6 ± 9.7 years old; Control arm: 58.3 ± 8.9 years old.
Sex (% male) in each arm: 93.3% (both arms pooled).

Number of diseased vessels: BMSC arm: 3; Control arm: 3.
Time from symptom onset to initial treatment: At least 3 month from last MI.
Statistically significant baseline imbalances between the groups? No

Interventions

Intervention arm: BMSC
Type of stem cells: BMSC from bone marrow aspirates.
Summary of stem cell isolation and type and route of delivery: After anaesthesia but before CABG, 60 ml of BM was aspirated from the participant's iliac crest and diluted with normal saline solution. The mononuclear cells were isolated using Ficoll density gradient centrifugation according to good manufacturing practice regulations and resuspended in 10 ml of saline solution. The cell suspension was filtered by a 70-um cell strainer before transplantation. The cells were counted under a light microscope and the viability was assessed by trypan blue dye. The final suspension of BMMNCs contained 10⁷ ml MN cells. Cells were delivered via the grafted vessel (saphenous vein graft).
Dose of stem cells: mean 13.17 ± 10.66 x 10⁷.
Timing of stem cell procedure: Within 24 hours and during CABG.

G-CSF details: No.

Comparator arm: The placebo solution was a mixture of 8 ml of saline solution and 2 ml of the participant's own serum.

Outcomes Primary outcomes: Changes in LVEF.
Secondary outcomes: LVEDV index (MRI); LVESV index (MRI); wall motion score index (Echo); perfusion score (SPECT), 6-mins walking test and BNP value.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: MRI.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA randomisation table was generated by statistical software.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe study processes were blinded to surgeons, participants, co-ordinators and investigators who were responsible for participant assessments. 
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe study processes were blinded to surgeons, participants, co-ordinators and investigators who were responsible for participant assessments. 
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Kang 2006

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Supported by a grant from Stem Cell Research Center, Republic of Korea (SC3150,  to Dr Y-B Park).

Study setting: Seoul, Korea.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 20; Control arm: 20.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 15; Control arm: 16.

Participants

Description: People with new STEMI over 14 days ago who were successfully revascularised with DES (Drug Eluting Stents) in the culprit lesion (defined in the paper as 'old MI').
Age distribution in each arm: BMSC arm: 59.8 ± 9.7 years old; Control arm: 60.1 ± 6.8 years old.
Sex (% male) in each arm: BMSC arm: 94%; Control arm: 81%.

Number of diseased vessels: BMSC arm: 1 (n = 6); 2 (n = 7); 3 (n = 3); Control arm: 1 (n = 5); 2 (n = 3); 3 (n = 8).
Time from symptom onset to initial treatment: > 14 days post-MI.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: Mobilised BMSC using G-SCF for 3 days.
Summary of stem cell isolation and type and route of delivery: Following G-CSF treatment for 3 days by apheresis. Peripheral blood  stem cells were mobilised by daily injection of G-CSF at 10 μg/Kg body weight for 3 days. PBSC were then collected on day 4 with COBE spectra apheresis system using mononuclear cell collection methods. Cell dose infused were 1 - 2 x 10⁹ monocytes per participant. Cells were infused via the coronary artery using an over-the-wire balloon catheter. 
Dose of stem cells: 1 - 2 x 10⁹ monocytes per participant.
Timing of stem cell procedure: BMSC arm: 514 ± 524 days after revascularisation; Control arm: 960 ± 832 days after revascularisation.

G-CSF details: Daily injection of G-CSF at 10 μg/Kg body weight for 3 days.

Comparator arm: Control participants did not received G-CSF or placebo.

Outcomes Primary outcomes: The primary endpoint to evaluate efficacy was the change in LVEF.
Secondary outcomes: Changes in LV volume, myocardial perfusion measured by coronary flow reserve (CFR), and the development of major adverse cardiac events: death, new MI, revascularisation, or hospitalisation because of aggravation of ischaemia or heart failure.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: MRI.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA randomisation table was used.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAngiography conducted by independent blinded specialist but other blinding not reported ("after randomisation, study processes were not blinded").
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Losordo 2007

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Supported in part by NIH grants and by a grant from Baxter Healthcare. Biosense-Webster provided the mapping and injection catheters for this study at no extra cost.

Study setting: USA.
Number of centres: multicentre.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC HD arm: 6; BMSC MD arm: 6; BMSC LD arm: 6 and Control arm: 6.
Number (N) of participants analysed (primary outcome) in each arm: BMSC HD arm: 6; BMSC MD arm: 6; BMSC LD arm: 6 and Control arm: 6.

Participants

Description: Participants with CCS class III - IV symptomatic of chronic refractory angina.
Age distribution in each arm: Mean 62.4 (range 48 to 84 years) for all groups.
Sex (% male) in each arm: 80% for all arms.

Number of diseased vessels: not reported.
Time from symptom onset to initial treatment: not reported, not applicable.
Statistically significant baseline imbalances between the groups? None reported.

Interventions

Intervention arm: Low Dose (LD), Medium Dose (MD) and High Dose (HD) of CD34+ cells.
Type of stem cells: CD34+ cells from mobilised peripheral blood.
Summary of stem cell isolation and type and route of delivery: G-CSF was given to all participants at 5 μg/kg for 5 days. Leukoapheresis was performed on the 5th day for collection of mononuclear cells. The cells were stored overnight at 4°C, and the following morning the CD34+ fraction was purified on a commercially available device (isolex 300i, Baxter Healthcare) according to manufacturer's instructions. Cells were then subjected to testing and were required to meet lot-release criteria. Once passed, the participants underwent NOGA electromechanical mapping and intramyocardial injection of CD34+ cells suspended in saline plus 5% autologous serum, versus cell diluent using the NOGA Myostar catheter. The dose was divided into 10 injections of 0.2 mL per injection.
Dose of stem cells: 5 x 10⁴ CD34 cells/kg (LD), 1 x 10⁵ CD34 cells/kg (MD) and 5 x 10⁵ CD34 cells/kg (HD).
Timing of stem cell procedure: On day 6 following G-CSF administration and within 24 hours of cell isolation.

G-CSF details: G-CSF was given to all  participants at 5 μg/kg for 4 - 5 days.

Comparator arm: Placebo. G-CSF was given to all  participants at 5 μg/kg for 4 - 5 days. No cells were injected, only  saline (0.9 % NaCl) with 5% autologous plasma.

Outcomes Primary outcomes: Not reported.
Secondary outcomes: Safety analysis (AEs), Efficacy (angina frequency, NTG use, exercise tolerance, CCS class, SPECT perfusion imaging, QOL testing).
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: Angina frequency and CCS angina class.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation codes were established by the study statistician.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll participants were administered G-CSF 4 - 5 days prior to treatment. All had CD34+ cells collected and all were injected with a solution in a syringe that was identical for treatment and control.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskRandomisation codes were only revealed to the stem cell laboratory technician responsible for separating the cells into aliquots or preparing the placebo material.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Losordo 2011

Methods

Type of study:Parallel RCT.
Type of publication: Full paper.
Source of funding: "Baxter Healthcare sponsored the study and was responsible for the conduct of the investigation, with oversight provided by the principle investigator and the scientific advisory board".

Study setting: USA.
Number of centres: 26 centres.
Length of follow-up: 12 months.
Number (N) of participants randomised to each arm: BMSC HD arm: 56; Control arm: 56.
Number (N) of participants analysed (primary outcome) in each arm: BMSC HD arm: 56; Control arm: 55.

Participants

Description: Participants with CCS class III - IV symptomatic of chronic refractory angina.
Age distribution in each arm: BMSC HD arm: 59.8 ± 9.2 yrs; Control arm: 61.8 ± 8.5.
Sex (% male) in each arm: BMSC HD arm: 87.5%; Control arm: 89.3%.

Number of diseased vessels: not reported.
Time from symptom onset to initial treatment: At least 40 days from previous MI.
Statistically significant baseline imbalances between the groups? Yes, Cardiovascular risk factors (HTN, smoking, DM); angina episodes per week.

Interventions

Intervention arm: Low Dose (LD) and High Dose (HD) of CD34+ cells.
Type of stem cells: CD34+ cells from mobilised peripheral blood.
Summary of stem cell isolation and type and route of delivery: G-CSF was given to all  participants at 5 μg/kg for 4 - 5 days. On day 5 leukapheresis was performed. The following day mononuclear cells were collected and CD34+ cells enriched using a commercially available device (Isolex 300im) magnetic cell separation system. Cell suspension with > 70% viability and > 50% CD34+ cells were given at 2 doses of body weight with a maximum of 100 kg. Cell suspension was diluted in saline (0.9 % NaCl) with 5% autologous plasma. Cells were injected into the myocardium. The injection was performed by NOGA mapping and at 10 sites (0.2 cc/ site) using a NOGA Myostar catheter.
Dose of stem cells: 1 x 10⁵ CD34 cells/kg and 5 x 10⁵ CD 34 cells/kg.
Timing of stem cell procedure: At least 3 months following MI.

G-CSF details: G-CSF was given to all  participants at 5 μg/kg for 4 - 5 days.

Comparator arm: Placebo. G-CSF was given to all  participants at 5 μg/kg for 4 - 5 days. No cells were injected, only  saline (0.9 % NaCl) with 5% autologous plasma.

Outcomes Primary outcomes: Angina frequency 6 months after treatment.
Secondary outcomes: Secondary efficacy endpoints included exercise tolerance testing, use of antianginal medication, CCS functional class, health-related QOL (Seattle Angina Questionnaire, SF-36 Survey, Dyspnea Questionnaire, Euro 5 Questionnaire); combined rate of MACE, SPECT, cardiac MRI (in a sub-study). Safety endpoints included adverse event reporting, chest Xray and echo and lab screening.
Outcome assessment points: Baseline, 6 and 12 months.
Method(s) of outcome measurement: CCS functional class
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskParticipants were randomly assigned to 1 of 3 treatment groups via a telephone call-in and an interactive voice-response system. .
Allocation concealment (selection bias)Low riskThe cell-processing laboratory at each centre was responsible for making the randomisation call and preparing the CD34+ cells or control injection accordingly.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll participants were administered G-CSF 4 - 5 days prior to treatment. All had CD34+ cells collected and all were injected with a solution in a syringe that was identical for treatment and control.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind study. An independent committee conducted the analysis. All study personnel remained blinded until the end of the study.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Patel 2005

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Not reported.

Study setting: Rosario, Argentina.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 10; Control arm: 10.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 10; Control arm: 10.

Participants

Description: Participants with documented ischaemic heart failure requiring revascularisation, undergoing off-pump CABG.
Age distribution in each arm: BMSC arm: 64.8 ± 7.1 years old; Control arm: 63.6 ± 5.2 years old.
Sex (% male) in each arm: BMSC arm: 80%; Control arm: 80%.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: At least 7 days after the last MI, all participants had history of MI and revascularisation by PCI.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: CD34+ cells.
Type of stem cells: CD34+ cells.
Summary of stem cell isolation and type and route of delivery: BM was harvested from the iliac bone in a sterile fashion after achievement of general anaesthesia. To minimise the anaesthetic time, a special multihold harvest needle with a 60 mL syringe was designed. It was introduced into the iliac bone between both posterior iliac spines at both sides. 500 - 600 mL of BM with a minimal number of puncture sites harvested. At least 250 mL BM must be harvested to continue with the protocol. Harvested BM was placed in a blood bag with 10,000 U of heparin sulfate and 400 microm of lysine acetylsalicylate to avoid platelet clumping. The BM was filtered on a 500 microm filter followed by a 200 microm filter. The resulting solution was mixed with hydroethylstarch 6%. The supernatant was centrifuged at 400 g for 15 mins. The cellular pellet was resuspended in PBS. The cell solution was mixed 3:1 with a solution of 155 mmol/L NH₄Cl, 10 mmol/L KHCO3 and 0.1 mmol/L EDTA and set for 5 mins at room temperature. Solution was then centrifuged at 400 g for 10 mins. The pellet was washed with PBS and resuspended. The cell suspension was placed over Ficoll Paque (1.077 density) 4:1 and centrifuged at 400 g for 30 mins. The upper layer was aspirated, leaving the mononuclear cell layer at the interphase. The interphase cells were transferred to a new conical tube with PBS and centrifuged at 300 g for 10 mins. The supernatant was completely removed, and the cell pellet was resuspended in PBS. Cell counts were performed, and the magnetic labeling with Isolex 300i was performed to obtain an enriched product of at least 70% CD34+ cells. The resulting cell solution was resuspended in 30 mL of the participant's own plasma and 10,000 U of heparin sulphate. 30 ml of cell preparation were delivered in 1 ml aliquots over a 2-second period. The injections into the myocardium were spaced 1cm apart and spaced to avoid coronary vessels. Injections were 3 - 5 mm in depth. 
Dose of stem cells: Median of 22 x 10⁶ CD34+ cells.
Timing of stem cell procedure: At least 7 days following the last MI.

G-CSF details: No.

Comparator arm: Control , no placebo.

Outcomes Primary outcomes: Not reported.
Secondary outcomes: Global LVEF, LVEDV, NYHA class.
Outcome assessment points: Baselina and 1, 3 and 6 months.
Method(s) of outcome measurement: SPECT or Echocardiography.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA person who did not participate in the trial had the choice of picking a coloured ball (red = BMSC arm; blue = control arm).
Allocation concealment (selection bias)Unclear riskA person who did not participate in the trial had the choice of picking a coloured ball (red = BMSC arm; blue = control arm).
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe clinicians were not blinded, but the study was blinded for the participants and reviewers of the imaging studies (cardiologists).
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe study was blinded for the participants and reviewers of the imaging studies (cardiologists).
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Perin 2011

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding:No extramural funding was used to support this work; the authors have no disclosures, no funding and no relationship with industry to report. 

Study setting: Texas and Minneapolis, USA.
Number of centres: Two.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 20; Control arm: 10.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 20; Control arm: 10.

Participants

Description: People with ischaemic heart failure (HF) and no option of revascularisation.
Age distribution in each arm: BMSC arm: 56.3 ± 8.6 years old; control arm: 60.5 ± 6.4 years old.
Sex (% male) in each arm: BMSC arm: 50%; Control arm: 80%.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: Not reported.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: 50 ml of BM was aspirated from the posterior iliac crest, approximately 4 hours before the cells were injected into the heart. Mononuclear cells were isolated using a density gradient centrifugation, washed in heparinised saline containing 5% human serum albumin and passed through a mesh. 3 x 10⁷ cells were resuspended in 3 ml saline containing serum albumin (5%). 3ml were preserved for further studies. 3 hours after bone marrow aspiration, participants underwent an electromechanical mapping to select myocardial segments for cell injection. Cells were injected into viable myocardium (> 6.9 mV unipolar voltage). Electromechanical maps comprised an average of 87 ± 16 points. Each injection of 2 million cells was delivered in a volume of 0.2 mL. Participants received an average of 15 cell injections in a mean of 6 ± 1 segments.
Dose of stem cells: 2 x 10⁶ cells.
Timing of stem cell procedure: Within 24 hours of harvesting the bone marrow.

G-CSF details: None.

Comparator arm: Electromechanical mapping using the NOGA system, intramyocardial injection. A simulated injection  procedure was performed, but no placebo material was administered to participants in this arm. 

Outcomes Primary outcomes: Safety of cell injections was assessed at 3 time points: i) early safety (periprocedural and up to 2 weeks); 2) at 3 months, and 3) at 6 months. Major adverse events were adjudicated (hospitalisation, arrhythmia, exacerbation of congestive HF, acute coronary syndrome, MI, stroke or death).
Secondary outcomes: Efficacy: at 3 and 6 months, functional status was assessed by MVO₂, SPECT and 2-D echocardiography. At 6 months, participants also underwent coronary and LV angiography and electromechanical mapping. Quality of life was assessed at baseline and 6-month follow-up. 
Outcome assessment points: Baseline, 3 and 6 months.
Method(s) of outcome measurement: Not applicable.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskNumbered sealed envelopes were used.
Allocation concealment (selection bias)Low riskNumbered sealed envelopes were used.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskClinicians were not blinded, but participants received a simulated mock injection procedure (although unclear whether BM aspiration undertaken in control group).
Blinding of outcome assessment (detection bias)
All outcomes
Low riskEfficacy studies were read by an independent blinded investigator. Blinding was maintained until the end of the assessment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Perin 2012a

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: NHLBI under co-operative agreement 5 U01 HL087318-04. In part by NHLBI contracts N01-HB37164 and HHSN268201000008C awarded to the Molecular and Cellular Therapeutics Facility, University of Minnesota and NO1-HB-37163 and HHSN268201000007C awarded to the Cell Processing Facility , Baylor College of Medicine and Nationall Centre for Research Resources CTSA grant UL1 TR000064 awarded to the University of Florida. The CCTRN also acknowledges its industry partners, Biosafe, Biologics Delivery Systems Group and Cordis Corporation for their contributions of equipment and technical support during the conduct of the trial.  [Full details and conflict of interest declarations in the paper].

Study setting: USA.
Number of centres: Five.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 61; Control arm: 31.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 54; Control arm: 28.

Participants

Description: People with chronic IHD and LV dysfunction who have no other revascularisation options.
Age distribution in each arm: BMSC arm: 63.95 ± 10.90 years old; Control arm: 62.32 ± 8.25 years old.
Sex (% male) in each arm: BMSC arm: 86.89%; Control arm: 93.65%.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: Not reported.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC
Type of stem cells: BMSC
Summary of stem cell isolation and type and route of delivery: Approx. 80 - 100 mL of BM was aspirated from the iliac crest using standard techniques.  The aspirate was processed using Ficoll with a closed, automated cell processing system (Sepax). Composition of CD34 and CD133 cells was determined by flow cytometry.Cells passed stipulated lot release criteria, included viability (> 70%) and sterility. The target dose was 100 x 10⁶ total BMCs. The BMC final product was suspended in normal saline containing 5% human serum albumin and adjusted to a concentration of 100 x 10⁶ cells in 3 mL distributed into 3 1 mL syringes. The placebo group received a cell-free suspension in the same volume. Mean (SD) volume of BM harvested was 93.7 (8.3) mL. Total dose of 100 x 10⁶ contained an average of 2.6% of CD34 cells and 1.2% of CD133 cells. Cells were delivered by intramyocardial injection. The cell-containing or cell-free preparation was delivered to viable myocardial regions identified during electromechanical mapping of the LV endocardial surface (NOGA).
Dose of stem cells: 100 x 10⁶ BMSC.
Timing of stem cell procedure: Within 12 hours of cell harvest.

G-CSF details: No.

Comparator arm: Approx. The placebo group received a cell-free suspension in the same volume. Mean (SD) volume of BM harvested was 93.7 (8.3) mL.

Outcomes Primary outcomes:
1. Change in LVESV.
2. Change in maximal oxygen consumption.
3. Change in defect size on SPECT.
Secondary outcomes: BM mononuclear cell characteristics, LVESV, LVEDV, myocardial oxygen consumption, % reversibility, LVEF, clinical improvement at 6 months; change in CCS anginal score, NYHA class, decrease in weekly need for antianginal meds; MACEs.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: Echocardiography and SPECT.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was computer-generated and used variable block sizes of 6 or 9, randomly selected and stratified by centre.
Allocation concealment (selection bias)Low riskTreatment assignment was masked to all but 1 designated cell processing team member at each centre not involved in participant care.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll caregivers and participants were masked to treatment. 
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blind study: "MACEs were assessed by 2 independent cardiologists not affiliated with any clinical site and masked to treatment assignment".
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Perin 2012b

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: "This work was supported solely by Aldagen, Inc, Durham, NC".

Study setting: Texas, USA.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 10; Control arm: 10.
Number (N) of participants analysed (primary outcome) in each arm:BMSC arm: 10; Control arm: 10.

Participants

Description: Advanced ischaemic heart failure and no other option for revascularisation.
Age distribution in each arm: BMSC arm: 58.2 ± 6.1 years old; Control arm: 57.8 ± 5.5 years old.
Sex (% male) in each arm: BMSC arm: 90%; Control arm: 80%.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: At least 1 month from the last MI.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: ALDH+ cells.
Type of stem cells: ALDH+ cells.
Summary of stem cell isolation and type and route of delivery: 100 mL (± 20) BM was harvested from the iliac crest under local anaesthesia unless institutional guidelines required general anaesthesia. BM cells were depleted of CD15 and glycophoris A-expresing cells using immunomagnetic beads (EasySep). The cells were reacted with ALDH substrate and ALDH bright (+) cells were isolated by using a cell sorter (MoFlo or FACSAria). After centrifugation, the cells were resuspended in 3.5 mL 5% pharmaceutical grade human serum albumin. The final products were transferred to a 3 mL fluorinated ethylene propylene bag with a needles entry port. ALDH (+) cells were administered intramyocardially via a NOGA Myostar catheter. Cells comprised a mean of 0.74% _/0 0.28% of the nucleared BM cells in the unprocessed aspirates from participants (median 0.73%, range 0.35% to 1.16%). Cell injections were targeted to areas of the myocardium identified as ischaemic or SPECT and as viable by EMM. 
Dose of stem cells: 15 injections in a volume of 0.2 mL per injection. Mean number of nucleated cells administered to the treatment group was 2.94 ± 1.58 x 10⁶ cells (median 2.78 x 10⁶, range 0.53 - 5.42 x 10⁶). When the total cell doses were corrected for the proportion of ALDH (+) cells in the cell product, the mean number of ALDH (+) cells administered to the cell treatment group was 2.37 ± 1.31 x 10⁶ (median 2.27 x 10⁶, range 0.35 - 4.42 x 10⁶).
Timing of stem cell procedure: Products manufactured at Aldagen were administered within 50 - 55 hours of BM aspiration, whereas those produced locally at the University of Texas were administered within 30 - 36 hours of aspiration. 

G-CSF details: No.

Comparator arm: Control participants underwent the same procedures but received transendocardial injections of placebo solution (5% albumin) instead of the cell preparation.

Outcomes Primary outcomes: Safety, assessed by MACE and hospitalisations: periprocedural (up to 2 weeks) and 6 months.
Secondary outcomes: Efficacy, evaluated by clinical status, LVEF, perfusion on SPECT imaging and MVO₂. 
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: SPECT.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomised sequence.
Allocation concealment (selection bias)Low riskComputer-generated randomised sequence.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used; all personnel involved were blinded. Personnel involved in the harvesting procedure acted independently of the study team, thus maintaining blinding. Control participants underwent an identical bone marrow harvest procedure, including insertion of the needle, except that BM was not aspirated. Control participants received transendocardial injections of placebo solution instead of cell preparation.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-blinded trial. "two blinded, independent echocardiologists reviewed the echocardiograms" and the average of the 2 readings was reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Pokushalov 2010

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Not reported.

Study setting: Russia.
Number of centres: One.
Length of follow-up: 12 months.
Number (N) of participants randomised to each arm: BMSC arm: 55; Control arm: 54.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 49; Control arm: 33 at the end of study.

Participants

Description: Chronic myocardial infarction and end-stage chronic heart failure.
Age distribution in each arm: BMSC arm: 61 ± 9 years old; Control arm: 62 ± 5 years old.
Sex (% male) in each arm: BMSC arm: 87%; Control arm: 85%.

Number of diseased vessels: BMSC arm: 1 (n = 2); 2 (n = 1); 3 (n = 52); Control arm: 1 (n = 3); 2 (n = 3); 3 (n = 48).
Time from symptom onset to initial treatment: A history of MI > 12 months before enrolment.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: On the day of surgery, BM was aspirated from the iliac crest under local anaesthesia by the standard technique. MNBMC were isolated by Ficoll density gradient centrifugation. Three washing steps were performed and the cells were resuspended in heparinised saline for further use. Cell viability was tested by Trypan Blue (exclusion method) and estimated at more than 98% for each transplant. Intramyocardial injection. Non-fluroscopic mapping with the NOGA system via femoral artery access and retrograde aortic approach using a 7-Fr NOGA Star catheter. An area of interest located by technetium-99m tetrofosmin SPECT was delineated in detail by means of NOGA mapping; it included ischaemic but viable myocardium. Immediately before injection, the catheter was positioned perpendicularly to endocardium with excellent loop stability and the extension of the needle to induce premature ventricular contraction. Ten successive intramyocardial injections (roughly 0.2 ml each) were administered into the infarction border zone.
Dose of stem cells: 41 ± 16 x 10⁶ BMSC, with 2.5 (1.6)% being CD34-positive cells.
Timing of stem cell procedure: Within 24 hours after cell harvesting.

G-CSF details: No.

Comparator arm: Not reported.

Outcomes Primary outcomes: Efficacy of the intramyocardial injection of autologous bone marrow mononuclear cells, measured by change in myocardial perfusion defects at rest and under pharmacological stress.
Secondary outcomes: Safety of the intramyocardial BMMC therapy, quality of life, CCS angina class, NYHA functional class, LV functions, life-threatening arrhythmias, mortality between 2 groups, NOGA change in voltage assessed by NOGA follow-up endocardial mapping.
Outcome assessment points: Baseline, 6 and 12 months.
Method(s) of outcome measurement: SPECT.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was carried out using an electronic system.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of clinicians and participants was not reported.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskSPECT imaging done by consensus of 2 readers blinded to the type of the study (baseline or follow-up) and clinical data; other blinding not reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Tse 2007

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding:This study was partially supported by the Sun Chieh Yeh Heart Foundation Fund; S K Ye Medical Foundation Grant  (project no 203217)  and The Research Grants Council of Hong Kong  (HKU 7357/02M). Two authors received consultant fee from Biosense-Webster, CA, USA. All other authors declare that they have no conflict of interest.

Study setting: Hong Kong (China) and Newcastle (Australia).
Number of centres: Two.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 19; Control arm: 9.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 19; Control arm: 9.

Participants

Description: People with severe CAD who had failed conventional therapy.
Age distribution in each arm: BMSC arm: 65.2 ± 8.3 years old; Control arm: 68.9 ± 6.3 years old.
Sex (% male) in each arm: BMSC arm: 79%; Control arm: 88%.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: Not reported.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: BM was harvested via posterior iliac crest puncture under local anaesthesia. A total of 40 mL of BM blood was aspirated, and an adequate trephine biopsy was performed. BMMNC were isolated by Ficoll density gradient centrifugation. BM cells were washed twice in phosphate-buffered saline, resuspended in phosphate-buffered saline enriched wit 10% autologous plasma to either 1 or 2 x 10⁷ MNC/mL and returned directly to cardiac catheterisation laboratory for use. BM suspensions were tested by flow cytometry with directly conjugated antibodies against CD34. Intramyocardial injection. Non-fluoroscopic LV electromechanical mapping (NOGA) to identify the foci of ischaemic myocardium. During the procedure, systemic anticoagulation was achieved with intravenous heparin to maintain an activated clotting time of 250 - 300 s throughout the procedure. The targeted injection regions were selected by matching the area of ischaemic myocardium identified by SPECT. After completion of the LV electromechanical mapping, the mapping catheter was replaced by a modified mapping catheter incorporated with a 27G needle at the tip that could be used for direct endomyocardial injection.
Dose of stem cells: 1.5 x 10⁷ BMNC.
Timing of stem cell procedure: Within 3 - 4 hours from cell harvest.

G-CSF details: No.

Comparator arm: In the placebo group the participants received cell-free phosphate buffered saline with 10% autologous serum. 8 - 12 injections of 0.1 mL of placebo preparation  were delivered evenly in each ischaemic region.

Outcomes Primary outcomes: Change from baseline in total exercise time on a modified Bruce protocol at 6 months follow-up.
Secondary outcomes: Changes in LVEF, NYHA, and CCS angina classification and sum of different scores on SPECT, global LVEF, LVEDV and LVESV by MRI.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: SPECT and MRI.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation table: randomisation was constrained, stratified on the study centre and conducted via a system of sealed and numbered envelopes provided to each investigative centre.
Allocation concealment (selection bias)Low riskSealed numbered envelopes were provided from the study centre (centralised) to each investigational centre.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAfter randomisation the study processes were blinded to participants (placebo). No details of the blinding of clinicians given.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAfter randomisation the study processes were blinded to study co-ordinators and investigators responsible for participants' assessment. Blinding was maintained until the end of the study.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Turan 2011

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Not reported.

Study setting: Germany.
Number of centres: One.
Length of follow-up: 12 months.
Number (N) of participants randomised to each arm:BMSC arm: 38; Control arm: 18.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 33; Control arm: 16.

Participants

Description: People with IHD.
Age distribution in each arm: BMSC arm: 62 ± 10 years old; Control arm: 60 ± 9 years old.
Sex (% male) in each arm: BMSC arm: 52.6%; Control arm: 55.6%.

Number of diseased vessels: BMSC arm: 1.5 ± 0.5; Control arm: 2.0 ± 0.6.
Time from symptom onset to initial treatment: Transmural myocardial infarction (MI) 28 ±14 months before treatment.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: 120 ml bone marrow was aspirated from the participant's own iliac crest, mononuclear cells were isolated using Harvest BMAC System (Germany) (most probably by density gradient centrifugation) and concentrated into 20 ml of cell suspension. Cell transplantation was performed via the coronary artery using 4 fractional infusions parallel to balloon inflation over 2 - 4 mins of 5 ml cell suspension. Cells were infused directly into the infarcted artery via an angioplasty balloon catheter that was inflated at a low pressure and was located within the previously stented coronary artery. Intracoronary infusion. After undergoing arterial puncture, all participants received 7500 - 10,000 units of heparin. Cell transplantation was performed via the intracoronary administration route using 4 fractional infusions parallel to balloon inflation over 2 - 4 mins of 5 ml of cell suspension. All cells were infused directly into the infarcted zone through the infarct-related artery via an angioplasty balloon catheter, which was inflated at a low pressure (4 atm) and was located within the previously stented coronary segments. This prevented back flow of cells and produced stop flow beyond the site of balloon inflation to facilitate high pressure infiltration of cells into the infarcted zone with prolonged contact time for cellular migration.
Dose of stem cells: 99 x 10⁶ (± 25) mononuclear cells.
Timing of stem cell procedure: Within 24 hours from cell harvest.

G-CSF details: No.

Comparator arm: No placebo.

Outcomes Primary outcomes: Change in global EF as well as the size of infarcted area measured by left ventriculography.
Secondary outcomes: Functional activity of BMSC immediately pre- and 3, 6 and 12 months after procedure; functional status assessed by NYHA classification and brain natriuretic peptide level in peripheral blood in both groups.
Outcome assessment points: Baseline, 3 and 12 months.
Method(s) of outcome measurement: Left ventriculography.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot reported for clinicians, no placebo given to participants.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskHaemodynamic investigations and lab results were obtained independently by 2 investigators.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Van Ramshorst 2009

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: This study is an academia-initiated exploratory Phase II study. No external sponsor was involved in study design, data collection, data analysis, data interpretation or writing of the report. No external funding was applicable for this study.

Study setting: Leiden, The Netherlands.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 25; Control arm: 25.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 25; Control arm: 25.

Participants

Description: People suffering from severe angina, ineligible for PCI or CABG.
Age distribution in each arm: BMSC arm: 64 ± 8 years old; Control arm: 62 ± 9 years old.
Sex (% male) in each arm: BMSC arm: 92%; Control arm: 80%.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: At least 6 months from the last MI.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: BM was aspirated from the iliac crest under local anaesthesia and placed in a heparinised Hanks balanced salt solution. The MNC were isolated using Ficoll density gradient centrifugation, washed in phosphate-buffered saline with 0.5% human serum albumin and resuspended in phosphate-buffered saline with 0.5% human serum albumin. The final suspension of BMMNC contained 40 x 10² mL. The filtered bone marrow was checked for the presence of clots and the BM cell population was analysed by fluorescence-activated cell sorting using anti-CD34 and anti-CD35 antibodies. Intramyocardial injection. During cell isolation and randomisation, a 3D electromechanical map of the LV was obtained using the NOGA system. The ischaemic regions on SPECT were visually matched with the 3D electromechanical map based on anatomical landmarks including LV long axis, position of apex, mitral valve area, aortic valve location and basal inferoseptal point. Cross-referencing was also performed using fluoroscopic identification of anterior, septal, lateral and inferior orientations.
Dose of stem cells: The cell suspension contained 98 ± 6 x 10⁶ BM cells with a cell viability of 98% (1%) and a CD34+ cell fraction of 2.4% (0.9%).
Timing of stem cell procedure: Within 2 hours of BM aspiration.

G-CSF details: No.

Comparator arm: Participants had bone marrow aspiration and received an intramyocardial injection.

Outcomes Primary outcomes: Summed stress score (myocardial perfusion).
Secondary outcomes: LVEF (and LV stroke volume, LVESV, LVEDV), CCS angina class, Seattle Angina Questionnaire QOL score.
Also reported: exercise capacity.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: SPECT.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequentially-numbered sealed envelopes provided by the Department of Medical Statistics and Bioinformatics. A block size of 4 was used without further stratification.
Allocation concealment (selection bias)Low riskSequentially-numbered sealed envelopes provided by the Department of Medical Statistics and Bioinformatics.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskA blinded syringe with either cell suspension or placebo was brought to the cath lab. All participants had BM aspirated. They were unaware of group assignment. A placebo was used.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants, study co-ordinators and investigators involved in participant assessments were unaware of group assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Wang 2009

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Not reported.

Study setting: Beiging, China.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 16; Control arm: 16.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 16; Control arm: 16.

Participants

Description: Angina, no AMI in 1 month prior to transplantation.
Age distribution in each arm: BMSC arm: 60.6; Control arm: 60.
Sex (% male) in each arm: BMSC arm: 56.25%; Control arm: 63.25%.

Number of diseased vessels: Not reported.
Time from symptom onset to initial treatment: At least 1 month from the last AMI, angina.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: CD34+ cells.
Type of stem cells: CD34+ cells.
Summary of stem cell isolation and type and route of delivery: 150 ml of BM was aspirated from the iliac crest. CD34+ cells were enriched by a cell separation device under GMP conditions. CD34+ cells were resuspended in normal saline and kept at room temperature. Cells were transported to the Cath lab. Cells were delivered using a microcatheter following PCI.
Dose of stem cells: 1.0 - 6.1 x10⁶ CD34+ cells.
Timing of stem cell procedure: Unclear, not reported.

G-CSF details: No.

Comparator arm: No cells were harvested, PCI only, no placebo.

Outcomes Primary outcomes: Not reported.
Secondary outcomes: Myocardial perfusion defect area, wall motion, angina frequency change, Nitrate triglycerine dose change, angina classification by CCS class.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement:
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of clinicians and participants was not reported.
Blinding of outcome assessment (detection bias)
All outcomes
High riskSpecified in the text that they are not blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Wang 2010

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Not reported.

Study setting: China.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 56; Control arm: 56.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 56; Control arm: 56.

Participants

Description: Intractable angina, no revascularisation.
Age distribution in each arm: BMSC arm: 42 - 80 years old; Control arm: 43 - 80 years old.
Sex (% male) in each arm: BMSC arm: 51.79%; Control arm: 50%.

Number of diseased vessels: 3.
Time from symptom onset to initial treatment: Not reported.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: CD34 + cells.
Type of stem cells: CD34 + cells.
Summary of stem cell isolation and type and route of delivery: 120 - 150ml bone marrow aspirates from the posterior iliac crest were obtained from all participants. CD34+ cells were isolated by labelling with the appropriate CD34 antibody and separating them magnetically using a CLINIMACS (Myltenyi Biotec). CD34+ cells were resuspended in 15 ml of saline + human serum albumin . Only the saline+human serum albumin was infused in the control group, using the same protocol as in the BMSC group. The cell were infused into the coronary artery using a GE Innoca 2000 DSA with 3000 units of heparin. Approximately 1 - 2 hours after cell separation, 10 ml of cells and 5 ml of saline were infused into the left coronary artery and right coronary artery separately by an over-the-wire balloon. 
Dose of stem cells: 5.6 ± 2.3 x 10⁷  CD34 cells.
Timing of stem cell procedure: Within 2 hours of cell harvest.

G-CSF details: No.

Comparator arm: Only the saline+human serum albumin was infused in the control group, using the same protocol as in the BMSC group.

Outcomes Primary outcomes: Safety (mortality and morbidities).
Secondary outcomes: Arrythmias, angina frequency, nitroglycerine use, exercise tolerance, CCS class, perfusion effect or myocardial perfusion.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: Number of deaths
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll participants and researchers were unaware of the treatments. No details about clinicians.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll participants and researchers were unaware of the treatments.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Yao 2008

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: This work was supported by Shanghai Scientific Research Fund (06DJ14001), Program for Shanghai Outstanding Medical Academic Leader (LJ06008_ and National Key Program (2006CB943704).

Study setting: Shanghai, China.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 24; Control arm: 23.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 24; Control arm: 23.

Participants

Description: People hospitalised with a history of transmural MI and revascularisation plus stent implantation at least 6 months earlier.
Age distribution in each arm: BMSC arm: 54.8 ± 11.5 years old; Control arm: 56.3 ± 7.9 years old.
Sex (% male) in each arm: BMSC arm: 96%; Control arm: 96%.

Number of diseased vessels: BMSC arm; 1 (67%); 2 (29%); 3 (4%); Control arm: 1 (70%); 2 (26%); 3 (4%).
Time from symptom onset to initial treatment: At least 6 months from last MI. 13 ± 8 months before entry into study.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: BM (95 (20) ml) was collected under local anaesthesia from the posterior superior iliac spine. BMC were isolated and enriched with the use of Ficoll-Hypaque gradient centrifugation procedures. BM aspirates were diluted with 0.9% NaCl (1:5) and mononuclear cells were isolated by density gradient centrifugation using Ficoll (800 g x 25 mins). Mononuclear cells were washed (800 g x 5 mins) 3 times with phosphate buffered saline and then resuspended in 16 ml of heparin-treated plasma at a density of 2.4 (1.2 x 10⁷) cells/ml at room temperature. Before intracoronary injection, the mononuclear cells were filtered (Falcon) and counted. These cells were used for therapy. To ensure that a certain % of stem cells were present in the infused MNC, a 1-ml suspension was subjected to FACS analysis after incubation with anti-human monoclonal antibodies: anti-human CD34 conjugated with FITC, or CD133 antibodies conjugated with APC. The FACS analysis revealed that 2.4% (0.9%) of BMC was positive for CD34 and 0.75% (0.2%) was positive for CD133. Intracoronary infusion. An over-the-wire angioplasty balloon catheter was inserted into the stent previously implanted during the acute reperfusion procedure. The balloon was inflated with low pressure (2 - 4 atm) to completely block blood flow for 2 mins and repeated 5 times. During each balloon inflation, 3 ml of BMC suspensions were infused distal to the occluding balloon into the infarct-related artery. 
Dose of stem cells: 7.2 x 10⁷ cells.
Timing of stem cell procedure: within 6 hours after bone marrow puncture.

G-CSF details: No.

Comparator arm: Placebo. The placebo solution consisted of 0.9% NaCl containing heparin.

Outcomes Primary outcomes: Improvement of LV function.
Secondary outcomes: LVEF, LVED diameter, LVES diameter (Echo).
LVEF, LVESV, LVEDV, infarct size (MRI).
Myocardial perfusion (SPECT); mortality and morbidities.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: Echocardiography, MRI and SPECT.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo method for generation of random sequences was reported.
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of clinicians and participants was not reported.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors (MRI, echocardiography, SPECT) were blinded to the assigned therapy.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised participants were included at follow-up.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the methods were reported in results; although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Zhao 2008

  1. a

    AE adverse events; ALDH: aldehyde dehydrogenase; AMI: acute myocardial infarction; APC: allophycocyanin ;BMMNC bone marrow mononuclear cells; BMSC bone marrow stem cells; CABG coronary artery bypass grafting; BNP brain natriuretic peptide; CAD: coronary artery disease; CCS Canadian Cardiovascular Society; DM: diabetes mellitus; CPC circulating progenitor cells; EF: ejection fraction; EMM: electromechanical mapping; EPC endothelial progenitor cells; FITC: fluorescein isothiocyanate; HTN: hypertension; IM intramuscular; IC intracoronary; LVEF left ventricular ejection fraction, LVEDV left ventricular end diastolic volume; LVESV left ventricular end systolic volume; MACE major adverse clinical events; MLHF Minnesota Living with Heart Failure; MRI magnetic resonance imaging; MVO₂ myocardial oxygen consumption; NTG: nitroglycerine; NYHA New York Heart Association; PBS: phosphate buffered saline; PBSC: peripheral blood stem cell; PCI percutaneous coronary intervention; RCT randomised controlled trial; SPECT: single-photon emission computed tomography; STEMI: ST elevation myocardial infarction; VEGF: vascular endothelial growth factor.

Methods

Type of study: Parallel RCT.
Type of publication: Full paper.
Source of funding: Shanghai Medical Development Research Fund, Grant Number 2000I-2D002.

Study setting: Shanghai , China.
Number of centres: One.
Length of follow-up: 6 months.
Number (N) of participants randomised to each arm: BMSC arm: 18; Control arm: 18.
Number (N) of participants analysed (primary outcome) in each arm: BMSC arm: 18; Control arm: 18

Participants

Description: People with ischaemic heart failure admitted for elective CABG. 
Age distribution in each arm: BMSC arm: 60.3 ± 10.4 years old; Control arm: 59.1 ± 15.7 years old.
Sex (% male) in each arm: BMSC arm: 83.3%; Control arm: 83.3%.

Number of diseased vessels: multivessel, 2 or more.
Time from symptom onset to initial treatment: Not reported.
Statistically significant baseline imbalances between the groups? No.

Interventions

Intervention arm: BMSC.
Type of stem cells: BMSC.
Summary of stem cell isolation and type and route of delivery: After heparinisation and median sternotomy, BM (about 30 mL) was aspirated from the sternum by a special suction appliance in both groups. The MNBMC were immediately isolated by density gradient centrifugation using Ficoll. Isolated cells were washed twice with heparinised saline and subsequently resuspended in 5 mL saline. The cells were counted and the viability was assessed by trypan blue dye exclusion. The cell suspension was filtered by a 70-micron cell strainer before transplantation. During CABG, intramyocardial injection in and around the infarct area at 10 points (approximately 0.5 ml per injection) with a 29-gauge syringe. 
Dose of stem cells: 6.59 ± 5.12 x 10⁸ (cell viability 96.48% ± 3.10%).
Timing of stem cell procedure: within 24 hours following cell harvest.

G-CSF details: No.

Comparator arm: Placebo, saline.

Outcomes Primary outcomes: Death, MI and recurrence of heart failure.
Secondary outcomes: Echo: infarction wall thickness; infarction wall motion velocity; LVED/LVES diameter; global LVEF; LV shortening fraction; mitral valve regurgitation.
SPECT: LV SRS; infarcted area SRS; clinical parameters; NYHA, CCS classification; 24-hour Holter analysis.
Outcome assessment points: Baseline and 6 months.
Method(s) of outcome measurement: Echocardiography and SPECT.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was achieved by using a sequence of random numbers generated by a computer. 
Allocation concealment (selection bias)Unclear riskNo method of allocation concealment was reported.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskBlinding of clinicians and participants was not reported.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe results were analysed by 2 independent experienced observers; investigators (Echo, SPECT) were blinded to the randomisation scheme.
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for loss to follow-up and withdrawals were given, with similar attrition rates in both treatment arms.
Selective reporting (reporting bias)Low riskAll outcomes mentioned in the Methods were reported in results, although it would be difficult to rule out selective reporting.
Other biasLow riskNo other sources of bias were identified.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    AMI acute myocardial infarction; RCT randomised controlled trial.

Beeres 2006Non-RCT, no control arm included.
Beeres 2007Non-RCT, no control arm included.
Beeres 2007aNon-RCT, no control arm included.
Beeres 2007bReview of imaging techniques for cardiac stem cell therapy.
Chang 2006AMI.
Charwat 2010AMI.
Chin 2010Non-RCT, no control arm included.
Gu 2011Non-RCT.
Haack-Sorensen 2013Non-RCT, no control arm included.
Kakuchaya 201024 participants with ischaemic dilated cardiomyopathy and 26 with idiopathic dilated cardiomyopathy.
Kang 2006bAMI.
Lai 2009Primary outcome measures for cardiac enzymes, not in the protocol.
Maureira 2012Non-RCT.
Perin 2003Non-RCT.
Peruga 2009AMI.
Pokushalov 2011Non-RCT for cell therapy.
Rivas-Plata 2010Non-RCT.
Stamm 2007aNon-RCT
Tuma 2011Non RCT, no control arm
Vicario 2004Non-RCT.
Wang 2006Not clear whether this is an RCT and chronic ischaemic heart disease.

Characteristics of studies awaiting assessment [ordered by study ID]

Bartunek 2012

MethodsBone marrow-derived cariopoietic cells, based on cardiac lineage commitment of mesenchymal stem cells. Bone marrow mesechymal cells are isolated from bone marrow aspirates and cultured in vitro. The cells are induced to express cardiac-specific markers by culturing them in a cocktail of cytokines. Cells are delivered intramyocardially into viable myocardium using electromechanical mapping (e.g. NOGA system) administered in 9 - 26 injections.
Participants

Participants (n = 48) with ischaemic heart failure due to chronic ischaemic heart disease, with LVEF 15 - 40%. Randomised to cardiopoietic mesechymal cells (c-MSC) (n = 21) and control (n = 15).

Age: 55.7 ± 10.4 years old in the treatment arm and 59.5 ± 8 years old in the control arm.

Male: 95% in treatment arm and 91% in control arm.

Interventions

Treatment arm: c-MSC.

Control arm: not reported.

Dose of cells: 7.33 x 10⁸ cells were delivered intramyocardially.

Outcomes

LVEF, LVESV, LVEDV, 6-minute walk test (exercise), quality of life, oxygen consumption, NYHA class, heart failure-related hospitalisation and mortality.

Duration: 6 months

Method of measurement: Echocardiography

Notes 

Cuzzola 2007

MethodsBone marrow mononuclear cells (BMMNC) were isolated from bone marrow aspirates and injected intramyocardially during cardiac surgery (CABG).
Participants

Participants eligible for inclusion had an acute MI at least 6 months prior to the treatment and LVEF lower than 35%.

Age: not reported.

Male: not reported.

Interventions

Treatment arm: BMMNC + CABG

Control arm: placebo + CABG

Dose of cells: not reported

Outcomes

Safety and LVEF

Duration: 12 months

Method of measurement: not reported.

Notes 

Jimenez-Quevedo 2011

MethodsParticipants were treated with G-CSF for 4 days. CD133+ cells were isolated from peripheral blood during apheresis using the CliniMacs technology (Miltenyi Biotec) to obtain 20 - 30 x 10⁶ cells. The cells were injected transendocardially guided by electromechanical mapping with the NOGA system.
Participants

Participants with angina class II - IV, and ischaemic viable myocardium demonstrated by SPECT, with no option of revascularisation.

Age: 64 ± 10.7 years old.

Male: 86%.

Interventions

Treatment arm: Dose of CD133+ cells : 30 x 10⁶ cells.

Control arm: not clear what they received.

Outcomes

Duration: 3 months.

Primary outcome: Safety.

Notes 

Kakuchaya 2011

Methods

Method of cell isolation: not reported.

Route of delivery: intramyocardial and Intracoronary.

Participants

50 participants, no details given of age, male to female ratio.

24 with ischaemic dilated cardiomyopathy; 26 with idiopathic dilated cardiomyopathy.

Interventions

Treatment arm: CD133+ cells.

Control arm: placebo.

Outcomes

Increase in LVEF and perfusion defects reduction..

Duration: 6 months

Notes 

Minjie 2011

MethodsNo details of cell isolation or cell dose or cell delivery method given.
Participants

50 participants with old miocardial infarction (OMI).

Age: 57.48 ± 7.98 years old.

Male: 94%.

Interventions

Treatment arm: BMSC + CABG.

Control arm: CABG alone.

Outcomes

Primary: LVEF measured and scar size.

Method of measurement: MRI.

Duration: 12 months.

NotesFull details will be required to assess this trial

Nasseri 2012

MethodsNo details of cells isolation.
Participants

60 participants with chronic HF and LVEF < 35%.

Age: 62 (37 - 78) years old.

Male: 97.5%.

Interventions

Treatment arm: CABG and BMSC CD133+ cells.

Control arm: CABG and placebo injection.

Dose of cells: 5.6 x 10⁶ cells (range 2 - 13 x 10⁶), cells were delivered intramyocardially in 20 injections.

Outcomes

LVEF and HF symptoms.

Duration: 6 months.

Method of measurement: MRI and 2D Echo.

Notes 

Shihong 2012

MethodsCD34+ cells were isolated from 120 - 150 ml of bone marrow aspirates by cell selection. Cells were administered via the coronary artery.
Participants

112 participants with refractory angina, randomised to CD34+ cells treatment (n = 56) or placebo arm (n = 56).

Age: 42 - 80 years old in BMSC arm and 43 - 80 years old in the control arm.

Male: 51.7% in BMSC arm and 50% in control arm.

Interventions

Treatment arm: CD34+ cells.

Control arm: placebo (saline).

Dose of cells: not reported.

Outcomes

Angina episodes, consumption of nitroglycerine, exercise time, CCS (angina) class and myocardial perfusion.

Duration: 6 months.

Method of measurement: CCS class and SPECT.

Notes 

Tuma 2010

MethodsBMMNCs were isolated from bone marrow. Cells were delivered via the coronary artery.
Participants

40 participants, 20 with ischaemic heart failure (IHF) and 20 with non-ischaemic heart failure (nIHF).

Age: 67 years old IHF and 64 years old nIHF.

Male: not reported.

Interventions

Treatment arm: BMMNCs.

Control arm: no placebo.

Dose of cells: 12 x 10⁸ cells were administered intracoronarily.

Outcomes

NYHA class, LVEF, LVESV, LVEDV.

Duration: 48 months.

Method of measurement: not reported.

Notes 

Zverev 2006

  1. a

    AE: adverse events; AMI: acute myocardial infarction; BMMNC: bone marrow mononuclear cells; BMSC: bone marrow stem cells; BNP: brain natriuretic peptide; CABG: coronary artery bypass grafting; CCS: Canadian Cardiovascular Society; CPC: circulating progenitor cells; EPC: endothelial progenitor cells; G-CSF: granulocyte colony-stimulating factor; HF: heart failure; IM: intramuscular; IC: intracoronary; LVEF: left ventricular ejection fraction; LVEDV: left ventricular end diastolic volume; LVESV: left ventricular end systolic volume; MACE: major adverse clinical events; MRI: magnetic resonance imaging; MSC: mesenchymal stem cells; MVO₂: myocardial oxygen consumption; NYHA: New York Heart Association; PCI: percutaneous coronary intervention; RCT: randomised controlled trial; SPECT: single-photon emission computed tomography.

MethodsMSCs were isolated form bone marrow and cultured in vitro. BMMNCs were isolated also from bone marrow. Cells were delivered via the coronary artery.
Participants

69 participants, randomised to MSC (n = 18), BMMNC (n = 38) and control (n = 13).

Age: not reported.

Male: not reported.

Interventions

Treatment arms: MSC and BMMNC.

Control arm: no placebo.

Dose of cells: 12 x 10⁸ cells were administered intracoronarily.

Outcomes

Angina episodes, nitroglycerine consumption, myocardial viability and perfusion, LVEF.

Duration: 9 months.

Method of measurement: SPECT and echocardiography.

Notes 

Characteristics of ongoing studies [ordered by study ID]

ACTRN12611000219987

Trial name or titleA study of the effect on heart function of direct myocardial injection of autologous bone marrow for treatment of patients with "end-stage" ischaemic heart failure.
MethodsA randomised, blinded, parallel, placebo-controlled, safety/efficacy study.
Participants

End-stage ischaemic heart failure:

  1. Age 18 - 80 years.

  2. CCS classification II - IV angina and/or NYHA classification II - III heart failure symptoms.

  3. Received stable and "best" cardiac medical therapy including diuretics, long-acting nitrates, beta-blocker, and angiotensin-converting enzyme inhibitors without control of symptoms.

  4. Not suitable for conventional revascularisation (due to diffuse disease, chronic total occlusion, lack of graftable vessels or any combination thereof).

  5. LVEF < 40% by echocardiography.

  6. Recent coronary angiogram (within the last 6 months) to document the coronary anatomy and insure the presence of coronary artery disease (CAD) that is not amenable to standard revascularisation procedures.

  7. Serum creatinine less than 250 mmol/L, normal liver function, and normal blood count: white blood cell (WBC) count, granulocytes, platelet count, haemoglobin (Hb).

  8. Reversible perfusion defect on SPECT.

  9. Hemodynamically stable.

  10. Participant is willing to comply with specified follow-up evaluations.

Interventions

Treatment arm 1: Endomyocardial injection of autologous bone marrow mononuclear cells (10 to 12 injections of 0.1 ml of bone marrow of concentration of 10⁷ cells per mL at each predetermined target site) via NOGA electromechanical mapping system.

Treatment arm 2: Blinded placebo percutaneous endomyocardial injection.

Outcomes

Primary outcome:

LVEF measured by MRI (6 months).

Secondary outcomes:

  1. Incidence of adverse events (6 months).

  2. Clinical status (NYHA, CCS, anginal attacks, 6-minute walk test) (3/6 months).

  3. Exercise capacity (modified Bruce protocol treadmill test; MVO₂ measurement) (3/6 months).

  4. Myocardial perfusion imaging (SPECT) (6 months).

Starting dateMay 2011
Contact informationDepartment of Medicine, The University of Hong Kong, MR 1928, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong (Principal Investigator: Dr HF Tse). Contact: Dr Suku Thambar (melissa.chaplin@hnehealth.nsw.gov.au)
Notes 

EUCTR2009-016364-36-NL

Trial name or titleInjection of autologous bone marrow cells into damaged myocardium of no-option patients with ischaemic heart failure: a randomised placebo controlled trail. - cell therapy for ischaemic heart failure
MethodsA randomised, double-blind, cross-over, placebo-controlled trial.
Participants

Ischaemic heart failure:

  1. Ischaemic heart failure NYHA class 3 or 4 despite optimal pharmacological and non- pharmacological therapy.

  2. No candidate for (repeat) surgery (revascularisation, valve repair or ventricular reconstruction).

  3. No candidate for (repeat) percutaneous revascularisation.

  4. Optimal resynchronisation therapy, or no candidate for resynchronisation therapy.

  5. Male or female, > 18 years and < 75 years old.

  6. Life expectancy more than 6 months.

  7. Able to perform an exercise tolerance test prior to therapy.

  8. Able and willing to undergo all the tests used in this protocol including the travelling involved.

  9. Written informed consent.

Interventions

Treatment arm 1: Intracardiac administration of bone marrow mononuclear cells.

Treatment arm 2: Intracardiac administration of placebo.

Outcomes

Primary outcomes:

  1. Left ventricular global ejection fraction as assessed by Gated SPECT.

  2. LV regional wall motion by echocardiography.

  3. FDG-SPECT for assessment of viability and hibernation.

  4. Myocardial innervation imaging (MIBG-SPECT) for assessment of myocardial innervation.

  5. Exercise capacity by bicycle exercise testing with VO₂ measurement.

  6. Quality of Life assessed using the MLHF questionnaire.

Secondary outcomes:

Safety (incidence of arrhythmias via Holter monitoring, inflammation and myocardial damage)

Starting dateJuly 2010
Contact informationNone identified
Notes 

EUCTR2011_001117-13-GB

Trial name or titleEfficacy and safety of bone marrow-derived mesenchymal cardiopoietic cells (C3BS-CQR-1) for the treatment of chronic advanced ischaemic heart failure.
MethodsA phase III, randomised, parallel, double-blind, sham-controlled safety/efficacy/pharmacoeconomic study.
Participants

Congestive heart failure:

  1. Age ≥ 18 and < 80 years.

  2. Systolic dysfunction with LVEF ≤ 30% as assessed by echocardiography.

  3. Ischaemic heart failure without known need for revascularisation.

  4. MLHFQ score > 30.

  5. Ability to perform a 6-minute walk test > 100 m and ≤ 400 m.

  6. History of hospitalisation for HF within 12 months prior to screening.

  7. NYHA Class III or IV despite optimal standard of care or INTERMACS class 4, 5, 6 or 7.

  8. Use of ACE inhibitor and/or ARB; and beta blocker, for at least 3 months prior to screening visit, unless intolerant or contraindicated.

  9. Stable dosing of ACE inhibitor, ARB, beta blocker, aldosterone blocker, and diuretics for at least 1 month prior to screening visit, defined as ≤ 50% change in total dose of each agent.

  10. Willing and able to give written informed consent.

Interventions

Treatment arm 1: autologous bone marrow-derived cardiopoietic stem cells

Treatment arm 2: Sham control.

Outcomes

Primary outcome:

Efficacy (9 months) based on a hierarchical composition of:

  1. All-cause mortality.

  2. Worsening of heart failure events requiring intensive care with intravenous diuretics or inotropic support or readmission.

  3. Change in MLHFQ total score.

  4. Change in 6-minute walk distance.

  5. Change in LVESV as assessed by echocardiography.

  6. Change in LVEF as assessed by echocardiography.

Secondary outcomes:

  1. Occurrence of the following clinical events: death and cause of death, readmissions and cause of readmission, cardiac transplantation, myocardial infarction, stroke (12/24 months).

  2. Incidence of serious adverse events [12/24 months]

  3. Incidence of non-serious adverse events (12 months).

  4. Time to all-cause mortality (12 months).

  5. Worsening of heart failure events requiring intensive care with intravenous diuretics or inotropic support or readmission (12 months).

  6. Aborted sudden death events, defined as resuscitated sudden death or appropriate AICD firing for severe ventricular tachyarrhythmias (12 months).

  7. Additional tertiary (explorative) outcomes including the effect of each of the components of the composite endpoint at 39 and 52 weeks.

Starting dateFebruary 2013
Contact informationCardio3 BioSciences SA, Mont-Saint-Guibert, 1435, Belgium. Contact: infor@c3bs.com
Notes 

ISRCTN71717097

Trial name or titleBone-marrow derived stem cell transplantation in patients undergoing left ventricular restoration surgery for dilated ischaemic end-stage heart failure: a randomised blinded controlled trial (TransACT 2)
MethodsA double-blind randomised placebo-controlled trial.
Participants

End-stage heart failure:

  1. Previous anterior myocardial infarction (with evidence of large surgically excludible scar at cardiac MRI).

  2. Significant LV dilation (LVESV index greater than or equal to 60 ml/m²).

  3. LVEF less than or equal to 35%.

  4. NYHA class III/IV and 1 episode of congestive heart failure (CHF) requiring medical attention.

  5. Elective left ventricular restoration surgery indicated.

  6. Elective CABG indicated to bypass stenoses or occlusions of coronary arteries.

  7. Participant aged ≥ 16 years and< 80 years old, either sex.

Interventions

Treatment arm 1: Surgical ventricular restoration and transplantation of autologous CD133+.

Treatment arm 2: Surgical ventricular restoration and injection of placebo, i.e. autologous plasma.

Outcomes

Primary Outcome:

Regional LV thickening of the 'affected' segments 6 months after surgery.

Secondary Outcomes:

  1. Mid-term generic and cardiac-specific health status and quality of life, measured at baseline and 6 months follow-up.

  2. End systolic volume and stroke volume quantified by cardiac MRI, measured at baseline (3 - 5 days postoperatively) and 6 months follow-up.

  3. Myocardial injury throughout the duration of the study by measuring troponin I levels (24 hours pre-operatively, surgery, 4, 12, 24 hours postoperatively, 6 weeks and 6 months follow-up).

Starting dateAugust 2009.
Contact informationUniversity of Bristol, Bristol Royal Infirmary. Contact: Mr R Ascione (r.ascione@bristol.ac.uk).
Notes 

ISRCTN75217135

Trial name or titleA pilot study to evaluate the efficacy of combined transplantation of progenitor cells and coronary artery bypass grafting (TOPCABG)
MethodsRCT
Participants10 participants undergoing CABG.
Interventions

Treatment arm 1: stem cells (5 participants).

Treamment arm 2: heparinised saline (5 participants).

Outcomes Primary outcome: to show improvements in myocardial function, regional wall motion and myocardial perfusion.
Starting dateJanuary 2004
Contact informationSouthampton University Hospitals NHS Trust, Level D, East Wing, Southampton General Hospital, Tremona Road, Southampton SO16 6YD. Contact: Mr D Varghese (dvarghese@btinternet.com).
NotesCompleted/not recruiting but no publications identified.

NCT00285454

Trial name or titleCell repair in heart failure
MethodsA phase I/II, parallel, randomised, double-blind, placebo-controlled, single-centre study.
Participants

Ischaemic heart failure and no revascularisation options:

  1. Symptomatic ischaemic multivessel coronary artery disease not suitable for standard revascularisation procedures such as CABG, PCI, LVAD, or heart transplant.

  2. Area of reversible inducible ischaemia (> 10% of LV on SPECT) performed not more than 6 months prior to study treatment.

  3. LVEF < 45% on optimal medical therapy.

  4. NYHA class II - IV stable on optimal medical therapy for at least 30 days.

  5. Written informed consent and agree to attend hospital appointments for 1 year.

  6. Men and women 18 to 80 years of age.

Interventions

Treatment arm 1: Autologous bone marrow mononuclear cells. 5% HSA.

Treatment arm 2: Placebo: 5% HSA.

Route of administration: retrograde coronary venous delivery The total dose of bone marrow mononuclear cells or placebo will be divided into 2, each administered as a 10 ml bolus into selected coronary veins. There will be significant participant heterogeneity regarding size of ischaemic viable territory present and anatomy of venous system. The aim is to treat 2 veins, individual SPECT and venogram results will be used to direct the venous anatomy to be targeted. An attempt will be made to cover as large an area as possible of a participant’s ischaemic viable territory. The total dose of cells will remain constant between participants.

Outcomes

Primary Outcomes:

  1. Safety (up to one year).

  2. Efficacy.

Co-primary endpoints at 180 Days

  1. Perfusion (MIBI SPECT).

  2. Function (CMR).

Secondary Outcomes:

  1. Efficacy (180 days).

  2. Perfusion (CMR).

  3. Function (ECHO, SPECT).

  4. Exercise (VO₂ Max).

  5. QOL.

Starting dateJanuary 2008
Contact informationThe Department of Gene Therapy, The National Heart and Lung Institute, Imperial College London (Principal Investigator: EWF Alton) and The Royal Brompton Hospital, London, UK (Principal Investigator: JR Clague). Contact: Amanda Heini-Green, (a.heinl-green@imperial.ac.uk); Eric Alton (e.alton@imperial.ac.uk).
Notes

Estimated completion date: December 2008.

The recruitment status of this study is unknown because the information has not been verified recently.

NCT00362388

Trial name or titleCell therapy in chronic ischaemic heart disease
MethodsA phase III, parallel, multicentre, randomised, double-blind, placebo-controlled study.
Participants

Severe, chronic IHD:

  1. Diagnosis of chronic, severe, diffuse, multivessel atherosclerotic coronary artery disease (CAD) referred for CABG.

  2. Echocardiogram-assessed LVEF between 25% and 55% (Simpson's rule).

  3. Angina (or equivalent) functional class II to IV (CCS) despite maximally tolerated medical therapy.

  4. Abnormal myocardial perfusion tests: i. Cardiac scintigraphy ii. Magnetic resonance imaging iii. Dobutamine-atropine stress-echocardiogram.

  5. Non-candidates for PCI due to ANY of the following: i. High risk lesion ii. Extensive lesion iii. Diffuse, small vessel disease.

  6. Non-candidates for a complete CABG, or candidates for a complete CABG in whom, according to an expert panel, there is a high probability of failure of the grafts due to the extension and severity of the disease, with diffuse, small vessel involvement.

  7. Signed, written informed consent, according to the National Guidelines for Clinical Trials.

Interventions

Treatment arm 1: Intramyocardial injection of autologous BMC.

Treatment arm 2: placebo.

Co-intervention: CABG

Outcomes

Primary Outcomes:

  1. Reduction in the ischaemic score (global/regional) (12 months).

  2. Increase in LVEF (12 months).

Secondary Outcomes: All-cause and cardiovascular mortality during the first year.

  1. Increase in VO₂max.

  2. Increase in quality of life.

  3. Reduction in angina/heart failure functional class (12 months).

  4. Percentage of participants with a 5% increase in LVEF (6 and 12 months).

Starting dateJanuary 2006.
Contact informationHeart Institute (InCor), Hospital das Clinicas, University of São Paulo Medical School, São Paulo, SP, Brazil, 05403-900 (Principal Investigator: Prof. Sergio A. de Oliveira).
NotesStudy terminated due to low enrolment.

NCT00418418

Trial name or titleCombined CABG and stem-cell transplantation for heart failure
MethodsA phase II, prospective, randomised, double-blind, placebo-controlled study.
Participants

Symptomatic heart failure with low LVEF scheduled to coronary bypass operation:

  1. Symptomatic heart failure.

  2. Scheduled for CABG.

  3. Aged 18 to 75 years.

  4. Informed consent obtained.

  5. People of either gender, evaluated in cardiovascular laboratory and scheduled for CABG with moderate heart failure, will be eligible.

  6. NYHA II - IV symptoms.

  7. LVEF in screening echocardiography 15% to 45%.

  8. Optimal heart failure medication and coronary medication before operation, containing at least 2 heart failure drugs: must have ACE inhibitor, or AT II blocker, and/or beta-blocker together with diuretics, digitalis or aldosterone antagonist, and coronary medication: a statin and anticoagulation, either aspirin or clopidogrel.

Interventions

Treatment arm 1: Coronary bypass operation performed via sternotomy during cardiac arrest. Bone marrow aspirated from the iliac crest (100 ml). During the operation, the aspirate is transported to the stem cell laboratory, where the sample is centrifugated through Ficoll. During cardiac arrest, stem cells are directly injected to myocardium. The amount of the cells varies individually (5 - 1000 x 10⁶ cells), the cells are diluted in autologous serum (5 ml).

Treatment arm 2: Identical procedure, with intramyocardial injection of autologous serum.

Outcomes Primary Outcomes: Does a bone marrow transplantation therapy increase the ejection fraction of the heart measured with MRI, when compared with placebo treatment? (12 months).
Secondary Outcomes: Does a bone marrow transplantation therapy increase any cardiac function parameter measured by an echocardiography, MRI or PET ischaemia area, when compared with no treatment group? (6/12 months).
Does a bone marrow transplantation therapy improve BNP-value? (3/6/12 months).
Does a bone marrow transplantation therapy decrease hospitalisation or the days stayed in hospital?
Do pericardial fluid growth factor concentrations correlate to left ventricular function improvement? (up to 12 months).
Does autologous cardiac stem cell quality correlate to left ventricular function improvement? (3/6/12 months).
Starting dateOctober 2006
Contact informationDepartment of Cardiothoracic Surgery, Helsinki University, Meilahti Hospital, Finland (Principal Investigator). Contact: (ari.harjula@hus.fi); Dr T Patila (tommi.patila@hus.fi)
Notes

Estimated completion date: December 2010.

The recruitment status of this study is unknown because the information has not been verified recently.

NCT00644410

Trial name or titleAutologous mesenchymal stromal cell therapy in heart failure
MethodsA phase I/II, randomised, parallel, double-blind (participant, caregiver, investigator, outcome assessor) safety/efficacy study.
Participants

Congestive heart failure:

  1. aged 30 - 80 years.

  2. LVEF < 45%.

  3. NYHA class II or III.

Interventions

Treatment arm 1: Mesenchymal stromal cells 20 - 40 ml administered by electromechanical mapping (NOGA-XP) and intramyocardial injections with the 8F-sized Myostar mapping-injection catheter.

Treatment arm 2: Saline placebo.

Outcomes

Primary outcome:

Change in LVESV, measured by MRI or computed tomography (1/3/56/12 months).

Secondary outcomes:

  1. LVEF, LVESV, LVEDV, wall thickness, systolic wall thickening measured by MRI or CT.

  2. Myocardial scar tissue measured by MRI.

  3. Safety of treatment.

  4. Clinical symptoms.

  5. Functional capacity.

  6. Weekly angina attacks.

  7. Use of short-term nitroglycerine.

  8. Quality of life.

Starting dateSeptember 2008
Contact informationCardiac Stem Cell Laboratory and Catheterisation Laboratory 2014, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (Dr AB Mathiasen (abbe@dadlnet.dk).
NotesEstimated completion date: September 2013.

NCT00690209

Trial name or titleBypass surgery with stem cell therapy in chronic ischaemic cardiopathy
MethodsA phase II, parallel, randomised, single-blind (participant) controlled study.
Participants

Ischaemic heart disease:

  1. Aged 18 - 75 years.

  2. Chronic IHD.

  3. LVESV > 140 ml.

  4. Poor global contractile function (LVEF < 40%).

  5. Substantial amount of residual viability (> 30% of left ventricle).

Interventions

Treatment arm 1: surgical revascularisation alone.

Treatment arm 2: surgical revascularisation associated with autologous bone marrow-derived stem cells injection in viable territories.

Outcomes

Primary outcome: Evolution of left ventricular volumes and contractility.

Secondary outcome: Functional status.

Starting dateMay 2008
Contact informationDepartments of CardiacSurgery, Cardiology and Radiology, University Hospital, Clermont-Ferrand, France (Principal Investigator: Dr J Lipiecki. Contact: Patrick Lacarin (placarin@chu-clermontferrand.fr).
Notes

Estimated completion date: June 2011.

The recruitment status of this study is unknown because the information has not been verified recently.

NCT00747708

Trial name or titleBone marrow derived adult stem cells for chronic heart failure (REGEN-IHD)
MethodsA phase II/III, randomised, parallel, double-blind (participant, investigator, outcome assessor), safety/efficacy study.
Participants

Chronic ischaemic heart failure:

  1. Symptomatic, with a diagnosis of heart failure secondary to ischaemic heart disease who are on optimal heart failure treatment and no further treatment options available.

  2. Participant has been considered for an implantable defibrillator in keeping with NICE guidelines.

Interventions

Treatment arm 1: G-CSF injections followed by bone marrow aspiration. Intramyocardial injections of bone marrow-derived stem/progenitor cells or placebo infusion through a percutaneous route.

Treatment arm 2: G-CSF injections followed by bone marrow aspiration. Intramyocardial injections of placebo infusion through a percutaneous route.

Outcomes

Primary Outcome:

Change in global LVEF (12 months).
Secondary Outcomes:

Change in quality of life (6 months).
Occurence of MACE (12 months).
Change in quality of life (12 months).
Change in NT-proBNP (6 months).
change in NYHA class (12 months).

Starting dateAugust 2005.
Contact informationLondon Chest Hospital, Barts and the London NHS Trust, London, UK (Prinicpal Investigator: Anthony Mathur).
NotesEstimated completion date: May 2013.

NCT00768066

Trial name or titleThe transendocardial autologous cells (hMSC or hBMC) in ischaemic heart failure Ttial (TAC-HFT)
MethodsA phase I/II, randomised, parallel, double-blind (participant, investigator), safety/efficacy study.
Participants

Ischaemic heart failure:

  1. Diagnosis of chronic ischaemic left ventricular dysfunction secondary to MI.

  2. Be a candidate for cardiac catheterisation.

  3. Been treated with appropriate maximal medical therapy for heart failure or post-infarction left ventricular dysfunction.

  4. Ejection fraction ≤ 50%.

  5. Able to perform a metabolic stress test.

Interventions

Treatment arm 1: 40 million autologous human mesenchymal cells/mL delivered in either a dose of 0.25 mL per injection for a total of 1 x 10⁸ hMSCs x 10 injections or a dose of 0.5 mL per injection for a total of 2 x 10⁸ x 10 injections. The injections will be administered transendocardially during cardiac catheterisation using the Biocardia Helical Infusion Catheter.

Treatment arm 2: 40 million autologous human bone marrow cells/mL delivered in either a dose of 0.25 mL per injection for a total of 1 x 10⁸ hBMCs x 10 injections or a dose of 0.5 mL per injection for a total of 2 x 10⁸ x 10 injections. The injections will be administered transendocardially during cardiac catheterisation using the Biocardia Helical Infusion Catheter.

Treatment arm 3: 0.5 mL injections of phosphate-buffered saline (PBS) and 1% HSA x 10 injections. The injections will be administered transendocardially during cardiac catheterisation using the Biocardia Helical Infusion Catheter.

Outcomes

Primary outcome:

Incidence of TE-SAE define as composite of death, non-fatal MI, stroke, hospitalisation for worsening heart failure, cardiac perforation, pericardial tamponade, ventricular arrhythmias > 15 sec. or with haemodynamic compromise or atrial fibrillation (1 month).

Secondary outcomes:

  1. Infarct scar size and regional LV function (MRI) (6/12 months).

  2. Wall thickening, LVEF, LVESV, LVEDV (MRI, echocardiogram) (6/12 months).

  3. Myocardial perfusion (MRI) (6/12 months).

  4. Peak VO₂ by treadmill determination (6/12 months).

  5. 6-minute walk test (6/12 months).

  6. NYHA functional class (6/12 months).

  7. MLHF questionnaire (6/12 months).

  8. Incidence of MACEs (6/12 months).

  9. Ectopic tissue formation (6/12 months).

  10. 48-hour ambulatory ECG recordings (6/12 months).

  11. Haematology, clinical chemistry and urinalysis values (6/12 months).

  12. Pulmonary function (forced expiratory volume in 1 second) (6/12 months).

  13. Serial troponin and CK-MB values (6/12 months).

  14. Post-cardiac catheterisation echocardiogram (day 1 post-catheterisation).

Starting dateAugust 2008.
Contact informationUniversity of Miami Miller School of Medicine, Miami, Florida, US 33136 (Principal Investigators: Dr JM Hare, Dr AW Heldman, Dr JP Zambrano).
NotesEstimated completed date: August 2012.

NCT00790764

Trial name or titlePhase II combination stem cell therapy for the treatment of severe coronary ischaemia
MethodsA phase II,randomised, placebo-controlled, safety/efficacy study.
Participants

Severe coronary ischaemia:

  1. Age 18 to 80.

  2. Men or women.

  3. Angina pectoris: CCS Class III or IV or symptoms consistent with angina equivalent (dyspnoea) CCS Class III or IV (Functional Class).

  4. Chronic coronary artery disease in at least 1 epicardial vessel with stenosis > 70% by coronary angiography within the last 6 months.

  5. Stable medical therapy for at least 1 month.

  6. Reversible perfusion defects by SPECT.

  7. Not a candidate for coronary artery by-pass surgery due to poor targets or small vessels and not a candidate for percutaneous intervention due to small vessels or unreachable coronary lesions due to complicated anatomy.

Interventions

Enrolled individuals (60) will be divided in 2 treatment groups for the infusion of the cell /placebo product:

  1. Treatment Group A (30 individuals, including patients and placebo controls) will receive the product by intracoronary infusion.

  2. Treatment Group B (30 individuals, including patients and placebo controls) will receive the product by transendocardial injections. In turn, each Treatment Group will consist of 2 subgroups of individuals that will receive the infusion of 1 of the 2 doses established of the cell product:

  3. In treatment SubGroup 1, 10 individuals will receive the 'low dose' of the cell product and 5 individuals will receive the placebo product.

  4. In treatment SubGroup 2, 10 individuals will receive the 'high dose' of the cell product and 5 individuals will receive the placebo product.

For the cell product, proper aliquots of each cell type will be taken to fulfill the doses established for this protocol. The 2 aliquots will be mixed and resuspended to a final volume of 3 ml in the 'Final Suspension Medium' which consists of Dulbecco's Phosphate Buffered Saline (DPBS), containing 5% HSA.

For placebo, 3 ml of the 'Final Suspension Medium' which consists of Dulbecco's Phosphate Buffered Saline (DPBS), containing 5% HSA will be transferred to a 5 ml syringe.

Outcomes Primary Outcome: Safety as measured by laboratory assessments, ECG and temperature (2 weeks).
Secondary Outcome: Efficacy as measured by SPECT scan, MUGA scan and 2D echoradiogram (6 months).
Starting dateNovember 2008.
Contact informationTCA Cellular Therapy, Covington, Louisiana, United States, 70433 (Principal Investigator: Dr Patrick Lacarin).
Notes

Estimated completion date: November 2011.

The recruitment status of this study is unknown because the information has not been verified recently.

NCT00820586

Trial name or titleIntramyocardial delivery of autologous bone marrow.
MethodsA phase II, parallel, randomised, double-blind (participant, investigator), safety/efficacy study.
Participants

Refractory angina:

  1. Participants > 21 years old.

  2. Participants with functional class (CCS) III or IV angina.

  3. Participants with LVEF < 30%.

  4. Attempted 'best' tolerated medical therapy.

  5. Clinical signs and symptoms of myocardial ischaemia with reversible ischaemia on perfusion imaging.

  6. Participant deemed to be a poor candidate or at high surgical risk.

  7. Participant must be able to complete a minimum of 2 minutes but no more than 10 minutes exercise test (Bruce Protocol).

  8. Participant (or their legal guardian) understands the nature of the procedure and provides written consent prior to the procedure.

  9. Participant is willing to comply with specified follow-up evaluations.

  10. Participant must develop angina and a horizontal or down-sloping ST-segment depression of < 1 mm during exercise, compared to pre-exercise ST segment, 80 ms from the J point or moderate angina with or without the above ST segment changes.

Angiographic inclusion criteria:

  1. Severe obstruction (lumen diameter stenosis > 70%) in a coronary or surgical conduit felt to be solely or partially responsible for angina and myocardial ischaemia.

  2. There must be at least 1 coronary or surgical conduit with < 70% diameter stenosis.

  3. Poor candidate for PCI of treatment zone.

  4. Poor candidates for surgical revascularisation procedures, such as inadequate target coronary anatomy or lack of potential surgical conduits.

Interventions

Treatment arm 1: Direct intramyocardial percutaneous delivery of autologous total bone marrow-derived total mononuclear cells or selected CD34+ bone marrow-derived cells.

Treatment arm 2: Not specified.

Outcomes

Primary Outcome:

Incidence of major adverse cardiac events (MACE), defined as a combined endpoint of death, acute MI (Q-wave and non-Q wave), revascularisation procedures (percutaneous or surgical), and periprocedural complications (i.e., left ventricular perforation with haemodynamic consequences requiring pericardiocentesis, and stroke) (1/3/6/12 months).

Secondary Outcomes:

  1. Change in CCS angina classification score from baseline (12 months).

  2. Changes in the quality of life, as assessed according to the Seattle Angina Questionnaire.

  3. Change in exercise duration and exercise tolerance using standardised treadmill exercise testing from baseline (6/12 months).

  4. Cumulative number of hospitalisations for coronary ischaemia and CHF (12 months).

  5. SPECT-chances in global and regional radionuclide perfusion at rest, peak stress, and redistribution from baseline (1/6/12 months).

  6. Change in angiographic collateral score (6 months).

  7. Change in global and regional myocardial contractility (assessed by echocardiography) from baseline (6/12 months).

Starting dateJanuary 2009.
Contact informationAntonio Colombo, Director of Invasive Cardiology Unit, IRCCS San Raffaele, Milan, Italy.
Notes

Estimated completion date: February 2012.

This study has suspended participant recruitment (due to lack of further funding support).

NCT00950274

Trial name or titleIntramyocardial transplantation of bone marrow stem cells in addition to coronary artery bypass graft (CABG) surgery (PERFECT)
MethodsA phase III, randomised, parallel, double-blind (participant, caregiver, investigator, outcomes assessor) efficacy study.
Participants

Chronic ischaemic coronary artery disease:

  1. Coronary artery disease after myocardial infarction with indication for CABG surgery.

  2. Currently reduced global LVEF assessed at site by cardiac MRI at rest (25% ≤ LVEF ≤ 50%).

  3. Presence of a localised akinetic/hypokinetic/hypoperfused area of LV myocardium for defining the target area.

  4. Informed consent of the participant.

  5. Aged ≥ 18 and < 80 years.

  6. Not pregnant and do not plan to become pregnant during the study. Women with childbearing potential must provide a negative pregnancy test within 1 - 7 days before OP and must be using oral or injectable contraception (non-childbearing potential is defined as post-menopausal for at least 1 year or surgical sterilisation or hysterectomy at least 3 months before study start).

Interventions

Treatment arm 1: Intramyocardial injection of 5 mL CD133+ cells (0.5 - 5 x 10⁶ cells) suspended in physiological saline + 10% autologous serum intramyocardially during CABG surgery.

Treatment arm 2: Intramyocardial injection of 5 mL of physiological saline + 10% autologous serum intramyocardially during CABG surgery.

Outcomes

Primary Outcome:

LVEF at rest, measured by MRI (6 months).
Secondary Outcomes:

  1. Change in LVEF as assessed by MRI and echocardiography (early postoperatively and 6 months).

  2. Regional contractility in the AOI/Change in LVESD, LVEDD as assessed by echocardiography (early postoperatively (discharge), 6 months).

  3. Physical exercise capacity determined by 6-minute walk test (early postoperatively (discharge), 6 months).

  4. NYHA and CCS class (early postoperatively (discharge), 6 months).

  5. MACE (cardiac death, myocardial infarction, secondary intervention/reoperation, ventricular arrhythmia) (6 months).

  6. QoL-score: MLHF Questionnaire, SF-36 Questionnaire, EQ-5D Questionnaire (3 months, 6 months).

Starting dateJuly 2009.
Contact informationUniversity of Rostock, Germany, 18057 (Principal Investigator: Dr G Steinhoff (gustav.steinhoff@med.uni-rostock.de)).
NotesEstimated completion date: December 2013.

NCT01033617

Trial name or titleIMPACT-CABG Trial: IMPlantation of Autologous CD133+ sTem cells in patients undergoing CABG
MethodsA phase II, parallel, randomised, double-blind (participant, caregiver, investigator, outcomes assessor), placebo-controlled safety/efficacy study.
Participants

Myocardial infarct; heart failure:

  1. Age ≥ 18 years, and ≤ 75 years.

  2. People with severe chronic ischaemic cardiomyopathy manifested by CCS class II or greater angina, and/or NYHA class II or greater, and who have undergone diagnostic coronary angiography demonstrating ≥ 70% diameter narrowing of at least 2 major coronary arteries or branches or ≥ 50% diameter narrowing of the left main coronary artery.

  3. A significant left ventricular systolic dysfunction evaluated by echocardiography or LV angiography (LVEF ≤ 45% but ≥ 25%) due to prior myocardial infarction. This area of left ventricular dysfunction should be akinetic or severely hypokinetic, not dyskinetic or aneurismal, when assessed by echocardiography or LV angiogram. This territory should be irrigated by 1 or a branch of the 3 major vascular territories (i.e. right coronary artery, left circumflex, or left anterior descending artery distribution) that will be bypassed during the surgical procedure.

  4. No contraindications or exclusions (see below).

  5. Willingness to participate and ability to provide informed consent.

Interventions

Treatment arm 1: Autologous CD133+ stem cells (total 2 ml with 10 - 15 injections) injected into the myocardium.

Treatment arm 2: Placebo solution containing plasma injected into the myocardium.

Outcomes

Primary Outcomes:

  1. Freedom from MACE: cardiac death, myocardial infarct, repeat coronary bypass grafting or percutaneous intervention of bypassed artery (6 months).

  2. Freedom from major arrhythmia: sustained ventricular tachycardia or survived sudden death (6 months).

Secondary Outcomes:

  1. Regional myocardial perfusion and function assessed by magnetic resonance scans (6 months).

  2. Device performance endpoint: Feasibility to produce from 100 ml of bone marrow aspiration a final cell product that contains a target CD133+ cells higher than 0.5 million with a purity superior to 30% and a recovery superior to 10% (baseline).

  3. Symptom severity and quality of life after CABG surgery (6 months).

Starting dateDecember 2009.
Contact informationCentre de recherche du CHUM (CRCHUM), Montreal, Quebec, Canada, H2W 1T8 (Principal Investigators: Dr N Noiseux, Dr S Mansour, Dr D-C Roy). Contact: Nicolas Noiseux, MD, MSc, FRCSC, (noiseuxn@videotron.ca).
Notes

Estimated completion date: July 2013.

This study is currently recruiting participants.

NCT01074099

Trial name or titleFeasibility study of BMAC enhanced CABG
MethodsA phase I/II randomised, single-blind (participant) safety/efficacy study.
Participants

Congestive heart failure:

  1. Age > 18 years and ability to understand the planned treatment.

  2. People with ischaemic congestive heart failure requiring bypass surgery.

  3. Congestive heart failure with LVEF ≤ 40%.

  4. Serum bilirubin, SGOT and SGPT ≤ 2.5 time the upper level of normal.

  5. Serum creatinine < 3.0 or no dialysis.

  6. NYHA performance status ≥ 3.

  7. Negative pregnancy test (in women with childbearing potential).

  8. Participant has read and signed the IRB-approved Informed Consent form

  9. Hematocrit ≥ 28.0%, WBC count ≤ 14,000, Platelet count ≥ 50,000, Creatinine ≤ 3.0 mg/Dl, and/or no dialysis, INR ≤ 1.6 unless on Coumadin, or PTT < 1.5 x control (to avoid bleeding complications). Participants on Coumadin will be corrected prior to the procedure and must have an INR < 1.6 at the time of randomisation/surgery.

Interventions

Treatment arm 1: 60 mL of bone marrow drawn, concentrated in a SmartPRep2 centrifuge and concentrated nucleated cells injected into areas of ischaemic myocardium during CABG.

Treatment arm 2: CABG only.

Outcomes

Primary Outcomes:

  1. Change in cardiac status (classification) (12 months).

  2. NYHA or CCS classification evaluation.

Secondary Outcome: Safety as measured by frequency and severity of adverse events (12 months.

Starting dateFebruary 2011.
Contact informationHarvest Technologies, University of Utah (Principal Investigator: Amit Patel, MD).
NotesStudy terminated (pilot results in change to protocol, new study needed).

NCT01150175

Trial name or titleDirect endomyocardial injection of autologous bone marrow cells to treat ischaemic heart failure (END-HF)
MethodsA phase II, randomised, double-blind (participant, investigator), parallel safety/efficacy study.
Participants

Ischaemic heart failure:

  1. Age 18 - 80 years old.

  2. CCS Class II - IV angina and/or NYHA class II - III HF symptoms.

  3. Received stable and "best" cardiac medical therapy including long-acting nitrates, beta-blocker, and ACE inhibitors without control of symptoms.

  4. Not suitable for conventional revascularisation by their referring cardiologist.

  5. LVEF < 40% by echocardiography.

  6. Recent coronary angiogram (within the last 6 months) to document the coronary anatomy and insure the presence of CAD that is not amenable to standard revascularisation procedures.

  7. Creatinine < 250 mmol/L, normal liver function, and normal blood count: WBC, granulocytes; platelet count, Hb.

  8. Reversible perfusion defect on SPECT.

  9. Able to walk on treadmill.

  10. Haemodynamically stable.

  11. Participant is willing to comply with specified follow-up evaluations.

  12. All participants give written informed consent.

Interventions

Treatment arm 1: Endomyocardial injection of autologous bone marrow cells.

Treatment arm 2: Endomyocardial injection of plasma.

Outcomes

Primary Outcome:

MRI ejection fraction changed from baseline (6 months).
Secondary Outcomes:

Changes in exercise duration and MVO₂ using standardised treadmill testing (modified Bruce protocol) from baseline (6 months).

Starting dateJuly 2008.
Contact informationUniversity of Hong Kong (Principal Investigator: Prof HF Tse). Contact: Dr T Santoso (tsantoso@cbn.net.id).
Notes

Estimated completion date: December 2011.

The recruitment status of this study is unknown because the information has not been verified recently.

NCT01214499

Trial name or titleProspective, controlled and randomised clinical trial on cardiac cell regeneration with laser and autologous bone marrow stem sells, in patients with coronary disease and refractory angina
MethodsA phase II, randomised, single-blind (outcome assessor), parallel safety/efficacy study.
Participants

Coronary disease and refractory angina:

  1. Aged > 18 years of age.

  2. At least 1 area of myocardial ischaemia or chronic myocardial infarction of the left ventricle demonstrated by any imaging technique not amenable to conventional revascularisation and angina refractory to medical treatment.

  3. LVEF > 25% measured in the 6 months prior to the procedure.

  4. Participants must be mentally competent to give consent for inclusion in the clinical trial.

Interventions

Treatment arm 1: Transmyocardial revascularisation (TMR) with Holmium YAG laser plus the participant's own stem cells extracted from bone marrow.

Treatment arm 2: Transmyocardial revascularisation (TMR) with Holmium YAG laser.

Outcomes

Primary Outcome:

NYHA classification for angina (12 months).
Secondary Outcomes:

  1. The demographic, intra and postoperative variables (12 months).

  2. Percentage of ischaemic area (SPECT) and maximum effort capacity before the occurrence of the angina (12 months).

  3. LVEF, LVESV, LVEDV will be examined through an echocardiogram and a pre- and postoperative cardiac magnetic resonance imaging study (12 months).

  4. The EQ-5D questionnaire (standardised instrument for use as a measure of health outcome) will be completed for the subjective assessment of the quality of life that the participant perceives to have (12 months).

Starting dateOctober 2010.
Contact informationCardiovascular Surgery Service, Hospital Universitario de La Princesa, Madrid, Spain, 28006 (Principal Investigator: Dr GR Copa (guillermo_reyes_copa@yahoo.es)).
Notes

Estimated completion date: October 2012.

The recruitment status of this study is unknown because the information has not been verified recently.

NCT01267331

Trial name or titleCell therapy in patients with chronic ischaemic heart disease undergoing cardiac surgery
MethodsA phase I/II, randomised, double-blind (participant, caregiver), parallel safety/efficacy study.
Participants

Severe, chronic ischaemic disease:

  1. Aged between 18 and 75 years.

  2. Scheduled to undergo CABG.

  3. At least 3 months since last episode of myocardial infarction.

  4. Echocardiogram-assessed LVEF between 15% and 40% (Simpson's rule).

  5. Abnormal wall motion of at least 1 segment due to prior myocardial infarction shown by echocardiography or left ventriculography.

  6. Abnormal myocardial perfusion in infarcted area by SPECT.

  7. Willingness to participate and ability to provide written informed consent.

Interventions

Treatment arm 1: Direct intramyocardial injection of autologous bone marrow mononuclear cells during CABG.

Treatment arm 2: Between 10 and 15 placebo injections that consist of saline and 5% HSA during CABG.

Outcomes

Primary Outcome:

Major adverse cardiac events (6 months)/
Secondary Outcomes:

Left ventricular function (global function, regional myocardial perfusion and function assessed by magnetic resonance imaging and echocardiogram (6 months)).

Starting dateDecember 2010
Contact informationChinese PLA General Hospital, Beijing, China (Principal Investigator: Dr C Gao (gaochq301@yahoo.com) and Dr L Zhang (drzhanglin@gmail.com)).
NotesEstimated completion date: June 2013

NCT01299324

Trial name or titleRetrograde delivery of BMAC (bone marrow aspirate concentrate) for congestive heart failure
MethodsA phase I, randomised, open-label, cross-over safety study.
Participants

Congestive heart failure:

  1. Age ≥ 18 years and ability to understand the planned treatment.

  2. People with congestive heart failure.

  3. LVEF ≤ 40% by echocardiogram, per ECHO completed 30 days prior to treatment.

  4. Symptomatic heart failure NYHA class III or IV.

  5. Able to comply with all study-related visits.

  6. Able to tolerate study procedures, including bone marrow aspiration, SPECT.

  7. Able to give informed consent.

  8. Negative for HcG with a serum pregnancy test.

  9. Participants with controlled diabetes mellitus (HbA1c < 9.0%).

  10. Hematocrit ≥ 28.0%, WBC count ≤ 14,000, Platelet count ≥ 50,000.

  11. Life expectancy of 6 months or more in the opinion of the investigator

  12. Participants requiring high-dose corticosteroid therapy (more than 7.5 mg/day) with 1 month before the aspiration or 6 months after the infusion.

  13. Serum bilirubin, ALT, AST ≤ 2.5 time the upper level of normal.

  14. Controlled blood pressure (systolic blood pressure ≤ 140 and a diastolic blood pressure of ≤ 90 mmHG) and established anti-hypertensive therapy as necessary prior to entry into the study.

  15. Participant has received stable, standard medical therapy for at least 1 month with no new medications to treat the disease introduced in the last 3 months.

  16. Pre-existing condition (e.g. thromboembolic risk, diabetes, hypercholesterolaemia are adequately controlled in the opinion of the investigator).

  17. Fertile participants (male and female) must agree to use an appropriate form of contraception while participating in the study.

Interventions

Treatment arm 1: Infusion of autologous BMAC nucleated cells into the coronary sinus.

Treatment arm 2: Control (no infusion)

Outcomes

Primary Outcome:

Number of participants with adverse events as a measure of safety and tolerability (12 months).
Secondary Outcomes:

  1. Effect of the infusion of bone marrow nucleated cells on the clinical course of angina (as measured by QOL questionnaire, MLHF questionnaire, NYHA and CCS classification and SPECT) (12 months).

  2. Effect of the infusion of bone marrow nucleated cells on the clinical course of heart failure (as measured by QOL questionnaire, MLHF questionnaire, NYHA and CCS classification and SPECT) (12 months).

Starting dateFebruary 2011.
Contact informationHarvest Technologies (Dr Amit Patel, Principal Investigator). Contact: Kevin Benoit (pkbenoit@harvesttech.com).
NotesEstimated completion date: October 2014.

NCT01337011

Trial name or titleIntra-coronary versus intramyocardial application of enriched CD133pos autologous bone marrow derived stem cells (AlsterMACS)
MethodsA phase I/II, parallel, randomised, single-blind (participant) study.
Participants

Chronic ischaemic cardiomyopathy:

  1. Aged 18 to 80 years old.

  2. Both genders.

  3. Reduced LVEF as evaluated by routine clinical angiogram, echocardiography or MRI (≤ 45%) due to ischaemic heart disease.

  4. Symptomatic heart failure NYHA ≥ II on optimal therapy.

  5. Coronary artery in the target region that can be used for cell infusion.

  6. Participant has been informed of the nature of the clinical trial and agrees to its provision and has provided written informed consent.

Interventions

Treatment arm 1: Intracoronary administration of autologous CD133+ stem cells.

Treatment arm 2: Intramyocardial administration of autologous CD133+ stem cells.

Outcomes

Primary Outcome: Change in LVEF measured via echocardiography (6 months).

Secondary Outcomes:

  1. The application of CD133pos cells into the coronary system or intra-myocardial via the NOGA system is safe and feasible; the route of application of CD133pos cells has no effect on MACE (5 years).

  2. Decrease of brain natriuretic peptide (6/12 months).

  3. Improvement of 6-minute walk (6/12 months).

  4. Improvement of peak oxygen consumption (6/12 months).

  5. The application of CD133pos cells intra-myocardial is equally effective to the intracoronary application route regarding LV function (6/12 months).

  6. Improvement of LV function as measured by cardiacMRI (6/12 months).

Starting dateJuly 2011.
Contact informationAsklepios proresearch, ASKLEPIOS Klinik St. Georg, Hamburg, Germany, 20099 (Principal Investigator: Dr Martin Bergmann (mar.bergmann@asklepios.com)).
NotesEstimated completion date: July 2017.

NCT01354678

Trial name or titleIntramyocardial multiple precision injection of bone marrow mononuclear cells in myocardial ischaemia (IMPI).
MethodsA phase I, parallel, randomised, double-blind (participant, caregiver, investigator), safety/efficacy study.
Participants

Ischaemic heart failure:

  1. Participants with coronary artery disease (CAD) and HF II - III NYHA class.

  2. MI > 6 months before the study.

  3. LVEF < 35%.

  4. Absence of indication to coronary revascularisation.

  5. Optimal pharmacological therapy no less than 8 weeks.

  6. Heart transplantation is contraindicated.

  7. Partcicipants with implantable cardioverter-defibrillator (ICD) or cardiac resynchronisation therapy defibrillator (CRT-D).

  8. Participants giving informed consent.

Interventions

Treatment arm 1: Intramyocardial multiple precision injection of bone marrow mononuclear cells.

Treatment arm 2: Intramyocardial multiple precision injection with placebo.

Outcomes Primary Outcome: Change in global LVEF and regional wall motion score index (6/12 months).
Secondary Outcomes: Incidence of the major adverse cardiac events (6/12 months).
Starting dateMay 2011.
Contact informationAlmazov Federal Center of Heart, Blood and Endocrinology (Principal Investigator: Prof EV Shlyakhto). Contact: Prof DS Lebedev (lebedevdmitry@mail.ru); Prof OM Moiseeeva (moiseeva@almazovcentre.ru).
NotesEstimated completion date: May 2015.

NCT01442129

Trial name or titleThe effect of intramyocardial injection of mesenchymal precursor cells on myocardial function in patients undergoing LVAD Implantation
MethodsA phase II, randomised, parallel, multicentre, double-blind (participant, caregiver, investigator, outcomes assessor), safety/efficacy study.
Participants

Heart failure, cardiomyopathy and ventricular dysfunction:

  1. Signed informed consent, inclusive of release of medical information, and Health Insurance Portability and Accountability Act (HIPAA) documentation.

  2. Aged 18 years or older.

  3. If the participant or partner is of childbearing potential, he or she must be willing to use adequate contraception (hormonal or barrier method or abstinence) from the time of screening and for a period of at least 16 weeks after procedure.

  4. Women of childbearing potential must have a negative serum pregnancy test at screening.

  5. Admitted to the clinical centre at the time of randomisation.

  6. Clinical indication and accepted candidate for implantation of an FDA-approved implantable, non-pulsatile LVAD as a bridge to transplantation or for destination therapy.

Interventions

Treatment arm 1: Intramyocardial injection of 25 million mesenchymal precursor cells at the time of LVAD implantation.

Treatment arm 2: Injection of control solution during LVAD implantation.

Outcomes

Primary Outcome:

Intervention-related adverse events (90 days).

Secondary Outcomes:

Functional status and ventricular function (90 days).

Starting dateApril 2012.
Contact informationMulticentre study (Study Chairs: Dr T Gardner, Christiana Care Health Services; Dr P O-Gara, Brigham and Women's Hospital).
NotesEstimated completion date: March 2014.

NCT01508910

Trial name or titleEfficacy and safety of targeted intramyocardial delivery of auto CD34+ stem cells for improving exercise capacity in subjects with refractory angina (RENEW)
MethodsA phase III, randomised, parallel, double-blind (participant, investigator), safety/efficacy study.
Participants

Refractory angina and chronic myocardial ischaemia:

  1. Men or women who are 21 - 80 years of age at the time of signing the informed consent.

  2. Participants with CCS class III or IV chronic refractory angina.

  3. Participants without control of their angina symptoms in spite of maximal tolerated doses of anti-angina drugs. Participants must be on optimal therapy for their angina and must have been on a stable anti-anginal medication regimen for at least 4 weeks before signing the informed consent form.

  4. Participants with obstructive coronary disease unsuitable for conventional revascularisation due to unsuitable anatomy or comorbidity as determined at the site and confirmed by an independent adjudication committee.

  5. Participants must have evidence of inducible myocardial ischaemia.

  6. Participants must experience angina episodes.

  7. Participants must be able to complete 2 exercise tolerance tests on the treadmill within 3 weeks of randomisation.

  8. If a woman of childbearing potential, she must not be pregnant and must agree to employ adequate birth control measures for the duration of the study.

Interventions

Treatment arm 1: Targeted intramyocardial delivery of 1 x 10⁵ Auto-CD34+ cells after G-CSF mobilisation and apheresis.

Treatment arm 2: Targeted intramyocardial delivery of placebo after G-CSF mobilisation and apheresis.

Outcomes

Primary Outcome:

Change from baseline in total exercise time on exercise tolerance test (ETT) using the Modified Bruce Protocol (12 months).
Secondary Outcomes:

  1. Angina frequency (episodes per week) (3/6/12 months).

  2. Change from baseline in total exercise time on ETT (6 months).

  3. Incidence of MACEs and other serious adverse events in all participants (24 months).

Starting dateApril 2012.
Contact informationBaxter Healthcare Corporation (Study Director: Dr A Nada). Contact: Lauren Davis, Clinical Project Manager (lauren.davis@ppdi.com).
NotesEstimated completion date: June 2016.

NCT01615250

Trial name or titleImplantation of peripheral stem cells in patients with ischaemic cardiomyopathy (ISCIC)
MethodsA phase I, randomised, parallel, open-label safety/efficacy study.
Participants

Ischaemic cardiomyopathy:

  1. People with ischaemic cardiomyopathy and HF II-IV NYHA class.

  2. MI > 6 months before the study.

  3. LVEF < 35%.

  4. Absence effect of coronary revascularisation during 6 months.

  5. Optimal pharmacological therapy no less than 8 weeks.

  6. Heart transplantation is contraindicated.

  7. Participants with implantable cardioverter-defibrillator (ICD) or cardiac resynchronisation therapy defibrillator (CRT-D).

  8. Participants giving informed consent.

Interventions

Treatment arm 1: Intramyocardial implantation of peripheral mononuclear cells with CD34+ stem cells in participant with ischaemic cardiomyopathy after preparatory course of shock-wave therapy.

Treatment arm 2: Cardiospec shock-wave therapy only.

Outcomes

Primary Outcomes:

Change in global LVEF and regional wall motion score index (6/12 months).
Secondary Outcomes:

Incidence of MACEs (6/12 months).

Starting dateJanuary 2012.
Contact informationOdessa Regional Clinical Hospital, Odessa, Ukraine, 65025 (Principal Investigator: Prof II Karpenko (arcard2@gmail.com)).
NotesEstimated completion date: January 2016.

NCT01660581

Trial name or titleIntracardiac CD133+ cells in patients with no-option resistant angina (Regent Vsel)
MethodsA phase II, randomised, parallel, double-blind (participant, investigator), efficacy study.
Participants

Stable angina:

  1. Stable angina CCS II - IV despite maximum pharmacotherapy for at least 2 weeks since last medications change.

  2. Presence of ≥ 1 myocardial segment with ischaemia features in Tc-99m SPECT.

  3. Participants disqualified from revascularisation procedures by Heart Team.

  4. Aged > 18 and < 75 years old.

  5. Participant must provide written informed consent for participation in study.

Interventions

Treatment arm 1: Intramyocardial injection (electromechanical mapping-based) of autological CD133+ cells, isolated from bone marrow.

Treatment arm 2: Intramyocardial injection (electromechanical mapping-based) of placebo - 0.9% NaCl plus 0.5% solution of participant's serum.

Outcomes

Primary Outcome:

Myocardial perfusion change (4 months).
Secondary Outcomes:

  1. Global and segmental contractility change and myocardial perfusion change (MRI: 4 months; echocardiography: 4/12 months).

  2. Exercise tolerance (4/12 months).

  3. Occurrence of symptomatic angina (1/4/6/12 months).

  4. Quality of life (1/4/6/12 months).

  5. Occurrence of ventricular arrhythmia (1/4/6/12 months).

  6. Occurrence of in-stent restenosis and progression of atherosclerotic lesions in remained coronary artery segments (4 months).

Starting dateJune 2012
Contact informationSamodzielny Publiczny Szpital Kliniczny nr 7 Śląskiego Uniwersytetu Medycznego w Katowicach Górnośląskie Centrum Medyczne im. prof. Leszka Gieca, Katowice-Ochojec, Silesian, Poland, 40-635 (Principal Investigator: Prof W Wojakowski (wojtek.wojakowski@gmail.com)).
NotesEstimated completion date: June 2014.

NCT01666132

Trial name or titleMETHOD - bone marrow derived mononuclear cells in chronic ischaemic disease
MethodsA phase I/II, randomised, cross-over, open-label, safety/efficacy study
Participants

Chronic ischaemic heart disease:

  1. Chronic cardiac ischaemic disease at least 4 months after 1 or more myocardial infarctions in a stable phase of the disease without option for revascularisation.

  2. LVEF at echocardiography ≤ 40%.

  3. Significant regional LV wall motion dysfunction in the infarct-related territory.

  4. Symptoms NYHA II - IV or CCS II - III (at least class III according to one of the 2 classifications).

  5. Participant agrees to comply with all follow-up evaluations.

  6. Age > 18 years old.

  7. Participant has been informed of the nature of the clinical trial and agrees to its provision and has provided written informed consent.

Interventions

Treatment arm 1: Intramyocardial, NOGA-guided injection on BM cells.

Treatment arm 2: Combination of intramyocardial, NOGA-guided injection of BM cells and intracoronary injection of those cells.

Treatment arm 3: Initially no intervention; cross-over to therapy 6 months after enrolment.

Outcomes

Primary Outcomes:

Troponin samples (1 day after cell injection).
Number of participants with adverse events at short term (within 1 week after cell injection).
Number of participants with adverse events at mid/long term (up to 12 months after cell injection).
Secondary Outcomes:

Change in LVEF (6 months) (Designated as safety issue: Yes).

First 10 participants + following randomisation phase (n = 54); assessment of short-term safety (1 week) and adverse events (within 1 year).
Change in quality of life (6 months).
Change in Vo2 max (6 months).

Starting dateJanuary 2011.
Contact informationCardiocentro Ticino, Lugano, Switzerland, 6900 (Principal Investigator: Dr T Moccetti). Contact: Dr D Suerder (daniel.suerder@cardiocentro.org).
NotesEstimated completion date: February 2014.

NCT01727063

Trial name or titleCell therapy in severe chronic ischaemic heart disease (MiHeart)
MethodsA phase II/III, randomised, parallel, double-blind (participant, investigator), safety/efficacy study.
Participants

Chronic ischaemic heart disease:

  1. Symptoms of angina or angina equivalent.

  2. Documented coronary artery disease (invasive angiography).

  3. Documented myocardial ischaemia (stress echo, cardiac scintigraphy, or MRI).

  4. Unsuitable for complete myocardial revascularisation (PCI or CABG) OR even if a complete procedure is feasible, it is anticipated that myocardial perfusion may not be restored due to poor distal beds.

Interventions

Treatment arm 1: Intramyocardial injection of autologous bone marrow-derived cells.

Treatment arm 2: Saline injection.

Outcomes

Primary Outcome:

Increase in myocardial perfusion assessed by MRI (1/6/12 months).
Secondary Outcomes:

  1. Improvement in LV function assessed by MRI (1/6/12 months).

  2. Improvement in angina functional class determined using the CCS classification (1/6/12 months).

Starting dateJanuary 2006.
Contact informationHeart Institute, Sao Paulo, SP, Brazil 05403-000 (Principal Investigator: Prof LHW Gowdak). Contact: Meyrielli A Vieira (meyri.vieira@incor.usp.br); Prof LHW Gowdak (luis.gowdak@incor.usp.br).
NotesEstimated completion date: July 2013.

NCT01768702

Trial name or titleSafety and efficacy of autologous cardiopoietic cells for treatment of ischaemic heart failure. (CHART-1)
MethodsA phase III, randomised, parallel, double-blind (participant, outcomes assessor), safety/efficacy study.
Participants

Ischaemic heart failure:

  1. Age ≥ 18 and < 80 years.

  2. Systolic dysfunction with LVEF ≤ 30% as assessed by echocardiography.

  3. Ischaemic heart failure without known need for revascularisation.

  4. MLHFQ score > 30.

  5. Ability to perform a 6-minute walk test > 100 m and ≤ 400 m.

  6. History of hospitalisation for HF within 12 months prior to screening.

  7. NYHA Class III or IV despite optimal standard of care or INTERMACS class 4, 5, 6 or 7.

  8. Use of ACE inhibitor and/or ARB and beta blocker, for at least 3 months prior to screening visit, unless intolerant or contraindicated.

  9. Stable dosing of ACE inhibitor, ARB , beta blocker, aldosterone blocker,and diuretics for at least 1 month prior to screening visit, defined as ≤ 50% change in total dose of each agent.

  10. Willing and able to give written informed consent.

Interventions

Treatment arm 1: Injection of C3BS-CQR-1 cardiopoietic cells using the C-Cath® injection catheter.

Treatment arm 2: Mimic injection procedure through insertion of a sham catheter. No injection actually performed.

Outcomes

Primary Outcome:

Efficacy between groups post-index procedure: change between groups from baseline in a hierarchical composite outcome comprising, from most to least severe outcome, days to death from any cause, number of worsening of heart failure events, change in score for the MLHF questionnaire (10-point deterioration, no meaningful change,10-point improvement), change in 6-minute walk distance (40 m deterioration, no meaningful change, 40 m improvement) and change in LVESV (15 mL deterioration, no meaningful change, 15 mL improvement), and LVEF (4% absolute deterioration, no meaningful change, 4% absolute improvement) (39 weeks).
Secondary Outcomes:

  1. Efficacy (time to all-cause mortality, time to worsening of heart failure, and time to aborted sudden death) and safety (number and cause of deaths and readmissions, number of cardiac transplantations, number of myocardial infarctions, number of strokes. Incidence of serious AEs and non-serious AEs) between groups post-index procedure (52/104 weeks).

  2. Efficacy and safety between groups post-index procedure (time to all-cause mortality, time to cardiovascular mortality, and rate of worsening heart failure requiring outpatient IV therapy for heart failure or readmission for heart failure, and other) (39/52 weeks post-index).

Starting dateNovember 2012.
Contact informationMulticentre study: Cardio3 Biosciences (Study Chairs: Dr A Terzic, Mayo Clinic, Division of Cardiovascular Diseases, Rochester, MN, USA and Dr J Bartunek, OLV Ziekenhuiz Aalst, Belgium). Contact: Dr Christian Homsy (chomsy@c3bs.com).
NotesEstimated completion date: March 2017.

NTR2516

  1. a

    ACE: angiotensin converting enzyme; AE: adverse events; AICD: automatic implantable cardioverter defibrillator; AMI: acute myocardial infarction; ARB: angiotensin receptor blocker; AST: aspartate transaminase ;BMAC: bone marrow aspirate concentrate; BMMNC: bone marrow mononuclear cells; BMSC: bone marrow-derived stem cells; BNP: brain natriuretic peptide; CABG: coronary artery bypass grafting; CCS: Canadian Cardiovascular Society; CMR: cardiac magnetic resonance; CPC: circulating progenitor cells; ECG: electrocardiogram; EDTA: ethylene-diamine-tetraacetic acid; EPC: endothelial progenitor cells; G-CSF: granulocyte-colony stimulating factor; HcG: human chorionic gonadotrophin; HSA: human serum albumin; IC: intracoronary; IM: intramuscular; InterMACS: Interagency Registry for Mechanically Assisted Circulatory Support; LVAD: left ventricular assist device; LVEF: left ventricular ejection fraction, LVEDV: left ventricular end diastolic volume; LVESV: left ventricular end systolic volume; MACE: major adverse clinical events; MLHFQ: Minnesota Living with Heart Failure Questionnaire; MRI: magnetic resonance imaging; MSC: mesenchymal stem cells; MUGA: multigated radionuclide angiography: MVO₂: myocardial oxygen consumption; NYHA: New York Heart Association; PCI: percutaneous coronary intervention; PET: positron emission tomography ; RCT: randomised controlled trial; SGOT: serum aspartic aminotransferase; SGPT: serum glutamate pyruvate transaminase ;SPECT: single-photon emission computed tomography; WBC: white blood cell.

Trial name or titleInjection of autologous bone marrow cells into damaged myocardium of no-option patients with ischaemic heart failure; a randomised placebo-controlled trial
MethodsA randomised, parallel, double-blinded, placebo-controlled trial.
Participants

Heart failure:

  1. Ischaemic heart failure NYHA class 2, 3 or 4 despite optimal pharmacological and non-pharmacological therapy.

  2. No candidate for (repeat) surgery (revascularisation, valve repair or ventricular reconstruction).

  3. No candidate for (repeat) percutaneous revascularisation.

  4. Optimal resynchronisation therapy or no candidate for resynchronisation therapy.

  5. Men or women, > 18 years and < 75 years old.

  6. Life expectancy > 6 months.

  7. Able to perform an exercise tolerance test prior to therapy.

  8. Able and willing to undergo all the tests used in this protocol including the travelling involved.

  9. Written informed consent.

Interventions

Treatment arm 1: Intramyocardial injection of autologous bone marrow-derived mononuclear cells via NOGA mapping.

Treatment arm 2: Intramyocardial injection of placebo via NOGA mapping.

Outcomes

Primary outcome:

Change in LVEF relative to baseline (3 months).

Secondary outcomes:

  1. NYHA grading of heart failure.

  2. Quality of life.

  3. Exercise capacity.

  4. CCS score.

  5. Regional myocardial perfusion at 3 months follow-up.

  6. Viability and sympatic innervation at 3 months follow-up.

  7. Occurence of arrhythmias.

  8. Pericardial effusion > 5 mm (echo).

  9. Myocardial damage.

  10. Severe inflammation.

Starting dateApril 2010.
Contact informationLeiden University Medical Center, Department of Cardiology, PO Box 9600, 2300 RC, Leiden, The Netherlands (Principal Investigator: Dr DE Atsma).
NotesEstimated completion date: December 2011.

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