Coenzyme Q10 for heart failure

  • Review
  • Intervention

Authors


Abstract

Background

Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria and as a coenzyme for mitochondrial enzymes. Coenzyme Q10 deficiency may be associated with a multitude of diseases including heart failure. The severity of heart failure correlates with the severity of coenzyme Q10 deficiency. Emerging data suggest that the harmful effects of reactive oxygen species are increased in patients with heart failure and coenzyme Q10 may help to reduce these toxic effects because of its antioxidant activity. Coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels and preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. Coenzyme Q10, although not a primary recommended treatment, could be beneficial to patients with heart failure. Several randomised controlled trials have compared coenzyme Q10 to other therapeutic modalities, but no systematic review of existing randomised trials has been conducted.

Objectives

To review the safety and efficacy of coenzyme Q10 in heart failure.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12); MEDLINE OVID (1950 to January Week 3 2013) and EMBASE OVID (1980 to 2013 Week 03) on 24 January 2013; Web of Science with Conference Proceedings (1970 to January 2013) and CINAHL Plus (1981 to January 2013) on 25 January 2013; and AMED (Allied and Complementary Medicine) (1985 to January 2013) on 28 January 2013. We applied no language restrictions.

Selection criteria

We included randomised controlled trials of either parallel or cross-over design that assessed the beneficial and harmful effects of coenzyme Q10 in patients with heart failure. When cross-over studies were identified, we considered data only from the first phase.

Data collection and analysis

Two authors independently extracted data from the included studies onto a pre-designed data extraction form. We then entered the data into Review Manager 5.2 for analysis. We assessed study risk of bias using the Cochrane 'Risk of bias' tool. For dichotomous data, we calculated the risk ratio and for continuous data the mean difference (MD). Where appropriate data were available, we performed meta-analysis. For this review we prioritised data from pooled analyses only. Where meta-analysis was not possible, we wrote a narrative synthesis. We provided a QUOROM flow chart to show the flow of papers.

Main results

We included seven studies with 914 participants comparing conenzyme Q10 versus placebo. There were no data on clinical events from published randomised trials. The included studies had small sample sizes. Meta-analysis was only possible for a few physiological measures and there was substantial heterogeneity.

Only one study reported on total mortality, major cardiovascular events and hospitalisation. Five trials reported on the New York Heart Association (NYHA) classification of clinical status, but it was impossible to pool data due to heterogeneity. None of the included trials considered quality of life, exercise variables, adverse events or cost-effectiveness as outcome measures. Pooled analysis suggests that the use of coenzyme Q10 has no clear effect on left ventricular ejection fraction (MD -2.26; 95% confidence interval (CI) -15.49 to 10.97, n = 60) or exercise capacity (MD 12.79; 95% CI -140.12 to 165.70, n = 85). Pooled data did indicate that supplementation increased blood levels of coenzyme Q10 (MD 1.46; 95% CI 1.19 to 1.72, n = 112). However, there are only a small number of small studies with a risk of bias, so these results should be interpreted with caution.

Authors' conclusions

No conclusions can be drawn on the benefits or harms of coenzyme Q10 in heart failure at this time as trials published to date lack information on clinically relevant endpoints. Furthermore, the existing data are derived from small, heterogeneous trials that concentrate on physiological measures: their results are inconclusive. Until further evidence emerges to support the use of coenzyme Q10 in heart failure, there might be a need to re-evaluate whether further trials testing coenzyme Q10 in heart failure are desirable.

Résumé scientifique

La coenzyme Q10 dans l'insuffisance cardiaque

Contexte

La coenzyme Q10, ou ubiquinone, est un supplément nutritionnel en vente libre. C’est une molécule liposoluble agissant comme transporteur d’électrons dans les mitochondries et comme coenzyme pour des enzymes mitochondriales. La carence en coenzyme Q10 peut être associée à une multitude de maladies, notamment l'insuffisance cardiaque. La gravité de l'insuffisance cardiaque est en corrélation avec la sévérité de la carence en coenzyme Q10. De nouvelles données suggèrent que les effets nocifs des espèces réactives de l'oxygène sont plus élevés chez les patients atteints d'insuffisance cardiaque et la coenzyme Q10 pourrait aider à réduire ces effets toxiques en raison de son activité antioxydante. La coenzyme Q10 pourrait également avoir un rôle en stabilisant les canaux ioniques myocardiques calcium-dépendants et en prévenant la consommation de métabolites essentiels pour la synthèse de l’adenosine-5'-triphosphate (ATP). La coenzyme Q10, bien qu'elle ne soit pas recommandée en traitement principal, pourrait être bénéfique pour les patients atteints d'insuffisance cardiaque. Plusieurs essais contrôlés randomisés ont comparé la coenzyme Q10 à d'autres modalités thérapeutiques, mais aucune revue systématique des essais randomisés existants n'a été réalisée.

Objectifs

Examiner l'efficacité et l'innocuité de la coenzyme Q10 dans l'insuffisance cardiaque.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) (2012, numéro 12) ; MEDLINE OVID (de 1950 à janvier 2013, semaine 3) et EMBASE OVID (de 1980 à 2013 semaine 3) le 24 janvier 2013; Web of Science avec Conference Proceedings (de 1970 à janvier 2013) et CINAHL Plus (de 1981 à janvier 2013) le 25 janvier 2013; et AMED (Allied and Complementary Medicine) (de 1985 à janvier 2013) le 28 janvier 2013. Nous n’avons appliqué aucune restriction concernant la langue.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés à plan parallèle ou croisé ayant évalué les effets bénéfiques et nocifs de la coenzyme Q10 chez les patients atteints d'insuffisance cardiaque. Lorsque des études croisées ont été identifiées, nous n’avons pris en compte que les données de la première phase.

Recueil et analyse des données

Deux auteurs ont indépendamment extrait les données des études incluses dans un formulaire prédéfini d'extraction de données. Nous avons ensuite saisi les données dans Review Manager 5.2 pour l'analyse. Nous avons évalué le risque de biais des études en utilisant l'outil Cochrane « Risque de biais ». Pour les données dichotomiques, nous avons calculé le risque relatif et pour les données continues, la différence moyenne (DM). Lorsque des données appropriées étaient disponibles, nous avons effectué une méta-analyse. Pour cette revue, nous avons privilégié les données issues d'analyses combinées uniquement. Lorsque la méta-analyse n'était pas possible, nous avons écrit une synthèse narrative. Nous avons rédigé un diagramme QUOROM pour montrer la sélection des articles.

Résultats principaux

Nous avons inclus sept études avec 914 participants comparant la conenzyme Q10 par rapport à un placebo. Il n'y avait pas de données sur les événements cliniques issues des essais randomisés publiés. Les études incluses avaient de petits effectifs. Une méta-analyse n'a été possible que pour quelques mesures physiologiques et l’hétérogénéité était substantielle.

Une seule étude a rapporté sur la mortalité totale, les événements cardio-vasculaires majeurs et l'hospitalisation. Cinq essais avaient rapporté des données de l'état clinique selon la classification de la New York Heart Association (NYHA), mais il était impossible de combiner les données en raison de l'hétérogénéité. Aucun des essais inclus n'examinait la qualité de vie, les variables relatives à l'exercice physique, les événements indésirables ou le rapport coût-efficacité comme mesures de résultats. L'analyse groupée suggère que l'utilisation de la coenzyme Q10 n’a aucun effet évident sur la fraction d'éjection ventriculaire gauche (DM -2,26 ; intervalle de confiance (IC) à 95 % -15,49 à 10,97, n = 60) ou la capacité d'exercice (DM 12,79 ; IC à 95 % -140,12 à 165,70, n = 85). Les données combinées révélaient que la supplémentation en coenzyme Q10 en augmentait le taux sanguin (DM 1,46 ; IC à 95 % 1,19 à 1,72, n = 112). Cependant, il n'existe qu'un petit nombre d'études de petite taille, avec des risques de biais, de sorte que ces résultats doivent être interprétés avec prudence.

Conclusions des auteurs

Actuellement, aucune conclusion ne peut être tirée sur les effets bénéfiques ou délétères de la coenzyme Q10 dans l'insuffisance cardiaque car les essais publiés à ce jour manquent d'informations sur des critères de jugement cliniquement pertinents. En outre, les données existantes sont dérivées d’essais de petite taille et hétérogènes qui se concentrent sur des mesures physiologiques : leurs résultats ne sont pas concluants. Jusqu’à l’émergence d’autres preuves pour recommander l'utilisation de la coenzyme Q10 dans l'insuffisance cardiaque, on pourrait avoir besoin de réévaluer si d'autres essais évaluant la coenzyme Q10 dans l'insuffisance cardiaque sont souhaitables.

アブストラクト

心不全に対する補酵素Q10

背景

補酵素Q10ユビキノンは処方箋不要の栄養剤である。ミトコンドリア内での電子の担体として、またミトコンドリア内酵素の補酵素として働く脂溶性分子である。補酵素Q10欠乏は、心不全を含む多数の疾患に関連している可能性がある。心不全の重症度は、補酵素Q10欠乏の重症度に相関している。新たに出てきたデータにより、活性酸素種の有害な影響は心不全患者において増大し、補酵素Q10はその抗酸化活性のためにこれらの有毒作用の低減に役立つ可能性がある。補酵素Q10は、心筋のカルシウム依存性イオンチャネルの安定化とアデノシン5’-三リン酸(ATP)合成に必須の代謝物の消費を防ぐ役割も果たす。補酵素Q10は、第一の推奨治療ではないが、心不全患者に利益があると考えられる。数件のランダム化比較試験では補酵素Q10を他の治療法と比較したが、既存のランダム化試験のシステマティックレビューは実施されていない。

目的

心不全における補酵素Q10の安全性と有効性をレビューすること。

検索戦略

2013年1月24日にCochrane Central Register of Controlled Trials (CENTRAL)(2012年12号)、MEDLINE OVID(1950年から2013年1月第3週まで)、EMBASE OVID(1980年から2013年第3週まで)を、2013年1月25日にWeb of Science with Conference Proceedings(1970年から2013年1月まで)、CINAHL Plus(1981年から2013年1月まで)を、2013年1月28日にAMED (Allied and Complementary Medicine)(1985年1月まで)を検索した。言語の制限は設けなかった。

選択基準

心不全患者を対象として補酵素Q10の有益または有害な影響を評価した並行またはクロスオーバーデザインのランダム化比較試験を選択した。クロスオーバー試験が同定された場合、第1期のみから得られたデータを対象とした。

データ収集と分析

2名の著者が別々に、事前にデザインされたデータ抽出書式上に選択した研究からデータを抽出した。その後、解析のためにReview Manager 5.2にデータを入力した。Cochrane ’Risk of bias’ツールを用いて研究のバイアスのリスクを評価した。2値データのためにはリスク比を、連続データには平均差(MD)を算出した。適切なデータが得られた場合、メタアナリシスを実施した。本レビューのために、統合解析のみから得られたデータを優先した。メタアナリシスが実施できない場合は、ナラティブ統合を記載した。論文の流れを示すためにQUOROMフローチャートを用いた。

主な結果

補酵素Q10をプラセボと比べた参加者914例の7件の試験を含めた。発表されたランダム化比較からは臨床イベントに関するデータは得られなかった。選択した試験は被験者数が少なかった。メタアナリシスは、少数の生理学的評価項目について可能であるのみで、大きな異質性はなかった。

1件の試験のみが総死亡率、主要な心血管イベント、入院に関して報告していた。5件が臨床状態のニューヨーク心臓協会(NYHA)分類を報告していたが、異質性のためにデータを統合することはできなかった。選択した試験はいずれも、評価項目としてQOL、運動の変数、有害事象、費用対効果を検討していなかった。統合解析により、補酵素Q10の使用は、左室駆出率に対し(MD -2.26、95%信頼区間(CI)-15.49 ~10.97、n = 60)、また運動能力に対し(MD 12.79、95% CI -140.12 ~ 165.70、 n = 85)明らかな効果を有さないことが示唆されている。統合データは、補充により血中補酵素Q10濃度が上昇したことを示した(MD 1.46、95% CI 1.19 ~1.72、n = 112)。しかし、バイアスのリスクを伴う小規模な試験が少数あるのみなので、このような結果の解釈には注意が必要である。

著者の結論

今日までに発表された試験には臨床的に重要な評価項目に関する情報が欠けているため、今回、心不全における補酵素Q10の利益または有害性に関して結論を導き出すことはできない。さらに、既存データは生理学的評価項目を重視した小規模な異質性のある試験から得られた。その結果は確定的ではない。心不全における補酵素Q10の使用を支持するさらなるエビデンスが出てくるまで、心不全における補酵素Q10を検証するさらなる試験が望ましいかどうかを再評価する必要があると考えられる。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.9]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Coenzyme Q10 for heart failure

Heart failure is a term used to describe the state that develops when the heart cannot maintain adequate cardiac output or can do so only at the expense of overfilling the heart chambers. People with heart failure commonly experience a relapsing and remitting disease course, with periods of stability and episodes of decompensation (failure to cope with heart damage) leading to worsening symptoms that necessitate hospitalisation. Treatment options for heart failure range from drugs to heart transplantation, with each having its own limitations. Coenzyme Q10 (or ubiquinone) has been suggested as a treatment option in some trials. Coenzyme Q10 is a non-prescription nutritional supplement. It is a fat-soluble molecule that has a role in energy production within the cells of the body. It may also have antioxidant properties. Low levels of conequme Q10 may be related to the severity of heart failure. Coenzyme Q10 has been found in all tissues and organs in the body, with the highest concentrations in the heart. Emerging data have suggested that the harmful effects of reactive oxygen species are increased in patients with heart failure and coenzyme Q10, given its antioxidant activity, may help to reduce these toxic effects, which damage the components of the cardiac cells and disrupt cellular signalling. Coenzyme Q10 also has a role in stabilising myocardial calcium-dependent ion channels and preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis. The concentration of coenzyme Q10 has been inversely related to the severity of heart failure. Supplementation with coenzyme Q10 may improve heart failure. Coenzyme Q10 is sometimes used because it is thought to have an acceptable safety profile with no significant side effects.

We conducted this review to assess the available evidence on the effects of coenzyme Q10 in heart failure patients. We included seven small randomised controlled trials in this review, that were at a risk of bias. Due to the variation in the way that the studies were done we were not able to combine many of the data in our review, meaning that it is difficult to explore the impact of this variation on the results of this review. Only one study reported on mortality, majro cardiovascular evetns and hospitalisation. The evidence collected in this review shows no clear effect of coenzyme Q10 on the improvement of clinical status (using the New York Heart Association (NYHA) classification) or on exercise capacity. There is no convincing evidence to support or refute the use of coenzyme Q10 for heart failure.

Résumé simplifié

La coenzyme Q10 dans l'insuffisance cardiaque

L'insuffisance cardiaque est un terme utilisé pour décrire l'état qui se développe lorsque le cœur ne peut plus maintenir le débit cardiaque ou ne peut le faire qu'au prix d'un remplissage excessif des cavités du cœur. Les patients atteints d'insuffisance cardiaque présentent communément une maladie évoluant avec des rémissions et des rechutes, avec des périodes de stabilité et des épisodes de décompensation (incapacité à surmonter les détériorations cardiaques) conduisant à une aggravation des symptômes nécessitant l’hospitalisation. Les options de traitement pour l'insuffisance cardiaque vont des médicaments à la transplantation cardiaque, chacune ayant ses propres limitations. La coenzyme Q10 (ou ubiquinone) a été proposée comme une option de traitement dans certains essais. La coenzyme Q10 est un supplément nutritionnel, en vente libre. C’est une molécule liposoluble qui a un rôle dans la production d'énergie dans les cellules de l'organisme. Elle pourrait également avoir des propriétés antioxydantes. De faibles niveaux de coenzyme Q10 pourraient être liés à la gravité de l'insuffisance cardiaque. La coenzyme Q10 a été trouvée dans tous les tissus et organes du corps, avec les concentrations les plus élevées, dans le cœur. De nouvelles données ont suggéré que les effets délétères des espèces réactives de l'oxygène sont plus élevés chez les patients atteints d'insuffisance cardiaque et la coenzyme Q10, compte tenu de son activité antioxydante pourrait aider à réduire ces effets toxiques, qui endommagent les composants des cellules du cœur et perturbent les signaux cellulaires. La coenzyme Q10 a également un rôle en stabilisant les canaux ioniques myocardiques calcium-dépendants et dans la prévention de la consommation de métabolites essentiels pour la synthèse de l’adenosine-5'-triphosphate (ATP). La concentration de la coenzyme Q10 a été trouvée inversement liée à la gravité de l'insuffisance cardiaque. La supplémentation en coenzyme Q10 pourrait améliorer l'insuffisance cardiaque. La coenzyme Q10 est parfois utilisée car elle est supposée avoir un profil de sécurité acceptable sans effets secondaires significatifs.

Nous avons réalisé cette revue pour évaluer les preuves disponibles concernant les effets de la coenzyme Q10 chez les patients atteints d'insuffisance cardiaque. Dans cette revue, nous avons inclus sept essais contrôlés randomisés de petite taille, présentant des risques de biais. En raison de la variation dans la manière dont les études ont été effectuées nous n'avons pas pu combiner beaucoup de données dans notre revue, ce qui signifie qu'il est difficile d'examiner l'impact de cette variation sur les résultats de cette revue. Une seule étude a rapporté sur la mortalité, les évènements majeurs cardio-vasculaires et l'hospitalisation. Les preuves recueillies dans cette revue ne montrent aucun effet évident de la coenzyme Q10 sur l'amélioration de l'état clinique (à l'aide de la classification de la New York Heart Association (NYHA) ou sur la capacité d'exercice. Il n'existe aucune preuve convaincante permettant d'étayer ou de réfuter l'utilisation de la coenzyme Q10 dans l'insuffisance cardiaque.

Notes de traduction

Traduit par: French Cochrane Centre 10th September, 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

平易な要約

心不全に対する補酵素Q10

心不全は、心臓が十分な心拍出量を維持できない、あるいは心室を過剰に満たすという犠牲を払ってのみ心拍出量を維持できる場合に発現する状態を説明する用語である。心不全患者は再発と寛解を繰り返す疾患経過をたどり、安定期と代償不全エピソード(心損傷に対処できない)を伴い、入院を要する症状悪化に至る。心不全の治療選択肢は、薬剤から心移植にまで及ぶが、それぞれに固有の限界がある。補酵素Q10(ユビキノン)は、いくつかの試験で治療選択肢として示唆されている。補酵素Q10は、処方箋不要の栄養剤である。身体の細胞内でのエネルギー産生に役割をもつ脂溶性分子である。抗酸化作用も有する。補酵素Q10の体内濃度低下は心不全の重症度に関連している可能性がある。補酵素Q10は体内のすべての組織、臓器に存在し、心臓において濃度が最高である。新たなデータにより、活性酸素種の有害な影響は心不全患者において増大し、補酵素Q10はその抗酸化活性を考えればこのような有毒作用の低減に役立つ可能性がある。有毒作用は心臓細胞の成分を損傷し、細胞シグナル伝達を遮断させる。補酵素Q10は、心筋のカルシウム依存性イオンチャネルの安定化とアデノシン5’-三リン酸(ATP)合成に必須の代謝物の消費を防ぐ役割も果たす。補酵素Q10濃度は心不全の重症度と逆相関している。補酵素Q10補充により心不全を改善できる可能性がある。補酵素Q10は、許容できる安全性プロファイルをもち、重大な副作用がないと考えられているために使用されることもある。

心不全患者における補酵素Q10の効果に関する利用可能なエビデンスを評価するために、本レビューを実施した。7件の小規模比較試験を本レビューに含めたが、それらにはバイアスのリスクがある。試験が行われた方法に差異があるため、このレビューではデータの多くを統合することができなかった。それは本レビューの結果に対するこの差異の影響を探索することは困難であるという意味である。1件の試験のみが死亡率、主要な心血管イベント、入院に関して報告していた。本レビューで収集されたエビデンスは、臨床状態の改善(ニューヨーク心臓協会(NYHA)分類を用いて)または運動能力に対する補酵素Q10の明らかな効果を示さなかった。補酵素Q10の心不全への使用を支持するあるいは異議を唱える説得力のあるエビデンスはない。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.9]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Laički sažetak

Koenzim Q10 za liječenje zatajenja srca

Zatajenje srca je naziv za stanje koje se razvija kada srce ne može održati dovoljno izbacivanje krvi ili to može učiniti jedino na račun prepunjavanja srčanih komora. Osobe sa zatajenjem srca obično imaju tijek bolesti obilježen relapsima i remisijama (razdobljima pogoršanja i smirenja bolesti), s razdobljima stabilnosti i periodima dekompenzacije (nemogućnost nošenja s oštećenjem srca) koji dovode do pogoršanja simptoma koji zahtijevaju liječenje u bolnici (hospitalizaciju). Terapijske mogućnosti kreću se u rasponu od lijekova do transplantacije. Svaka od tih terapija ima svoja ograničenja. Koenzim Q10 (ili ubikinon) u nekim studijama se predlaže kao moguća terapija za zatajenje srca. Koenzim Q10 je dodatak prehrani koji se može naći u slobodnoj prodaji. To je molekula topiva u mastima koja ima ulogu u proizvodnji energije u stanicama. Moguće je i da ima antioksidativna svojstva. Niske razine koenzima Q10 mogle bi biti povezane s težinom zatajenja srca. Koenzim Q10 može se naći u svim tkivima i organima u tijelu, s najvećim koncentracijama u srcu. Sve više podataka upućuje da su štetni učinci reaktivnih kisikovih oblika povećani kod pacijenata sa zatajenjem srca i da bi koenzim Q10, ako se daje kao antioksidans, mogao pomoći smanjiti te toksične učinke koji oštećuju sastavnice srčanih stanica i ometaju stanično signaliziranje. Koenzim Q10 također ima ulogu u stabiliziranju srčanih ionskih kanala ovisnih o kalciju i sprečavanju potrošnje metabolita nužnih za sintezu ATP-a. Koncentracija koenzima Q10 obrnuto proporcionalno je povezana s težinom zatajenja srca. Dodatak koenzima Q10 bi mogao poboljšati zatajenje srca. Koenzim Q10 se povremeno koristi jer se smatra da ima prihvatljiv sigurnosni profil bez značajnih nuspojava.

Ovaj Cochrane sustavni pregled proveden je kako bi se ocijenili dostupni dokazi o učinku koenzima Q10 na pacijente sa zatajenjem srca. U sustavni pregled je uključeno sedam malih randomiziranih kontroliranih studija. Sve su imale rizik od pristranosti. Zbog razlika u načinu na koji su provedene studije uključene u ovaj pregled literature nije bilo moguće kombinirati brojne podatke. To znači da je teško istražiti utjecaj tih razlika na rezultate sustavnog pregleda. U samo jednoj studiji prikazani su rezultati o smrtnosti, ozbijlnim srčano-žilnim incidentima i hospitalizacijama. Dokazi prikupljeni u ovom sustavnom pregledu ne pokazuju jasne učinke koenzima Q10 na poboljšanje kliničkog statusa (za procjenu je korištena klasifikacija Njujorškog udruženja za srce - engl. New York Heart Association, NYHA) ili na kapacitet vježbanja. Ne postoje uvjerljivi dokazi ni da podupru ni da opovrgnu upotrebu koenzima Q10 za zatajenje srca.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Background

Description of the condition

Heart failure is a term used to describe the state that develops when the heart cannot maintain adequate cardiac output or can do so only at the expense of an elevated filling pressure (Boon 2006). Heart failure may be acute or chronic and can be caused by a variety of conditions including ischaemic heart disease (coronary artery disease), hypertension, elevated blood pressure, diseases of the heart valves, cardiomyopathy and congenital heart diseases (Drexler 2004; Ho 1993; Richardson 1996; Teerlink 1991). The most commonly used classification system to quantify the degree of heart failure-associated functional limitation was first developed by the New York Heart Association (NYHA) (NYHA 1964). This system assigns patients to one of four functional classes, depending on the degree of effort needed to elicit symptoms:

  • class I - symptoms of heart failure only at activity levels that would limit normal individuals;

  • class II - symptoms of heart failure with ordinary exertion;

  • class III - symptoms of heart failure with less than ordinary exertion;

  • class IV - symptoms of heart failure at rest.

It is now appreciated that heart failure often occurs with normal left ventricular systolic function, i.e. diastolic dysfunction (Redfield 2003; Vasan 1995). Various studies estimate that as many as 40% to 60% of patients with heart failure have diastolic dysfunction as defined by a normal left ventricular ejection fraction (Elesber 2001; Gottdiener 2002).

A 2010 update of heart disease statistics from the American Heart Association (AHA) estimated that there were 5.8 million people with heart failure in the United States in 2006 (Lloyd-Jones 2010). There are an estimated 23 million people with heart failure worldwide (McMurray 1998). Chronic heart failure is a common condition and is one of the most frequent causes of disability and admission to hospital in older individuals (Carbajal 2003; Massie 1997). The prevalence of heart failure increases with age and is associated with high morbidity and mortality worldwide (Rodriguez 2004). Despite major advances in the drug treatment of this disorder, mortality rates in patients with heart failure often exceed 10% per year and range from 20% to 50% in the most severely affected patients (Ho 1993).

People with chronic heart failure commonly experience a relapsing and remitting disease course, with periods of stability and episodes of decompensation leading to worsening symptoms that necessitate hospitalisation. The clinical picture depends on the nature of the underlying heart disease, the type of heart failure that it has evoked, and the neural and endocrine changes that have developed (Boon 2006).

Description of the intervention

Coenzyme Q10, or ubiquinone, is a non-prescription nutritional supplement. It is a fat-soluble molecule that acts as an electron carrier in mitochondria and as a coenzyme for mitochondrial enzymes (Langsjoen 1985a). Coenzyme Q10 is obtained both through tissue synthesis and diet (Langsjoen 1985a). Supplementary oral administration of coenzyme Q10 has been found to increase coenzyme Q10 levels in plasma, platelets and white blood cells (Niklowitz 2007). Absorption of dietary coenzyme Q10 is slow and limited because of its hydrophobicity and large molecular weight. Solubilised coenzyme Q10 formulations show enhanced bioavailability with Tmax of approximately six hours and an elimination half-life of approximately 33 hours. Oral preparations of coenzyme Q10 are used in human therapeutics (Bhagavan 2007).

Coenzyme Q10 is considered a cell membrane stabiliser and thought to be useful in preventing atherosclerosis, abnormal protein synthesis and age-related degenerative diseases (Migliore 2004). Coenzyme Q10 deficiency may be associated with a multitude of diseases as diverse as coronary artery disease and congestive heart failure, Parkinson's disease, diabetes, breast cancer and hypertension (Niklowitz 2007).

Coenzyme Q10 appears to be generally safe with no significant side effects. Potential adverse effects include abdominal discomfort, headache, nausea and vomiting (Singh 1999). Coenzyme Q10 may reduce the effectiveness of warfarin and may limit or prevent effective anticoagulation (Heck 2000).

Some drugs can cause depletion of coenzyme Q10, such as statins (Berthold 2006; Folkers 1990; Mortensen 1997), and beta-blockers (Kishi 1977).

How the intervention might work

Emerging data suggest that oxidative stress is increased in patients with heart failure and may predict outcome. Markers of oxidative stress have been shown to be elevated in patients with ischaemic and non-ischaemic cardiomyopathy (McMurray 1990; McMurray 1993), to be inversely correlated with the left ventricular ejection fraction (Belch 1991) and directly correlated with the chronicity and severity of heart failure (Diaz-Velez 1996; Nishiyama 1998), and to predict mortality in patients with heart failure (Tsutsui 2002). Coenzyme Q10 may reduce oxidative stress because of its antioxidant activity (Rauchova 1995), which has been shown to be similar to that of vitamin E (Tappel 1972).

Besides preventing oxidative stress in heart failure, coenzyme Q10 may also have a role in stabilising myocardial calcium-dependent ion channels and in preventing the consumption of metabolites essential for adenosine-5'-triphosphate (ATP) synthesis (Greenberg 1990). Moreover, coenzyme Q10 myocardial tissue levels in chronic heart failure patients are on average 33% lower than in control patients (Mortensen 1990; Mortensen 1993). The severity of heart failure correlates with the severity of coenzyme Q10 deficiency (Mortensen 1984). Supplementing this deficiency may therefore play a role in the treatment of heart failure.

Why it is important to do this review

Despite the suggested potential benefits, the quality of evidence for the use of coenzyme Q10 in the treatment of heart failure has not been determined and it is not included in therapeutic guidelines for heart failure (Arnold 2006; HFSA 2006; Hunt 2005; Swedberg 2005). This review is important because it summarises the best available evidence for the safety and efficacy of coenzyme Q10 in heart failure patients. The information derived from this review could assist clinicians and heart associations to determine whether coenzyme Q10 could be a recommended choice for heart failure.

Objectives

To review the safety and efficacy of coenzyme Q10 in heart failure.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised controlled trials that had assessed the beneficial and harmful effects of coenzyme Q10 in heart failure. We placed no restrictions on blinding, publication status, abstracts, conference proceedings or language. We excluded quasi-randomised and observational studies. When cross-over studies were identified, we only considered data from the first phase. When first-phase data were not available, we contacted the authors to obtain these data if possible.

Types of participants

  • We included all patients regardless of age with chronic heart failure, defined as a clinical syndrome characterised by breathlessness and fatigue that is caused by an inability of the heart to support adequate circulation, which may limit exercise tolerance and may lead to pulmonary congestion and peripheral oedema; also, if possible, defined by more objective evidence of left ventricular systolic function (e.g. echocardiography, radionuclide ventriculography).

  • We included patients with heart failure with reduced ejection fraction (HFREF) or heart failure with normal ejection fraction (HFNEF).

  • We included participants with chronic heart failure of any severity.

  • Chronic heart failure included left-sided and right-sided heart failure.

  • We not include patients with "acute HF defined as development of dyspnoea associated with the rapid accumulation of fluid within the lung interstitial and alveolar spaces as a result of acutely elevated cardiac filling pressures" (Ware 2005).

Types of interventions

  • Coenzyme Q10 versus placebo.

  • Coenzyme Q10 versus another active agent for use in heart failure.

  • High-dose versus low-dose coenzyme Q10.

Types of outcome measures

Primary outcomes
  • Total mortality (all-cause mortality, cardiovascular mortality)

  • Major cardiovascular events: fatal and non-fatal myocardial infarction, fatal non-fatal stroke and re-vascularisation procedures (PCI and CABG)

  • Hospitalisation (due to heart failure or for any other reason)

  • New York Heart Association (NYHA) classification of clinical status

Secondary outcomes
  • Left ventricular ejection fraction, as determined by echocardiography or contrast or radionuclide angiography

  • Symptoms improvement, as measured by individual trials and/or by exercise capacity (exercise duration or walking distance, or both)

  • Other exercise variables (peak VO2, exercise haemodynamics)

  • Quality of life

  • Brain natriuretic peptide (BNP)

  • Measurement of baseline and post-therapeutic serum levels of coenzyme Q10

  • Adverse events

  • Cost-effectiveness

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12); MEDLINE OVID (1950 to January Week 3 2013) and EMBASE OVID (1980 to 2013 Week 03) on 24 January 2013; Web of Science with Conference Proceedings (1970 to January 2013) and CINAHL Plus (1981 to January 2013) on 25 January 2013; and AMED (Allied and Complementary Medicine) (1985 to January 2013) on 28 January 2013. We applied no language restrictions.

We applied the RCT filter for MEDLINE and EMBASE according to the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). The RCT filter for CINAHL is a combination of the SIGN RCT filter (http://www.sign.ac.uk/methodology/filters.html#random) and terms from the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011).

We have shown the search strategies in Appendix 1.

Searching other resources

We checked the bibliographic references of identified randomised controlled trials and meta-analyses to find randomised controlled trials not identified by the electronic searches. When possible, we approached the principal authors of the identified randomised controlled trials and enquired about any other randomised controlled trials they might know of. We looked for unpublished or ongoing studies by searching the metaRegister of controlled trials (including the International Standard Randomised Controlled Trial Number Register (ISRCTN) and the National Institutes of Health (NIH) ClinicalTrials.gov) at www.controlled-trials.com/.

Data collection and analysis

We performed the meta-analyses according to the recommendations of The Cochrane Collaboration (Higgins 2011), using Review Manager 5.2 (RevMan 2012).

Selection of studies

Two authors (MME, TAK) independently assessed the identified trials for their fulfilment of the inclusion criteria. We listed the excluded trials with the reasons for exclusion. We resolved disagreements by discussion. We summarised the flow of papers through the search and selection process using a QUOROM flow chart (Figure 1).

Figure 1.

QUOROM flow chart

Data extraction and management

Two authors (MME and AYS) extracted data independently and resolved disagreements by discussion. We used a standardised data collection form to extract data on methods, participants, interventions and outcomes. If more than one publication on a single randomised controlled trial was identified, we extracted the most appropriate data.

Assessment of risk of bias in included studies

We assessed methodological quality according to the level of confidence that the design and report of a published trial restricted bias in the intervention comparison (Moher 1998). In assessing the risk of bias we used The Cochrane Collaboration's tool for assessing risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Measures of treatment effect

Dichotomous data

We planned to calculated risk ratios (RR) with 95% confidence intervals (CI). If the overall results had been statistically significant using a random-effects model, we would have calculated the relative risk reduction (RRR), the number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH), if possible.

Continuous data

We calculated mean differences (MD) with 95% CIs.

Unit of analysis issues

When we retrieved cross-over studies from the search, we only took the first arm into consideration.

Dealing with missing data

We performed all analyses on an intention-to-treat basis, using the last reported observed response ('carry forward') and including all participants, irrespective of compliance or follow-up. In addition, we planned to perform 'a worst-case scenario' analysis, considering all participants with missing data as treatment failures.

Assessment of heterogeneity

We assessed statistical heterogeneity using a Chi2 test and we used the I2 statistic to quantify inconsistency across included studies (Higgins 2003). We also assessed statistical heterogeneity by examining the graphical presentations ('forest plots') (Egger 1997).

Assessment of reporting biases

We tried to locate the protocol for each included randomised controlled trial (RCT). If the protocol was available, we compared its outcomes with those in the published RCT report. If it was not available, we compared the outcomes listed in the methods section of the report with the actual reported results. We panned to use a funnel plot of all included trials to check the presence of publication bias, but there were not sufficient trials (Egger 1997).

Data synthesis

We aimed to undertake meta-analysis where there were sufficient data of a suitable type, using RevMan 5.2 (RevMan 2012). Where there were too few clinically homogeneous trials for us to be able to perform a meta-analysis, we presented a narrative synthesis.

We used the random-effects model to avoid the risk that the variability between the studies may be exclusively because of a random sampling variation around a fixed effect. Using the random-effects model is also recommended by Clinical Evidence (Clinical Evidence).

Subgroup analysis and investigation of heterogeneity

We did not carry out any subgroup analysis because of the small number of included studies.

Sensitivity analysis

We did not carry out any sensitivity analysis because of the small number of included studies.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

We originally retrieved a total of 721 papers by searching the databases, of which we judged 568 papers to be clearly irrelevant by reading the title (i.e. not related to our main area of interest regarding the use of coenzyme Q10 in heart failure). We retrieved the abstracts of the remaining 155 papers as they appeared to be relevant. Of these, we excluded 111 as they did not meet one or more of the inclusion criteria. After retrieving the full articles for the remaining 44 papers, we excluded 29 as they did not meet our inclusion criteria. We initially considered the remaining 15 studies to be included studies in our review. Fourteen of these papers were in English and one in Japanese. After translation to English, we excluded the Japanese study as it was not a randomised controlled trial (RCT). Seven studies were RCTs with a parallel design and seven studies were RCTs with a cross-over design. As per our protocol, we planned only to analyse data from the first arm of any cross-over design studies. The cross-over studies identified provided unusable data despite our attempt to obtain the raw data. Therefore, we excluded the RCTs with cross-over designs.

Please refer to the QUOROM flow chart (Figure 1).

Included studies

This review included seven studies with 914 participants. The sample size in all studies was small except in one study, which included 641 participants (Morisco 1993). In all other studies the sample size was 87 or fewer. All included studies were RCTs with a parallel design.

Two studies were conducted in Europe (Morisco 1993; Munkholm 1999). Three studies were conducted in Asia (Adarsh 2008; Berman 2004; Kocharian 2009), one was conducted in Australia (Keogh 2003), and one was conducted in the USA (Khatta 2000).

All studies were in adults except Kocharian 2009, which included 38 patients younger than 18 years. The NYHA class of the patients in all studies was II or more.

Patients were given 200 mg of oral coenzyme Q10 daily in Adarsh 2008, Khatta 2000 and Munkholm 1999. In Berman 2004, patients were given 60 mg of oral coenzyme Q10 daily. In Kocharian 2009 and Morisco 1993, patients received 2 mg/kg of oral coenzyme Q10 daily. In Keogh 2003, patients received 150 mg of oral coenzyme Q10 daily. The comparison groups in all studies were given placebo.

The follow-up period for the patients in all studies was six months or less, except in Morisco 1993, where the follow-up period was one year.

See Characteristics of included studies.

Excluded studies

Out of the 721 papers identified in the search, we excluded 568 early in the selection process because the title was irrelevant to our main area of interest. Of the remaining 153 papers, 139 did not meet one or more of the inclusion criteria. We excluded the RCT studies with a cross-over design later as their data were unsuitable for analysis. See Characteristics of excluded studies.

Risk of bias in included studies

After two of the authors assessed each of the seven included studies independently, we found that there was risk of bias in the included studies in this review (see the 'Risk of bias' tables in Characteristics of included studies).

We used the 'Risk of bias' summary and graph figures to illustrate the proportion of studies with each of the judgements ('low risk', 'high risk', 'unclear risk' of bias) for each domain of the tool (Figure 2; Figure 3).

Figure 2.

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

Figure 3.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Four studies were conducted using random sequence generation, however the methods used were unclear and therefore the risk of selection bias is unclear (Berman 2004; Khatta 2000; Kocharian 2009; Munkholm 1999).

Adarsh 2008 did not mention whether or not random sequence generation was used, therefore the risk of selection bias is unclear.

Khatta 2000 was conducted using random sequence generation (random number generator). However, it did not mention how allocation concealment was achieved and therefore the risk of selection bias is unclear.

Morisco 1993 mentioned using central randomisation to define the sequence generation. Allocation was computer-generated. We classified this study as having a low risk of selection bias.

Blinding

Six studies had a double-blind design, therefore we classified them as having a low risk of performance bias (Berman 2004; Keogh 2003; Khatta 2000; Kocharian 2009; Morisco 1993; Munkholm 1999). None of these studies mentioned how the blinding was achieved, therefore we could not define the risk of detection bias.

Adarsh 2008 did not provide any information on whether blinding was considered or not and thus we could not define the risk of bias.

Incomplete outcome data

In Munkholm 1999 and Kocharian 2009 all patients completed the trial. We considered these studies to be at low risk of attrition bias.

In five studies, some of the patients did not finish the study (Adarsh 2008; Berman 2004; Keogh 2003; Khatta 2000; Morisco 1993). The incomplete outcome data were clearly reported in these studies. However, we considered these studies to be at high risk of attrition bias.

Selective reporting

We had no concerns over the selective availability of data. All studies' outcomes were clearly reported and we considered them to be at low risk of reporting bias.

Other potential sources of bias

No other potential sources of bias could be found.

Effects of interventions

All seven included studies compared coenzyme Q10 with placebo.

Coenzyme Q10 versus placebo

Primary outcomes

Only one study reported on each of the following primary outcomes: total mortality (Adarsh 2008), major cardiovascular events (Morisco 1993), and hospitalisation for any reason (Morisco 1993). Since these data come only from individual studies, we cannot produce a pooled estimate of the effects of the intervention for these outcomes.

Total mortality (all-cause mortality, cardiovascular mortality)

Adarsh 2008 reported that there was no significant change in mortality between the placebo and coenzyme Q10 group. The percentage of deaths in the coenzyme Q10 group was 2.2% and in the placebo group was 2.4%.

Major cardiovascular events

Morisco 1993 reported that the percentage incidence of acute pulmonary oedema was significantly smaller in the coenzyme Q10 group than in the placebo group (P value < 0.001). Similarly, the incidence of cardiac asthma was lower in the coenzyme Q10-treated patients than in the placebo group (P value < 0.001). The incidence of arrhythmia was higher in the placebo group than in the coenzyme Q10 group (P value < 0.001).

Hospitalisation (due to heart failure or for any other reason)

Morisco 1993 reported that the percentage of patients who required one or more hospitalisations during the follow-up period was about 40% in the placebo group and about 20% in the coenzyme Q10 group (P value < 0.01).

New York Heart Association (NYHA) classification of clinical status

Five trials reported on NYHA functional classification per-protocol (Adarsh 2008; Berman 2004; Keogh 2003; Morisco 1993; Munkholm 1999). These studies used different methods to report the change in NYHA clinical status and therefore pooling the results of these studies was not possible.

Adarsh 2008 reported that there was a significant improvement in the NYHA class > 1. The percentage of patients who had improvement in the NYHA class > 1 was about 63% in the coenzyme Q10 group and about 36.6% in the placebo group (P value < 0.005).

Berman 2004 reported that the NYHA class in the coenzyme Q10 group decreased from 3.1 to 2.4, whereas no change was reported in the placebo group (from median 3.68 to 3.6).

Keogh 2003 reported that the NYHA class in the coenzyme Q10 group showed a small (0.5) but significant (P value = 0.0001) improvement, whereas the placebo group showed no significant change. In the coenzyme Q10 group the NYHA class was improved, from 2.9 (± 0.06) (P value = 0.91) to 2.4 (± 0.12) (P value = 0.0). The difference in improvement between the coenzyme Q10 group and the placebo group in mean NYHA class was 0.5 units, which was statistically significant for the t-test (P value = 0.012) and for the Wilcoxon test (P value = 0.02).

Morisco 1993 reported that there was a progressive reduction in the NYHA class in the coenzyme Q10 group, indicating an improvement in functional status that was statistically significant after three, six and at 12 months. No significant change in functional class was observed in the placebo group.

Munkholm 1999 reported that the patients in the coenzyme Q10 group tended to improve with respect to their functional class (from 3A to 2B), whereas no improvement were reported in the placebo group (2B). However, the improvement in the treatment group was not statistically significant.

Secondary outcomes

None of the included trials considered quality of life as measured according to a recognised scale, exercise variables (exercise haemodynamics), adverse events, cost-effectiveness or brain natriuretic peptide (BNP) levels as one of their outcome measures. One study measured peak VO2 consumption (Khatta 2000), but as the data for this outcome come only from a single study, we could not estimate the effects of the intervention for this outcome.

Left ventricular ejection fraction, as determined by echocardiography or contrast or radionuclide angiography

Three trials reported on left ventricular ejection fraction per-protocol (Khatta 2000; Kocharian 2009; Munkholm 1999). Pooling of results was only possible for Kocharian 2009 and Munkholm 1999. The pooled data indicate no effect of coenzyme Q10 on left ventricular ejection fraction (mean difference (MD) -2.26; 95% confidence interval (CI) -15.49 to 10.97; n = 60) (Analysis 1.1).

Symptoms improvement, as measured by individual trials and/or by exercise capacity (exercise duration or walking distance, or both)

Three trials reported on exercise capacity using the six-minute walk test (Adarsh 2008; Berman 2004; Keogh 2003). These studies used different methods to report on exercise capacity and pooling of results was not possible.

Two studies reported on exercise capacity using the Naughton exercise test (Keogh 2003; Khatta 2000). Pooled data indicated no effect of coenzyme Q10 on exercise capacity (MD 12.79; 95% CI -140.12 to 165.70; n = 85) (Analysis 1.2).

Measurement of baseline and post-therapeutic serum levels of coenzyme Q10

Four studies reported baseline and post-therapeutic serum levels of coenzyme Q10 (Berman 2004; Keogh 2003; Khatta 2000; Munkholm 1999). Pooling of results was only possible for three studies (Keogh 2003; Khatta 2000; Munkholm 1999). The pooled data indicate that coenzyme Q10 treatment increases serum levels of coenzyme Q10 (MD 1.46; 95% CI 1.19 to 1.72; n = 112) (Analysis 1.3).

Discussion

Summary of main results

All seven included studies compared coenzyme Q10 with placebo. There was variability in the outcomes reported in these studies. We were able to combine results from at least two studies for the following outcomes: exercise capacity measured by a graded exercise evaluation using the Naughton protocol, left ventricular ejection fraction, and baseline and post-therapeutic serum levels of coenzyme Q10. There was clearly substantial heterogeneity in these analyses. For the remaining outcomes (New York Heart Association (NYHA) classification of clinical status, symptoms improvement as measured using the six-minute walk test), we could not combine any two studies together and all results came from individual studies. Most estimates could not be pooled because of substantial heterogeneity and the small number of included studies.

There was no significant difference between the studies in terms of coenzyme Q10 dose, patient population or study design. The follow-up period was variable and in most of the studies was equal to or less than 12 weeks. In Morisco 1993, the follow-up period was one year and in Kocharian 2009 it was six months. Kocharian 2009 enrolled young patients (age < 18 years), but all the other studies enrolled adult patients with an established diagnosis of heart failure. All seven included studies used a parallel design (Adarsh 2008; Berman 2004; Keogh 2003; Khatta 2000; Kocharian 2009; Morisco 1993; Munkholm 1999).

There were insufficient data to compare results for total mortality, major cardiovascular events, hospitalisation, NYHA clinical status, exercise capacity (six-minute walk test), oxygen consumption, adverse events or brain natriuretic peptide (BNP) levels.

By combining data from Kocharian 2009 and Munkholm 1999, which both reported the effects of coenzyme Q10 on left ventricular ejection fraction, we found that coenzyme Q10 has no clear effect (mean difference (MD) -2.26; 95% confidence interval (CI) -15.49 to 10.97) (Analysis 1.1). When we combined the data from Keogh 2003 and Khatta 2000, we found that coenzyme Q10 also has no clear effect on exercise capacity (MD 12.79; 95% CI -140.12 to 165.70) (Analysis 1.2). Four studies reported that coenzyme Q10 treatment increased serum levels (Berman 2004; Keogh 2003; Khatta 2000; Munkholm 1999). We combining the data from three of these studies (Keogh 2003; Khatta 2000; Munkholm 1999), which showed that the treatment with coenzyme Q10 increases its concentration in the blood (MD 1.46; 95% CI 1.19 to 1.72) (Analysis 1.3).

Overall completeness and applicability of evidence

The main limitation in this review was the unavailability of first-phase data from the randomised controlled trials with cross-over designs (Belardinelli 2005; Hofman-Bang 1995; Mazzola 1987; Morisco 1994; Permanetter 1992; Schneeberger 1984; Watson 1999). These studies had to be excluded as their available data were unsuitable. We need these first-phase data in order to provide more complete evidence. For the time being we can not comment on the applicability of the evidence presented here until a more complete analyses has been conducted.

Quality of the evidence

We included the data from seven studies with a total of 914 patients (Adarsh 2008; Berman 2004; Keogh 2003; Khatta 2000; Kocharian 2009; Morisco 1993; Munkholm 1999), which were at risk of bias.

Only two of the seven included studies reported the method used for randomisation (Khatta 2000; Morisco 1993). Only Morisco 1993 reported the method used for allocation concealment. The remaining studies only reported that the study was randomised without specifying the method used; this can increase the risk of selection bias.

Potential biases in the review process

We conducted our systematic review according to a protocol and following the recommendations of The Cochrane Collaboration.

Seven trials in total were included in this review, but only one reported patient mortality (Adarsh 2008).

The current results and conclusions are drawn from trials that recruited small numbers of patients, which might also have had a role in the final results. It could also be argued that longer trials are needed in order to confirm any beneficial effect of coenzyme Q10 in heart failure.

One limitation was the unavailability of first-phase data from cross-over studies. We tried to overcome this problem by contacting the authors to retrieve the data for the first phase only, but no additional data were provided.

There is a lag time between the last search and the publication of this review; it is possible that new trials have been published.

Finally, we used the random-effects model in our analyses, this being a conservative approach. However, when we used a fixed-effect model, the results were unchanged.

The main methodological limitation of this review is that many articles lacked information on one or more of the quality criteria.

Agreements and disagreements with other studies or reviews

Data were only reported from single studies and therefore we cannot state whether the findings are in agreement or disagreement with other studies.

Authors' conclusions

Implications for practice

This review provides no convincing evidence to support or refute the use of coenzyme Q10 for patients with heart failure. Although coenzyme Q10 is associated with improvement in the New York Heart Association (NYHA) classification of clinical status and exercise capacity, the evidence is based on small trial numbers and is thus incomplete.

Implications for research

Until further evidence emerges to support the use of coenzyme Q10 in heart failure, there might be a need to re-evaluate whether further trials testing coenzyme Q10 in heart failure are desirable.

Acknowledgements

We would like to thank Dr Joey Kwong, Managing Editor of the Cochrane Heart Group and Claire Williams, Assistant Managing Editor, for their great support during the whole process. We would also like to thank Nicole Martin, Trials Search Co-ordinator, for her help in developing the search strategy and Kensuke Takaoka for his help with translating a Japanese paper.

Data and analyses

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Comparison 1. Coenzyme Q10 versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Left ventricular ejection fraction            260Mean Difference (IV, Random, 95% CI)-2.26 [-15.49, 10.97]
2 Exercise capacity (measured by a graded exercise evaluation using the Naughton protocol)285Mean Difference (IV, Random, 95% CI)12.79 [-140.12, 165.70]
3 Baseline and post-therapeutic serum levels of coenzyme Q103112Mean Difference (IV, Random, 95% CI)1.46 [1.19, 1.72]
Analysis 1.1.

Comparison 1 Coenzyme Q10 versus placebo, Outcome 1 Left ventricular ejection fraction            .

Analysis 1.2.

Comparison 1 Coenzyme Q10 versus placebo, Outcome 2 Exercise capacity (measured by a graded exercise evaluation using the Naughton protocol).

Analysis 1.3.

Comparison 1 Coenzyme Q10 versus placebo, Outcome 3 Baseline and post-therapeutic serum levels of coenzyme Q10.

Appendices

Appendix 1. Search strategy

CENTRAL

#1 MeSH descriptor: [Ubiquinone] this term only
#2 ubiquinon*
#3 ubidecarenone
#4 q10 or "q 10"
#5 coq10 or "coq 10"
#6 coenzyme next Q*
#7 co-enzyme next Q*
#8 neuquinon*
#9 "quinone"
#10 ubiquinol
#11 Bio-Quinone next Q10
#12 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11)
#13 MeSH descriptor: [Heart Failure] explode all trees
#14 heart next failure*
#15 cardiac next failure*
#16 cardiomyopath*
#17 #13 or #14 or #15 or #16
#18 #12 and #17

MEDLINE OVID

1. Ubiquinone/
2. ubiquinon*.tw.
3. ubidecarenone.tw.
4. q10.tw.
5. coq10.tw.
6. coenzyme Q*.tw.
7. co-enzyme Q*.tw.
8. neuquinon*.tw.
9. quinone.tw.
10. ubiquinol.tw.
11. Bio-Quinone Q10.tw.
12. q 10.tw.
13. coq 10.tw.
14. or/1-13
15. exp Heart Failure/
16. (heart adj2 failure*).tw.
17. (cardiac adj2 failure*).tw.
18. (myocardial adj2 failure*).tw.
19. cardiomyopath*.tw.
20. or/15-19
21. 14 and 20
22. randomized controlled trial.pt.
23. controlled clinical trial.pt.
24. randomized.ab.
25. placebo.ab.
26. drug therapy.fs.
27. randomly.ab.
28. trial.ab.
29. groups.ab.
30. 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29
31. exp animals/ not humans.sh.
32. 30 not 31
33. 21 and 32

EMBASE OVID

1. ubidecarenone/
2. ubiquinone/
3. ubiquinon*.tw.
4. ubidecarenone.tw.
5. q10.tw.
6. coq10.tw.
7. coenzyme Q*.tw.
8. co-enzyme Q*.tw.
9. neuquinon*.tw.
10. quinone.tw.
11. ubiquinol.tw.
12. Bio-Quinone Q10.tw.
13. q 10.tw.
14. coq 10.tw.
15. or/1-14
16. exp heart failure/
17. (heart adj2 failure*).tw.
18. (cardiac adj2 failure*).tw.
19. (myocardial adj2 failure*).tw.
20. cardiomyopath*.tw.
21. or/16-20
22. 15 and 21
23. random$.tw.
24. factorial$.tw.
25. crossover$.tw.
26. cross over$.tw.
27. cross-over$.tw.
28. placebo$.tw.
29. (doubl$ adj blind$).tw.
30. (singl$ adj blind$).tw.
31. assign$.tw.
32. allocat$.tw.
33. volunteer$.tw.
34. crossover procedure/
35. double blind procedure/
36. randomized controlled trial/
37. single blind procedure/
38. 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37
39. (animal/ or nonhuman/) not human/
40. 38 not 39
41. 22 and 40

ISI Web of Science

#16 #15 AND #10
#15 #14 OR #13 OR #12 OR #11
#14 TS=cardiomyopath*
#13 TS=(myocardial SAME failure*)
#12 TS=(cardiac SAME failure*)
#11 TS=(heart SAME failure*)
#10 #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1
#9 TS="Bio-Quinone Q10"
#8 TS=ubiquinol
#7 TS=quinone
#6 TS=neuquinon*
#5 TS=("coenzyme Q*" or "co-enzyme Q*")
#4 TS=ubidecarenone
#3 TS=ubiquinon*
#2 TS=("q 10" or "coq 10")
#1 TS=(q10 or coq10)

CINAHL

S41 S22 and S40
S40 S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39
S39 TX cross-over*
S38 TX crossover*
S37 TX volunteer*
S36 (MH "Crossover Design")
S35 TX allocat*
S34 TX control*
S33 TX assign*
S32 TX placebo*
S31 (MH "Placebos")
S30 TX random*
S29 TX (doubl* N1 mask*)
S28 TX (singl* N1 mask*)
S27 TX (doubl* N1 blind*)
S26 TX (singl* N1 blind*)
S25 TX (clinic* N1 trial?)
S24 PT clinical trial
S23 (MH "Clinical Trials+")
S22 S15 and S21
S21 S16 or S17 or S18 or S19 or S20
S20 (TI cardiomyopath*) or (AB cardiomyopath*)
S19 (TI (myocardial N2 failure*)) or (AB (myocardial N2 failure*))
S18 (TI (cardiac N2 failure*)) or (AB (cardiac N2 failure*))
S17 (TI (heart N2 failure*)) or (AB (heart N2 failure*))
S16 (MH "Heart Failure, Congestive+")
S15 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14
S14 (TI coq 10) or (AB coq 10)
S13 (TI q 10) or (AB q 10)
S12 (TI Bio-Quinone Q10) or (AB Bio-Quinone Q10)
S11 (TI Bio-Quinone Q10) or (AB Bio-Quinone Q10)
S10 (TI ubiquinol) or (AB ubiquinol)
S9 (TI quinone) or (AB quinone)
S8 (TI neuquinon*) or (AB neuquinon*)
S7 (TI co-enzyme Q*) or (AB co-enzyme Q*)
S6 (TI coenzyme Q*) or (AB coenzyme Q*)
S5 (TI coq10) or (AB coq10)
S4 (TI ubidecarenone) or (AB ubidecarenone)
S3 (TI ubiquinon*) or (AB ubiquinon*)
S2 (TI q10) or (AB q10)
S1 (MH "Coenzyme Q")

AMED 

1 coenzymes/
2 Ubiquinone.tw.
3 ubidecarenone.tw.
4 Q10.tw.
5 CoQ10.tw.
6 coenzym$ Q$.tw.
7 co-enzym$ Q$.tw.
8 neuquinon$.tw.
9 quinone.tw.
10 ubiquinol.tw.
11 Q-10.tw.
12 or/1-11
13 heart failure congestive/
14 heart failure.tw.
15 cardiac failure.tw.
16 cardiomyopathies/
17 cardiomyopath$.tw.
18 or/13-17
19 12 and 18

Contributions of authors

Mohammed E Madmani: protocol development, trial identification, data extraction, data analysis and drafting the review.

Ahmad Y Solaiman: protocol development, data extraction.

Yasser Shahrour: protocol development, data analysis.

Yasser Madmani: data analysis and drafting the review.

Khalil Tamr Agha: protocol development, trial identification.

Adib Essali: protocol and review revision and providing consultation.

Waleed Kadro: protocol and review revision and providing consultation.

All authors have contributed to and approved the final version of the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • Psychiatry Centre, Teshreen Hospital, Syrian Arab Republic.

  • Damascus University-Medical College, Syrian Arab Republic.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adarsh 2008

MethodsRCT with parallel design
Participants

87 patients
46 patients with HCM diagnosed clinically and by echocardiography and by excluding cases of longstanding hypertension were given 200 mg/day of oral coenzyme Q10 in addition to conventional therapy. A comparable group of 41 patients received only conventional therapy

All patients had > 1 mitral regurgitation

Adults (> 18 years)

Interventions

Intervention: coenzyme Q10 100 mg twice daily

Control: placebo

Outcomes

Symptoms improvement (NYHA classification)

Quality of life on detailed questionnaire and on 6-minute walk test

Mortality

Improvement in diastolic dysfunction

Improvement in mitral regurgitation

Reduction in LVOT gradient in obstructive cases

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information given
Allocation concealment (selection bias)Unclear riskNo information given
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo information given
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
High risk2 drop-outs; 1 in the treatment group and 1 in the placebo group: clearly reported
Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasLow riskNo other bias could be found

Berman 2004

MethodsRCT with parallel design
Participants32 patients with end-stage heart failure awaiting heart transplantation were randomly allocated to receive 60 mg U/day of Ultrasome coenzyme Q10 or placebo for 3 months
Adults (> 18 years)
All patients continued their regular medication regimen
Interventions

Intervention: coenzyme Q10 60 mg twice daily

Control: placebo

Outcomes

Symptoms improvement (NYHA classification)

Symptoms improvement measured on the Minnesota Living with Heart Failure Questionnaire

Quality of life on 6-minute walk test

Blood tests for ANP and TNF
Echocardiography

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised
Allocation concealment (selection bias)Low riskGroup allocation was done by a third (external) party. Patients were given a personal addressed, sealed envelope containing the words "code A" or "code B"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
High risk5 patients failed to complete the study because of death, need for heart transplantation, drug-induced intestinal upset, inconvenient travel connections and lack of compliance (1 patient each)
Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasHigh riskDid not report the number of patients in the treatment and placebo groups

Keogh 2003

MethodsRCT with parallel design
Participants39 patients with NYHA class II or III heart failure were randomised in a double-blind, placebo-controlled study to 150 mg/day of oral coenzyme Q10 or placebo
19 patients in the coenzyme Q10 group and 20 in the placebo group
Adults (> 18 years)
Interventions

Intervention: coenzyme Q10 150 mg/day

Control: placebo

Outcomes

Symptom class by NYHA and SAS

Exercise tolerance by a 6-minute walk test
Walk test and treadmill exercise test (modified Naughton stress test) assessment for clinical outcomes of heart failure

Plasma levels of coenzyme Q10

Assessment for the clinical outcomes of heart failure including readmission, transplantation or death, serum creatinine, sodium and potassium

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised
Allocation concealment (selection bias)Unclear riskNo information given
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
High risk

In the placebo group, 2 patients withdrew: 1 because of a rash and nausea and the other for epigastric burning with a history of peptic ulceration

In the active group, 1 patient withdrew after 56 days due to increased lethargy and 1 withdrew in order to start carvedilol (prohibited medication)

Clearly reported

Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasLow riskNo other bias could be found

Khatta 2000

MethodsRCT with parallel design
Participants55 patients who had congestive heart failure with NYHA class III and IV symptoms to receive either coenzyme Q10 200 mg/day or placebo for a period of 6 months
28 in the treatment group and 27 in the placebo group
Adults (> 18 years)
Interventions

Intervention: coenzyme Q10 200 mg/day

Control: placebo

Outcomes

Left ventricular ejection fraction (measured by radionuclide ventriculography)

Peak oxygen consumption

Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was performed using a random number generator
Allocation concealment (selection bias)Unclear riskNo information given
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

All patients and study personnel were blinded to study group assignment until all data were final

Double-blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
High risk9 patients did not finish the study: 5 in the coenzyme Q10 group and 4 in the placebo group; clearly reported
Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasLow riskNo other bias could be found

Kocharian 2009

MethodsRCT with parallel design
Participants

38 patients younger than 18 years with idiopathic dilated cardiomyopathy were assigned to receive either coenzyme Q10 or placebo for a period of 6 months

17 patients in the coenzyme Q10 group and 21 in the placebo group
Children (< 18 years)

Interventions

Intervention: coenzyme Q10 2 mg/kg/day in 2 or 3 divided doses, these being increased to the maximum dose of 10 mg/kg/day according to tolerance or the appearance of side effects

Control: placebo

OutcomesLeft ventricular ejection fraction
NotesThis is the only study that evaluated the use of coenzyme Q10 in children
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised
Allocation concealment (selection bias)Unclear riskNo information given
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients completed the trial
Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasUnclear riskNo other bias could be found

Morisco 1993

MethodsRCT with parallel design
Participants

641 patients with NYHA III or IV heart failure

319 patients in the coenzyme Q10 group and 322 in the placebo group
Adults (> 18 years)

Interventions

Intervention: coenzyme Q10 50 mg twice or 3 times daily

Control: placebo

Outcomes

NYHA clinical status

Incidence of severe cardiovascular complications (pulmonary oedema, cardiac asthma, arrhythmia)

Length of hospitalisation

NotesThis is the only study which recruited a large number of patients
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised
Allocation concealment (selection bias)Low riskComputer-generated allocation
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
High risk

37 patients dropped out in the treatment group and 41 dropped out in the placebo group

Clearly reported

Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasLow riskNo other bias could be found

Munkholm 1999

  1. a

    NYHA: New York Heart Association
    RCT: randomised controlled trial

MethodsRCT with parallel design
Participants

22 participants with NYHA II or III heart failure

11 patients in the treatment group and 11 in the placebo group
Adults (> 18 years)
Before and after the treatment period, a right heart catheterisation was done

Interventions

Intervention: coenzyme Q10 100 mg twice daily for 12 weeks

Control: placebo

Outcomes

Baseline and post-therapeutic serum levels of coenzyme Q10

Left ventricular ejection fraction

NYHA clinical status

NotesThis study is an invasive study investigating the treatment of congestive heart failure
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised
Allocation concealment (selection bias)Unclear riskNo information given
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information given
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed the study
Selective reporting (reporting bias)Low riskAll outcomes were reported
Other biasLow riskNo other bias could be found

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomised controlled trial

Azuma 1992Title is not related to our main area of interest
Baggio 1993Not a RCT
Belardinelli 2005RCT study with a cross-over design. First-phase data are unavailable
Belardinelli 2008Title is not related to our main area of interest
Cascone 1985Not a RCT
Chew 2008Title is not related to our main area of interest
Davini 1992Title is not related to our main area of interest
Hall 1990Not a RCT
Hanping 1997Title is not related to our main area of interest
Hofman-Bang 1995RCT study with a cross-over design. First-phase data are unavailable
Ishiyama 1976Not a RCT
Iwabuchi 1972Not a RCT
Khatta 1999Title is not related to our main area of interest
Kumar 2007Title is not related to our main area of interest
Lampertico 1993Not a RCT
Langsjoen 1985Not a RCT
Langsjoen 1985aTitle is related to our main area of interest but none of the selected patients were in frank congestive heart failure
Langsjoen 1988Not a RCT
Langsjoen 1990Not a RCT
Langsjoen 1994Not a RCT
Langsjoen 2008Title is not related to our main area of interest
Manzoli 1990Not a RCT
Mazzola 1987RCT study with a cross-over design. First-phase data are unavailable
Morisco 1994RCT study with a cross-over design. First-phase data are unavailable
Mortensen 1985Not a RCT
Nishimura 1996Title is not related to our main area of interest
Permanetter 1992RCT study with a cross-over design. First-phase data are unavailable
Poggesi 1991Title is related to our main area of interest but none of the selected patients were in frank congestive heart failure
Sacher 1997Not a RCT
Schneeberger 1984RCT study with a cross-over design. First-phase data are unavailable
Sinatra 2000Title is not related to our main area of interest
Sinatra 2004Title is not related to our main area of interest
Watson 1999RCT study with a cross-over design. First-phase data are unavailable
Witte 2005Title is not related to our main area of interest

Ancillary