Peroxisome proliferator-activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack

  • Review
  • Intervention

Authors


Abstract

Background

Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowing glucose in diabetes, these drugs may also protect against hyperlipidaemia and arteriosclerosis, which are risk factors for stroke.

Objectives

To assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events for people with stroke or transient ischaemic attack (TIA).

Search methods

We searched the Cochrane Stroke Group Trials Register (August 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 9), MEDLINE (1949 to October 2013), EMBASE (1980 to October 2013), CINAHL (1982 to October 2013), AMED (1985 to October 2013) and 11 Chinese databases (October 2013). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. There were no language restrictions.

Selection criteria

We included randomised controlled trials (RCTs) evaluating PPAR-γ agonists versus placebo for the secondary prevention of stroke and related vascular events in people with stroke or TIA, with the outcomes of recurrent stroke, vascular events and adverse events.

Data collection and analysis

Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality.

Main results

We identified four eligible studies with 1163 participants; only one study had a low risk of bias for all domains. The participants in different studies were heterogeneous. The number of participants with recurrent stroke was evaluated in two studies, where PPAR-γ agonists reduced the recurrence of stroke compared with placebo (risk ratio (RR) 0.52, 95% confidence interval (CI) 0.34 to 0.80). PPAR-γ agonists given over a mean duration of 34.5 months in a single trial were found to reduce a composite outcome of total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99). Data on additional composite outcomes reflecting serious adverse events (all-cause death and other major vascular events; all-cause mortality, non-fatal myocardial infarction or non-fatal stroke) were similar although the confidence intervals were wider and the effects were not statistically significant. In addition, two studies respectively measured insulin sensitivity and the ubiquitin-proteasome activity in carotid plaques with significant differences in these outcomes between PPAR-γ agonists and placebo. None of the studies reported the number of participants with disability due to vascular events or improvement in quality of life. Three RCTs reported information about adverse events. Frequent adverse events included oedema, cardiac failure and anaemia. Evidence that adverse events occurred more frequently in participants treated with PPAR-γ agonists when compared with placebo was imprecise and inconsistent (risk difference (RD) 10%, 95% CI -8% to 28%, I² = 86%).

Authors' conclusions

PPAR-γ agonists were demonstrated to reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and improve insulin sensitivity and the stabilisation of carotid plaques. There is evidence of limited quality that they are well-tolerated. However, the conclusions should be interpreted with caution considering the small number and the quality of the included studies. In future, well-designed, double-blind RCTs with large samples are required to test the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA.

Résumé scientifique

Les agonistes des récepteurs activés par les proliférateurs de peroxysomes pour la prévention de la récurrence de l'AVC et d'autres événements vasculaires chez les patients victimes d'AVC ou d'accident ischémique transitoire

Contexte

Les agonistes des récepteurs activés par les proliférateurs de peroxysomes (PPAR) sont des médicaments sensibilisants à l'insuline utilisés pour le traitement de la résistance à l'insuline. En plus de diminuer le glucose dans le diabète, ces médicaments peuvent également protéger contre l'hyperlipidémie et l'athérosclérose, qui sont des facteurs de risque pour l'accident vasculaire cérébral (AVC).

Objectifs

Évaluer l'efficacité et l'innocuité des agonistes des PPAR dans la prévention secondaire de l'AVC et des événements vasculaires chez les victimes d'AVC ou d'accident ischémique transitoire (AIT).

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais du groupe Cochrane sur les accidents vasculaires cérébraux (août 2013), le registre Cochrane des essais contrôlés (CENTRAL) (La Bibliothèque Cochrane 2013, numéro 9), MEDLINE (de 1949 à octobre 2013), EMBASE (de 1980 à octobre 2013), CINAHL (de 1982 à octobre 2013), AMED (de 1985 à octobre 2013) et 11 bases de données chinoises (octobre 2013). En vue d'identifier d'autres essais publiés, non publiés et en cours, nous avons effectué des recherches dans des registres d'essais en cours, les références bibliographiques et les actes de conférence pertinents et contacté les auteurs et des sociétés pharmaceutiques. Il n'y avait aucune restriction concernant la langue.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés (ECR) évaluant les agonistes des PPAR par rapport à un placebo pour la prévention secondaire de l'AVC et des événements vasculaires chez les personnes victimes d'un AVC ou d'un AIT, avec les critères de jugement de la récurrence d'AVC, des événements vasculaires et des effets indésirables.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment passé au crible les titres et résumés des dossiers identifiés, sélectionné les études à inclure, extrait les données éligibles, recoupé les données pour en vérifier l'exactitude et évalué la qualité méthodologique.

Résultats principaux

Nous avons identifié quatre études éligibles, portant sur 1 163 participants; une seule étude présentait un faible risque de biais pour tous les domaines. Les participants dans les différentes études étaient hétérogènes. Le nombre de participants avec un AVC récurrent a été évalué dans les deux études, où les agonistes PPAR réduisaient la récurrence d'AVC par rapport à un placebo (risque relatif (RR) 0,52, intervalle de confiance à 95% (IC) de 0,34 à 0,80). Les agonistes des PPAR administrés pendant une durée moyenne de 34,5 mois dans un essai unique réduisaient le résultat composite du nombre total de décès cardio-vasculaire, d'infarctus du myocarde non mortel ou d'AVC non mortel (RR 0,73, IC à 95% 0,54 à 0,99). Les données sur les résultats composites supplémentaires qui reflétaient les effets indésirables graves (décès toutes causes confondues et autres événements vasculaires graves; mortalité toutes causes confondues, infarctus du myocarde non mortels ou AVC non mortels) étaient similaires, bien que les intervalles de confiance soient plus larges et que les effets ne soient pas statistiquement significatifs. De plus, deux études mesuraient respectivement la sensibilité de l'insuline et l'activité ubiquitine-protéasome dans les plaques carotidiennes avec des différences significatives dans ces résultats entre les agonistes des PPAR et un placebo. Aucune des études n'a rapporté le nombre de participants souffrant d'incapacité en raison d'événements vasculaires ou une amélioration de la qualité de vie. Trois ECR ont rapporté des informations sur les effets indésirables. Les effets indésirables fréquents incluaient l'Sdème, l'insuffisance cardiaque et l'anémie. Les preuves indiquant que les effets indésirables se produisaient plus fréquemment chez les participants traités avec des agonistes des PPAR par rapport à un placebo était imprécises et incohérentes (différence de risques (DR) 10%, IC à 95% -8% à 28 ; I² = 86 %).

Conclusions des auteurs

Les agonistes des PPAR démontraient réduire la récurrence d'AVC et le nombre total d'événements de décès cardio-vasculaire, d'infarctus non mortel du myocarde ou d'accident vasculaire cérébral (AVC) non mortel et améliorer la sensibilité à l'insuline et la stabilisation des plaques carotidiennes. Des preuves de qualité limitée démontrent qu'ils sont bien tolérés. Cependant, les conclusions doivent être interprétées avec prudence compte tenu du petit nombre et de la qualité des études incluses. De futurs ECR bien conçus, en double aveugle et avec de grands échantillons sont nécessaires pour tester l'efficacité et l'innocuité des agonistes des PPAR dans la prévention secondaire de l'AVC et des événements vasculaires chez les personnes victimes d'AVC ou d'AIT.

Plain language summary

Drugs for preventing recurrent stroke and other vascular events in people who have already had a stroke or transient ischaemic attack

Question: We wanted to evaluate the effectiveness and safety of PPAR-γ agonists versus placebo in the secondary prevention of stroke and related vascular events for people who have already had a stroke or transient ischaemic attack.

Background: Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are drugs that improve the way insulin works in the human body. They are widely used in the treatment of adult type diabetes (type 2 diabetes). Moreover, they may also protect against hyperlipidaemia (the presence of excess fats in the blood) and arteriosclerosis (where the walls of the arteries become thickened and hardened), which are risk factors for stroke.

Study characteristics: Four studies were identified up to October 2013. These studies included a total of 1163 participants. Three studies evaluated the drug pioglitazone and one study evaluated rosiglitazone. Three studies included participants who had no history of diabetes, and one study included only participants with diabetes.

Key results: Compared with placebo, PPAR-γ agonists reduced recurrent strokes and other vascular events, improved insulin sensitivity (that is, the body's response to insulin) and stabilised carotid plaques (fatty deposits on artery walls). PPAR-γ agonists also appeared to be well-tolerated.

Quality of the evidence: The conclusions of the review should be interpreted with caution considering the small number of included studies and the quality limitations in some of the included studies. Further well-designed, double-blind randomised controlled trials with large sample sizes are required.

Résumé simplifié

Médicaments pour la prévention de la récurrence de l'AVC et autres événements vasculaires chez les patients ayant déjà eu un AVC ou un accident ischémique transitoire

Question : Nous avons voulu évaluer l'efficacité et l'innocuité des agonistes des PPAR-³ par rapport à un placebo dans la prévention secondaire de l'AVC et des événements vasculaires chez les patients ayant déjà eu un accident vasculaire cérébral ou un accident ischémique transitoire (AIT).

Contexte : Les agonistes des récepteurs activés par les proliférateurs de peroxysomes (PPAR) sont des médicaments qui améliorent la manière dont l'insuline fonctionne dans le corps humain. Ils sont couramment utilisés dans le traitement des patients adultes atteints de diabète (diabète de type 2). De plus, ils pourraient aussi protéger contre l'hyperlipidémie (présence d'excès de lipides dans le sang) et l'athérosclérose (où les parois des artères deviennent épaisses et durcissent), qui sont des facteurs de risque d'accident vasculaire cérébral (AVC).

Caractéristiques de l'étude : Quatre études ont été identifiées jusqu'en octobre 2013. Ces études portaient sur un total de 1 163 participants. Trois études évaluaient la pioglitazone et une étude évaluait la rosiglitazone. Trois études incluaient des participants sans antécédents de diabète et une étude incluait uniquement des participants atteints de diabète.

Résultats : Comparé à un placebo, les agonistes des PPAR réduisaient la récurrence d'AVC et d'autres événements vasculaires, amélioraient la sensibilité à l'insuline (réponse de l'organisme à l'insuline) et stabilisaient les plaques carotidiennes (dépôts graisseux sur les parois des artères). Les agonistes des PPAR semblaient également être bien tolérés.

Qualité des preuves : Les conclusions de la revue doivent être interprétées avec prudence compte tenu du petit nombre d'études incluses et de la qualité limitée dans certaines des études incluses. Des essais contrôlés randomisés supplémentaires, bien conçus, en double aveugle et avec de grands effectifs sont nécessaires.

Notes de traduction

Traduit par: French Cochrane Centre 15th June, 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

Background

Description of the condition

Stroke is one of the most common neurological diseases and one of the most common causes of mortality worldwide (WHO 2010). On average 80% of strokes are caused by ischaemia, and recurrent strokes account for around 30% of all events (Goldstein 2006; Simon 2009). Significantly higher mortality was found in recurrent stroke compared with first-ever stroke (Jørgensen 1997). Therefore, secondary prevention plays an important role in reducing stroke recurrence and other related vascular events. Diabetes is an important risk factor for ischaemic stroke. It has been estimated that around one in eight or nine strokes in people with a history of stroke or transient ischaemic attack (TIA) could be attributed to diabetes (Emerging Risk Factors Collaboration 2010). Therefore, management of blood glucose can be regarded as one possible target for stroke prevention.

Description of the intervention

Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of hyperglycaemia with insulin resistance. To date, PPAR-γ agonists, such as rosiglitazone and pioglitazone, have been widely recommended in the treatment of people with type 2 diabetes (Mooradian 2002). In certain cases PPAR-γ agonists can be used in combination with insulin or other hypoglycaemic agents. In view of its effect on lowering glucose, PPAR-γ agonists are believed to be beneficial for stroke prevention. The common adverse events induced by PPAR-γ agonists mainly include oedema, anaemia, liver dysfunction and cardiac failure (Fogg 2009). Moreover, an increased risk of mortality and vascular events was found with rosiglitazone compared with pioglitazone in patients with diabetes older than 65 years of age (Graham 2010).

How the intervention might work

The mechanisms of hyperglycaemia and stroke have been widely discussed. Blood flow and vascular reactivity can be affected by hyperglycaemia due to the abnormal metabolism of endothelium-derived nitric oxide (Melikian 2009). Hyperglycaemia is also associated with reduced penumbral salvage in the large-vessel thromboembolic stroke (Els 2002). Therefore, PPAR-γ agonists can prevent these pathological processes by controlling blood glucose. In addition to lowering glucose, PPAR-γ agonists may also protect against hyperlipidaemia and arteriosclerosis, which are complications of diabetes and risk factors for stroke (Collino 2010; Dasu 2009). Moreover, it has been found that PPAR-γ agonists can reduce inflammation, which may prevent vascular events to some extent (Nakamura 2007).

Why it is important to do this review

Trial evidence indicates the benefits of aspirin, clopidogrel, ticlopidine, triflusal and the combination of aspirin and dipyridamole in the secondary prevention of stroke and other vascular events (Costa 2005; De Schryver 2007; Sudlow 2009). Anticoagulants appear to be less effective, at least where the cause is not cardioembolic (Sandercock 2009). Vitamin K antagonists are not more efficacious than antiplatelet therapy (De Schryver 2012). PPAR-y agonists have been tested in clinical trials that focused on the prevention of stroke and other vascular events, particularly for people with diabetes. Thus, we aim to evaluate the efficacy and safety of PPAR-γ agonists for preventing recurrent stroke and other vascular events in people with stroke or TIA. To our knowledge, no systematic review or meta-analysis on this topic exists in the literature.

Objectives

To assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events for people with stroke or TIA.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) and excluded quasi-randomised or confounded studies.

Types of participants

We included people over 18 years old with a history of stroke or TIA. We used the definition of TIA as provided in the original publications. We excluded people with diabetes who lacked a clear history of stroke or TIA.

Types of interventions

We included trials comparing PPAR-γ agonists (e.g. pioglitazone or rosiglitazone) with placebo, regardless of the length of treatment period and dosage of treatment. We included other concomitant therapies providing they were administered in both the intervention and control groups.

Types of outcome measures

Primary outcomes
  • The number of participants with recurrent stroke. Recurrent stroke was as defined in the original publications.

  • The number of participants who experienced any adverse events, such as oedema, anaemia or cardiac failure.

Secondary outcomes
  • The number of participants with serious vascular events, such as myocardial infarction, stroke or vascular death.

  • The number of deaths due to vascular events.

  • The number of participants with disability due to vascular events.

  • Improvement in quality of life.

  • Insulin sensitivity.

  • Ubiquitin-proteasome activity in carotid plaques.

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module. We searched for trials in all languages and arranged for the translation of relevant articles where necessary.

Electronic searches

We searched the Cochrane Stroke Group Trials Register (August 2013) and the following electronic bibliographic databases:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 9) (Appendix 1);

  • MEDLINE (Ovid) (1949 to October 2013) (Appendix 2);

  • EMBASE (Ovid) (1980 to October 2013) (Appendix 3);

  • CINAHL (EBSCO) (1982 to October 2013) (Appendix 4);

  • AMED (Ovid) (1985 to October 2013) (Appendix 5);

  • Chinese Stroke Trials Register (October 2013);

  • CBM-disc (China Biological Medicine Databases) (1979 to October 2013);

  • CNKI (China National Knowledge Infrastructure) (1979 to October 2013);

  • Chinese MD and DD Dissertations in CNKI (October 2013);

  • CACP (Chinese Academic Conference Papers Database) (1998 to October 2013);

  • CDDB (Chinese Dissertations Database) (1977 to October 2013);

  • Chinese Evidence-Based Medicine Database (October 2013);

  • CMAC (China Medical Academic Conferences) (1994 to October 2013);

  • CMCC (Chinese Medical Current Contents) (1994 to October 2013);

  • Chinese Science and Technique Journals Database (VIP) (1989 to October 2013);

  • Wanfang Data (www.wanfangdata.com/) (1984 to October 2013).

We developed all the search strategies with the help of the Cochrane Stroke Group Trials Search Co-ordinator.

We also searched the following ongoing trials registers in October 2013 with the keywords mainly including PPAR-γ agonist, thiazolidinedione, pioglitazone, rosiglitazone, stroke and TIA:

Searching other resources

We also:

  • used Science Citation Index Cited Reference Search for forward tracking of important articles;

  • searched reference lists of relevant reviews and retrieved articles;

  • searched relevant conference proceedings, including the 6th to 22th European Stroke Conference (from 1997 to 2013) and the 4th, 5th, 6th, 7th and 8th World Stroke Congress (2000, 2004, 2008, 2010 and 2012);

  • contacted authors where necessary for missing information;

  • contacted the manufacturers (Takeda Pharmaceutical Company and GlaxoSmithKline Pharmaceuticals) for updated information in October 2013.

Data collection and analysis

Selection of studies

Two review authors (LJ, WLN) independently screened titles and abstracts of the references obtained as a result of our searching activities and excluded obviously irrelevant reports. We retrieved the full-text articles for the remaining references and the same two review authors independently screened the full-text articles and identified studies for inclusion, and also identified and recorded reasons for exclusion of the ineligible studies. We resolved any disagreements through discussion or, if required, we consulted a third party. We collated multiple reports of the same study so that each study, not each reference, was the unit of interest in the review. We recorded the selection process and completed a PRISMA flow diagram (Figure 1).

Figure 1.

Study flow diagram.

Data extraction and management

Two review authors (LJ, WLN) independently extracted data from the published reports onto standardised forms, and cross-checked them for accuracy. We used checklists to independently record details including methods of generating the randomisation schedule, method of concealment of allocation, blinding of assessors, intention-to-treat (ITT) analysis, adverse events and dropouts for all reasons, important imbalance in prognostic factors, participants (socio-demographic and related clinical information), interventions (medications and non-pharmacological interventions) and outcomes. We resolved disagreements with a third party.

Assessment of risk of bias in included studies

Two review authors (LJ, WLN) independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreements by discussion or by involving a third party. We assessed the risk of bias according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias.

We graded the risk of bias for each domain as high, low or unclear and provided information from the study report together with a justification for our judgement in the 'Risk of bias' tables.

Measures of treatment effect

We expected the RCTs to measure dichotomous data. We expressed dichotomised data as risk ratios (RR) with their 95% confidence intervals (CI). If a trial (or group within a trial) reported no adverse events or dropouts, we calculated risk differences (RD) instead of RRs with 95% CI. We entered and analysed data using the latest version of the Review Manager software (RevMan 2012).

Unit of analysis issues

We dealt with any unit of analysis issues according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Dealing with missing data

We planned to contact the authors of the studies for further details if any data were missing or to establish the characteristics of unpublished trials through correspondence with trial co-ordinators or principal investigators. According to the intention-to-treat (ITT) principle, all randomised participants should be included. We considered different scenarios (best-case and worst-case) to account for missing data.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials in each analysis and took I² values over 50% as suggestive of substantial heterogeneity.

Assessment of reporting biases

We planned to use funnel plots to examine potential publication bias if there was a sufficient number of trials (Egger 1997).

Data synthesis

Where we considered studies to be sufficiently similar, we conducted a meta-analysis by pooling the appropriate data using RevMan 5.2 (RevMan 2012). We calculated the overall effects using a random-effects model regardless of the level of heterogeneity. We provided a descriptive summary of the results when substantial heterogeneity between the studies prevented us from combining outcome data.

Subgroup analysis and investigation of heterogeneity

We intended to undertake subgroup analyses according to the age and ethnicity of participants, TIA definition, different PPAR-γ agonists, and dosage and duration of treatment. We intended to use the Chi² test to examine the significance of differences between subgroups.

Sensitivity analysis

We analysed sensitivity by assessing the robustness of results in fixed-effect versus random-effects models, and studies at high risk versus low risk of bias. We also examined potential sources of methodological heterogeneity.

Results

Description of studies

Results of the search

We identified a total of 1159 references from the electronic database searches after excluding duplicates (Figure 1). After screening titles and abstracts, we obtained 28 full-text articles relating to 15 studies and assessed them for eligibility. We included four studies (J-SPIRIT; Kernan 2003; Marfella 2006; PROactive) and identified one ongoing RCT.

Included studies

In accordance with the inclusion criteria, we included four studies with 1163 participants. J-SPIRIT tested the effect of pioglitazone on the reduction of recurrent stroke in participants with abnormal glucose metabolisms and insulin resistance after ischaemic stroke. Kernan 2003 evaluated the effect of pioglitazone in improving insulin sensitivity among non-diabetic patients with a recent TIA or non-disabling ischaemic stroke. Marfella 2006 investigated the effect of rosiglitazone in participants with symptomatic carotid stenosis by testing ubiquitin-proteasome activity in carotid plaques. PROactive focused on the efficacy and safety of pioglitazone on the reduction of stroke recurrence and related vascular events in participants with type 2 diabetes. The details of the included studies are provided in the Characteristics of included studies table. In addition, one ongoing RCT (IRIS) investigated the efficacy of pioglitazone in participants with insulin resistance and ischaemic stroke or TIA no less than 14 days and no more than six months before randomisation. The details of this ongoing study are provided in the Characteristics of ongoing studies table.

Excluded studies

We excluded 11 studies (CIMT Trial; Dehnavi 2005; Forst 2008; Hedblad 2007; Koshiyama 2001; Meisner 2006; Sidhu 2004; TART; TIDE; TRIPOD; Varghese 2009) after full-text evaluation. We have provided the reasons for exclusion in the Characteristics of excluded studies table.

Risk of bias in included studies

The information regarding risk of bias is provided in Figure 2 and Figure 3. Because the data for J-SPIRIT were only released in abstracts, insufficient information was available for us to judge the risk of bias.

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

Only one study (Kernan 2003) clearly stated the methods of randomisation and allocation concealment; insufficient information was found in the other included studies. Therefore, we judged selection bias as an unclear risk of bias.

Blinding

Information regarding blinding was insufficient in two studies (J-SPIRIT; PROactive). In Kernan 2003, information about performance bias and detection bias was provided, while only information about detection bias was reported in Marfella 2006. Therefore, we assessed this as an unclear risk of bias.

Incomplete outcome data

J-SPIRIT did not report on completeness of outcome data. No dropouts were reported in Kernan 2003 or Marfella 2006. In PROactive, there were 882 of 984 participants (90%) who completed the final visit: 439 of 486 (90%) in the pioglitazone group and 443 (89%) in the placebo group. We assessed this as a high risk of bias.

Selective reporting

In addition to J-SPIRIT, all the pre-specified outcomes were reported in the other included trials. Therefore, we assessed this as a low risk of bias.

Other potential sources of bias

We did not find any other potential bias. We could not examine publication bias by a funnel plot analysis due to the insufficient numbers of studies.

Effects of interventions

Primary outcome measures

The number of participants with recurrent stroke

Two studies (J-SPIRIT; PROactive) with 1103 participants reported the number of recurrent strokes at the end of the study: 29 of 544 (5%) participants in the PPAR-γ agonist group and 58 of 559 (10%) participants in the placebo group (RR 0.52, 95% CI 0.34 to 0.80) (Analysis 1.1). When we conducted a sensitivity analysis with a fixed-effect model, we found no significant difference (RR 0.51, 95% CI 0.33 to 0.79).

The number of participants who experienced any adverse events

Three studies (Kernan 2003; Marfella 2006; PROactive) with 1044 participants reported adverse events. In the PPAR-γ agonists and placebo groups, there were 247 of 516 (48%) and 260 of 528 (49%) participants with adverse events (RD 10%, 95% CI -8% to 28%), with strong heterogeneity (test for heterogeneity I² = 86%) (Analysis 2.1). We conducted a sensitivity analysis with a fixed-effect model and found no significant difference (RD -1%, 95% CI -7% to 5%). In Kernan 2003, certain adverse events such as nausea, oedema, muscle aches, sore throat and dizziness were more common in the pioglitazone group. In Marfella 2006, no participant experienced any clinical events in either group during the study. The proportion of participants who experienced adverse events in PROactive was the highest, with the definitions of adverse events including: resulting in death, life-threatening, needing or prolonging in-patient admission, resulting in persistent or significant disability, or needing intervention to prevent any of the above. As a result, heart failure requiring hospitalisation was reported in 31 (6.4%) participants in the pioglitazone group versus 20 (4.0%) in the placebo group (P = 0.09). Fatal heart failure was reported in six (1.2%) in the pioglitazone group versus four (0.8%) in the placebo group (P = 0.50).

Secondary outcomes measures

In addition to the pre-defined outcomes, we also added insulin sensitivity and ubiquitin-proteasome activity in carotid plaque as secondary outcomes.

The number of participants with serious vascular events

Only one study (PROactive) reported the number of participants with serious vascular events. For the total events of all-cause death, non-fatal myocardial infarction, acute coronary syndrome and cardiac intervention, stroke, major leg amputation, or bypass surgery or leg revascularisation, there were 98 of 486 (20%) and 126 of 498 (25%) participants respectively in the PPAR-γ agonists and placebo groups (RR 0.80, 95% CI 0.63 to 1.01). For the total events of all-cause death, non-fatal myocardial infarction or non-fatal stroke, there were 76 of 486 (16%) and 98 of 498 (20%) participants respectively in the PPAR-γ agonists and placebo groups (RR 0.79, 95% CI 0.61 to 1.04). Pioglitazone reduced fatal or non-fatal stroke (RR 0.54, 95% CI 0.35 to 0.85) and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99).

The number of deaths due to vascular events

None of the studies reported the number of deaths due to vascular events. However, PROactive reported all-cause mortality: 46 of 486 (9%) and 49 of 498 (10%) deaths in the PPAR-γ agonists and placebo groups respectively (RR 0.96, 95% CI 0.66 to 1.41).

The number of participants with disability due to vascular events

None of studies reported the number of participants with disability due to vascular events.

Improvement in quality of life

None of studies reported improvement in quality of life.

Insulin sensitivity

In Kernan 2003, insulin sensitivity was measured with the composite insulin sensitivity index. The change in the composite index was 1.2 ± 0.6 in the pioglitazone group, and -0.1 ± 0.6 in the placebo group (P < 0.01). The C-reactive protein concentration declined from 0.30 to 0.20 mg/L in the pioglitazone group, but increased from 0.41 to 0.45 mg/L in the placebo group (P = 0.06).

Ubiquitin-proteasome activity in carotid plaques

In Marfella 2006, the ubiquitin-proteasome activity in carotid plaques was examined. Compared with the placebo group, symptomatic carotid plaques in the rosiglitazone group showed fewer inflammatory cells (P < 0.01); less ubiquitin (322 ± 79 ng/mg in the rosiglitazone group and 468.7 ± 89 ng/mg in the placebo group, P < 0.01), proteasome 20S (46.8 ± 10 pmol/mg in the rosiglitazone group and 79.8 ± 25 pmol/mg in the placebo group, P < 0.01) and NFkB (P < 0.01); less nitrotyrosine (2.2 ± 0.21 nmol/pg in the rosiglitazone group and 3.5 ± 0.42 nmol/pg in the placebo group, P < 0.01) and superoxide anion production (3.57 ± 1.1 pmol/L in the rosiglitazone group and 6.26 ± 1.4 pmol/L in the placebo group, P < 0.01); and more collagen content (P < 0.01), suggesting greater plaque stabilisation.

Discussion

Summary of main results

Four studies with 1163 participants met the inclusion criteria. Three of them (J-SPIRIT; Kernan 2003; PROactive) evaluated the effect of pioglitazone versus placebo; the fourth (Marfella 2006) focused on rosiglitazone versus placebo. The number of participants with recurrent stroke was evaluated in two studies (J-SPIRIT; PROactive), where PPAR-γ agonists reduced the recurrence of stroke compared with placebo (RR 0.52, 95% CI 0.34 to 0.80). Moreover, we found PPAR-γ agonists reduced total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke and improved insulin sensitivity and stabilisation of carotid plaques (Kernan 2003; Marfella 2006; PROactive). Regarding safety, there was very little evidence of a difference in reported adverse events in the PPAR-γ agonists group versus the placebo group (RD 10%, 95% CI -8% to 28%) in three studies (Kernan 2003; Marfella 2006; PROactive).

Overall completeness and applicability of evidence

All participants had a past history of stroke or TIA; however, none of the RCTs precisely described stroke type or diagnosis criteria. Marfella 2006 focused on non-diabetic participants, J-SPIRIT focused on participants with an abnormal glucose metabolism and insulin resistance, PROactive focused on participants with type 2 diabetes, and Marfella 2006 focused on participants with carotid plaques. The clinical heterogeneity of participants in different studies could potentially induce heterogeneity in the results of the meta-analysis. Three studies (J-SPIRIT; Kernan 2003; PROactive) evaluated pioglitazone versus placebo, and one study (Marfella 2006) evaluated rosiglitazone versus placebo. Regarding outcomes, recurrent stroke and other vascular events were recorded in two studies (J-SPIRIT; PROactive). Insulin sensitivity and ubiquitin-proteasome activity in carotid plaques were investigated in the other two studies respectively (Kernan 2003; Marfella 2006). Due to insufficient data, we did not undertake any subgroup analyses.

Quality of the evidence

Only Kernan 2003 was of high quality with a low risk of bias for all domains. J-SPIRIT was only published as abstracts, therefore insufficient information was available to judge. For PROactive and Marfella 2006 we found an unclear risk in the method of randomisation, allocation concealment and blinding. High risk of bias in incomplete outcome data was found in PROactive. In summary, the methodological limitations of the included studies should be considered when interpreting the results. In addition, the sample sizes in Kernan 2003 and Marfella 2006 were relatively small.

Potential biases in the review process

We performed the search strategy as per protocol and identified four completed studies and one ongoing study. However, we cannot confirm if there are other unpublished studies that we failed to identify. There was no additional information available when we contacted relevant authors and manufacturers. In preparing this review, we independently screened trials for inclusion, extracted data and assessed the quality of included trials to minimise potential biases. We used the RD as a way of addressing studies with zero events. The event rates quoted, based on the aggregate event rates for the two groups, were 48% versus 49%, a difference of 1%. With the random-effects model, the outlying estimate from Kernan 2003 effectively pushed the RD out towards 10%. This might well explain why the difference in the aggregate data of 1% did not translate to a RD of 10% (the fixed-effect result was much closer to the aggregate events). We found no other potential biases.

Agreements and disagreements with other studies or reviews

To our knowledge, this is the first systematic review of this intervention in the field of secondary prevention of stroke and related vascular events for people with stroke or TIA.

Authors' conclusions

Implications for practice

Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists appear to reduce recurrent stroke and other vascular events, and improve insulin sensitivity and the stabilisation of carotid plaques. In addition, they appeared to be well-tolerated. However, the conclusions of this review should be interpreted with caution considering the small number of included studies and the quality of some of them.

Implications for research

In future, well-designed, double-blind RCTs with large sample sizes are required to test the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events for people with stroke or TIA.

Acknowledgements

The authors acknowledge the help provided by the Cochrane Stroke Group.

Data and analyses

Download statistical data

Comparison 1. Efficacy in the secondary prevention of stroke
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Recurrence of stroke21103Risk Ratio (M-H, Random, 95% CI)0.52 [0.34, 0.80]
Analysis 1.1.

Comparison 1 Efficacy in the secondary prevention of stroke, Outcome 1 Recurrence of stroke.

Comparison 2. Safety in the secondary prevention of stroke
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Reported adverse events31044Risk Difference (M-H, Random, 95% CI)0.10 [-0.08, 0.28]
Analysis 2.1.

Comparison 2 Safety in the secondary prevention of stroke, Outcome 1 Reported adverse events.

Appendices

Appendix 1. Cochrane Central Register of Controlled Trials (CENTRAL)

#1 [mh ^"cerebrovascular disorders"] or [mh "basal ganglia cerebrovascular disease"] or [mh "brain ischemia"] or [mh "carotid artery diseases"] or [mh "cerebrovascular trauma"] or [mh "intracranial arterial diseases"] or [mh "intracranial arteriovenous malformations"] or [mh "intracranial embolism and thrombosis"] or [mh "intracranial hemorrhages"] or [mh ^stroke] or [mh "brain infarction"] or [mh ^"vasospasm, intracranial"]
#2 (stroke or poststroke or "post-stroke" or cerebrovasc* or brain next vasc* or cerebral next vasc* or cva* or apoplex* or SAH):ti,ab
#3 ((brain* or cerebr* or cerebell* or intracran* or intracerebral) near/5 (isch*mi* or infarct* or thrombo* or emboli* or occlus*)):ti,ab
#4 ((brain* or cerebr* or cerebell* or intracerebral or intracranial or subarachnoid) near/5 (haemorrhage* or hemorrhage* or haematoma* or hematoma* or bleed*)):ti,ab
#5 ((transi* near/3 isch*m* near/3 attack*) or TIA or TIAs):ti,ab
#6 #1 or #2 or #3 or #4 or #5
#7 [mh ^"PPAR gamma"/AG,DE,ME,PD,TU]
#8 [mh ^"Peroxisome Proliferator-Activated Receptors"/AG,DE,ME,PD,TU] or [mh ^"Transcription Factors"/AG,DE,ME,PD,TU]
#9 [mh ^Thiazolidinediones]
#10 (("peroxisome proliferator-activated receptor gamma" or "PPAR gamma" or "PPAR-gamma" or "PPARgamma" or PPARG or NR1C3) near/5 (agonist* or modulator* or stimulat* or stimulant* or activat*)):ti,ab
#11 (thiazolidinedione* or glitazone* or pioglitazone or rosiglitazone or troglitazone or netoglitazone or rivoglitazone or ciglitazone or balaglitazone or darglitazone or edaglitazone or englitazone or lobeglitazone):ti,ab
#12 #7 or #8 or #9 or #10 or #11
#13 #6 and #12

Appendix 2. MEDLINE search strategy (Ovid)

1. cerebrovascular disorders/ or exp basal ganglia cerebrovascular disease/ or exp brain ischemia/ or exp carotid artery diseases/ or exp cerebrovascular trauma/ or exp intracranial arterial diseases/ or exp intracranial arteriovenous malformations/ or exp "intracranial embolism and thrombosis"/ or exp intracranial hemorrhages/ or stroke/ or exp brain infarction/ or vasospasm, intracranial/
2. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or SAH).tw.
3. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial or subarachnoid) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
5. ((transi$ adj3 isch?em$ adj3 attack$) or TIA$1).tw.
6. 1 or 2 or 3 or 4 or 5
7. PPAR gamma/ag, de, me, pd, tu
8. Peroxisome Proliferator-Activated Receptors/ag, de, me, pd, tu or Transcription Factors/ag, de, me, pd, tu
9. Thiazolidinediones/
10. ((peroxisome proliferator-activated receptor gamma or PPAR gamma or PPAR-gamma or PPARgamma or PPARG or NR1C3) adj5 (agonist$ or modulator$ or stimulat$ or stimulant$ or activat$)).tw.
11. (thiazolidinedione$ or glitazone$ or pioglitazone or rosiglitazone or troglitazone or netoglitazone or rivoglitazone or ciglitazone or balaglitazone or darglitazone or edaglitazone or englitazone or lobeglitazone).tw,nm.
12. 7 or 8 or 9 or 10 or 11
13. Randomised Controlled Trials as Topic/
14. random allocation/
15. Controlled Clinical Trials as Topic/
16. control groups/
17. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/
18. double-blind method/
19. single-blind method/
20. Placebos/
21. placebo effect/
22. Drug Evaluation/
23. Research Design/
24. randomised controlled trial.pt.
25. controlled clinical trial.pt.
26. (clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt.
27. random$.tw.
28. (controlled adj5 (trial$ or stud$)).tw.
29. (clinical$ adj5 trial$).tw.
30. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
31. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
32. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
33. placebo$.tw.
34. controls.tw.
35. (RCT or RCTs).tw. or trial.ti.
36. or/13-35
37. 6 and 12 and 36
38. exp animals/ not humans.sh.
39. 37 not 38

Appendix 3. EMBASE search strategy (Ovid)

1. cerebrovascular disease/ or exp basal ganglion hemorrhage/ or exp brain hematoma/ or exp brain hemorrhage/ or exp brain infarction/ or exp brain ischemia/ or exp carotid artery disease/ or cerebral artery disease/ or exp cerebrovascular accident/ or exp intracranial aneurysm/ or exp occlusive cerebrovascular disease/ or vertebrobasilar insufficiency/ or stroke/ or stroke patient/ or stroke unit/
2. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or SAH).tw.
3. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial or subarachnoid) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
5. ((transi$ adj3 isch?em$ adj3 attack$) or TIA$1).tw.
6. 1 or 2 or 3 or 4 or 5
7. peroxisome proliferator activated receptor gamma agonist/
8. peroxisome proliferator activated receptor gamma/ct, ad, dt [Clinical Trial, Drug Administration, Drug Therapy]
9. peroxisome proliferator activated receptor gamma 2/dt [Drug Therapy]
10. peroxisome proliferator activated receptor/ct, ad, dt [Clinical Trial, Drug Administration, Drug Therapy]
11. transcription factor/ct, ad, dt [Clinical Trial, Drug Administration, Drug Therapy]
12. peroxisome proliferator activated receptor gamma coactivator 1alpha/ct, dt [Clinical Trial, Drug Therapy]
13. peroxisome proliferator activated receptor gamma coactivator 1beta/dt [Drug Therapy]
14. exp glitazone derivative/
15. ((peroxisome proliferator-activated receptor gamma or PPAR gamma or PPAR-gamma or PPARgamma or PPARG or NR1C3) adj5 (agonist$ or modulator$ or stimulat$ or stimulant$ or activat$)).tw.
16. (thiazolidinedione$ or glitazone$ or pioglitazone or rosiglitazone or troglitazone or netoglitazone or rivoglitazone or ciglitazone or balaglitazone or darglitazone or edaglitazone or englitazone or lobeglitazone).tw.
17. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16
18. 6 and 17
19. Randomized Controlled Trial/
20. Randomization/
21. Controlled Study/
22. control group/
23. clinical trial/ or phase 1 clinical trial/ or phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/ or controlled clinical trial/
24. Double Blind Procedure/
25. Single Blind Procedure/ or triple blind procedure/
26. placebo/
27. "types of study"/
28. random$.tw.
29. (controlled adj5 (trial$ or stud$)).tw.
30. (clinical$ adj5 trial$).tw.
31. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
32. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
33. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
34. placebo$.tw.
35. (RCT or RCTs).tw. or trial.ti.
36. or/19-35
37. 18 and 36
38. (exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/) not (human/ or normal human/ or human cell/)
39. 37 not 38

Appendix 4. CINAHL search strategy (EBSCO)

S16. S11 AND S15
S15. S12 OR S13 OR S14
S14. TI thiazolidinedione* or glitazone* or pioglitazone or rosiglitazone or troglitazone or netoglitazone or rivoglitazone or ciglitazone or balaglitazone or darglitazone or edaglitazone or englitazone or lobeglitazone or AB thiazolidinedione* or glitazone* or pioglitazone or rosiglitazone or troglitazone or netoglitazone or rivoglitazone or ciglitazone or balaglitazone or darglitazone or edaglitazone or englitazone or lobeglitazone
S13. ( TI peroxisome proliferator-activated receptor gamma or PPAR gamma or PPAR-gamma or PPARgamma or PPARG or NR1C3 or AB peroxisome proliferator-activated receptor gamma or PPAR gamma or PPAR-gamma or PPARgamma or PPARG or NR1C3 ) AND ( TI agonist* or modulator* or stimulat* or stimulant* or activat* or AB agonist* or modulator* or stimulat* or stimulant* or activat* )
S12. (MH "Thiazolidinediones") OR (MH "Troglitazone") OR (MH "Rosiglitazone") OR (MH "Pioglitazone")
S11. S1 OR S2 OR S3 OR S6 OR S9 OR S10
S10. TI transient ischaemic attack* or TI transient ischemic attack* or AB transient ischaemic attack* or AB transient ischemic attack* or TI TIA or TI TIA s or AB TIA or AB TIAs
S9. S7 and S8
S8. TI ( haemorrhage* or hemorrhage* or haematoma* or hematoma* or bleed* ) or AB ( haemorrhage* or hemorrhage* or haematoma* or hematoma* or bleed* )
S7. TI ( brain* or cerebr* or cerebell* or intracerebral or intracranial or subarachnoid ) or AB ( brain* or cerebr* or cerebell* or intracerebral or intracranial or subarachnoid )
S6. S4 and S5
S5. TI ( ischemi* or ischaemi* or infarct* or thrombo* or emboli* or occlus* ) or AB ( ischemi* or ischaemi* or infarct* or thrombo* or emboli* or occlus* )
S4. TI ( brain* or cerebr* or cerebell* or intracran* or intracerebral ) or AB ( brain* or cerebr* or cerebell* or intracran* or intracerebral )
S3. TI ( stroke or poststroke or post-stroke or cerebrovasc* or brain vasc* or cerebral vasc or cva or apoplex or SAH ) or AB ( stroke or poststroke or post-stroke or cerebrovasc* or brain vasc* or cerebral vasc or cva or apoplex or SAH )
S2. (MH "Stroke Patients") OR (MH "Stroke Units")
S1. (MH "Cerebrovascular Disorders") OR (MH "Basal Ganglia Cerebrovascular Disease+") OR (MH "Carotid Artery Diseases+") OR (MH "Cerebral Ischemia+") OR (MH "Cerebral Vasospasm") OR (MH "Intracranial Arterial Diseases+") OR (MH "Intracranial Embolism and Thrombosis") OR (MH "Intracranial Hemorrhage+") OR (MH "Stroke") OR (MH "Vertebral Artery Dissections")

Appendix 5. AMED search strategy (Ovid)

1. cerebrovascular disorders/ or cerebral hemorrhage/ or cerebral infarction/ or cerebral ischemia/ or cerebrovascular accident/ or stroke/
2. (stroke or poststroke or post-stroke or cerebrovasc$ or brain vasc$ or cerebral vasc$ or cva$ or apoplex$ or SAH).tw.
3. ((brain$ or cerebr$ or cerebell$ or intracran$ or intracerebral) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$)).tw.
4. ((brain$ or cerebr$ or cerebell$ or intracerebral or intracranial or subarachnoid) adj5 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$)).tw.
5. ((transi$ adj3 isch?em$ adj3 attack$) or TIA$1).tw.
6. 1 or 2 or 3 or 4 or 5
7. ((peroxisome proliferator-activated receptor gamma or PPAR gamma or PPAR-gamma or PPARgamma or PPARG or NR1C3) adj5 (agonist$ or modulator$ or stimulat$ or stimulant$ or activat$)).tw.
8. (thiazolidinedione$ or glitazone$ or pioglitazone or rosiglitazone or troglitazone or netoglitazone or rivoglitazone or ciglitazone or balaglitazone or darglitazone or edaglitazone or englitazone or lobeglitazone).tw.
9. 7 or 8
10. 6 and 9

Contributions of authors

Liu J and Wang L conceived and developed the review. Liu J was in charge of searching, identifying and assessing studies, data extraction and analyses, and writing the draft of review. Wang L gave general advice on the review, identified trials, assessed studies, extracted data and revised the draft. Liu J supervised the quality of the methodology and statistics. Liu J will be responsible for future review updates.

Declarations of interest

None known.

Differences between protocol and review

We added insulin sensitivity and ubiquitin-proteasome activity in carotid plaques as secondary outcomes, which were not included in the protocol.

We calculated the overall effects using a random-effects model regardless of the level of heterogeneity. If heterogeneity was 0% then the results using a random-effects model would be the same as the results from a fixed-effect model.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

J-SPIRIT

MethodsA multicentre, randomised, double-blind, placebo-controlled trial to test the effect of pioglitazone on the reduction of recurrent stroke in patients with abnormal glucose metabolism and insulin resistance after ischaemic stroke
Participants

People aged 35 to 85 years with symptomatic ischaemic stroke and no history of diabetes and no evidence of diabetes by initial blood test were included

119 eligible people from 3 hospitals in Tokyo or neighbouring cities in Japan were randomised

InterventionsPioglitazone or matching placebo
OutcomesRecurrence of stroke; recurrence of ischaemic stroke
NotesMean observation periods were 25 ± 19.9 months in the pioglitazone group and 30 ± 16 months in the control group
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation was not described
Allocation concealment (selection bias)Unclear riskAllocation concealment was not reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to judge
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to judge
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information to judge
Selective reporting (reporting bias)Unclear riskInsufficient information to judge
Other biasUnclear riskInsufficient information to judge

Kernan 2003

MethodsA randomised, double-blind, placebo-controlled trial to test the effect of pioglitazone compared with placebo for improving insulin sensitivity among non-diabetic patients with a recent TIA or non-disabling ischaemic stroke
ParticipantsNon-diabetic men and women aged > 45 years with TIA or non-disabling ischaemic stroke were included. 20 eligible patients from 3 hospitals were randomised as 1:1 into the trial
InterventionsPioglitazone 45 mg per day or placebo was given for 3 months
OutcomesMean proportional changes in insulin sensitivity; mean C-reactive protein concentration; adverse events
NotesA repeated oral glucose tolerance test was done at the endpoint of the 3-month therapy. The mean age was 66 years among participants assigned to pioglitazone and 67 years among participants assigned to placebo
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA master schedule of computer-generated random treatment assignments (placebo or pioglitazone) was stored at the investigational pharmacy at Yale-New Haven hospital
Allocation concealment (selection bias)Low riskAfter screening for eligibility, a research associate contacted the investigational pharmacist, who assigned the participant to the next available treatment as specified by the master schedule
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants were blinded to treatment assignment throughout the study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskResearch staff and investigators were blinded to treatment assignment throughout the study
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participant permanently discontinued the treatment
Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow riskNo other bias was found

Marfella 2006

MethodsA randomised, placebo-controlled trial
Participants40 patients who presented with symptoms of cerebral ischaemic attack were included and randomised as 1:1 into the trial
InterventionsRosiglitazone 8 mg per day or placebo was given for 4 months
OutcomesUbiquitin-proteasome activity
Notes38 patients with asymptomatic carotid stenosis were not included in this review
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation was not described
Allocation concealment (selection bias)Unclear riskAllocation concealment was not reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to judge
Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe specimens were analysed by an expert pathologist blinded to the participant's diagnosis
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo participant in either group discontinued the treatment
Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow riskNo other bias was found

PROactive

  1. a

    TIA: transient ischaemic attack

MethodsA multicentre, randomised, double-blind, placebo-controlled trial
ParticipantsPatients aged 35 to 75 years with type 2 diabetes and a previous stroke (6 months before randomisation) were included
984 eligible patients were randomised into the trial, with 486 in the pioglitazone group and 498 in the placebo group
InterventionsPioglitazone titration from 15 to 45 mg per day depending on tolerability or placebo was given until the first occurrence of any of the events described in primary outcomes. The mean duration was 34.5 months
Outcomes

Primary outcomes: all-cause mortality, non-fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, cardiac intervention (including coronary artery bypass graft surgery or percutaneous coronary intervention), leg revascularisation and amputation above the ankle

Secondary outcomes: all-cause death, non-fatal myocardial infarction or non-fatal stroke; adverse events

NotesData for patients without previous stroke were not included
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation was not described
Allocation concealment (selection bias)Unclear riskAllocation concealment was not reported
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskInsufficient information to judge
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInsufficient information to judge
Incomplete outcome data (attrition bias)
All outcomes
High risk

882 of 984 (90%) participants completed the final visit: 439 (90%) of 486 in the pioglitazone group and 443 (89%) in the placebo group

Intention-to-treat analysis was used

Selective reporting (reporting bias)Low riskAll pre-specified outcomes were reported
Other biasLow riskNo other bias was found

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    PPAR-γ: peroxisome proliferator-activated receptor gamma

CIMT TrialThe intervention was not PPAR-γ agonist
Dehnavi 2005The participants were not eligible
Forst 2008There was no subgroup of stroke patients for whom separate results were available
Hedblad 2007The participants were not eligible
Koshiyama 2001The participants were not eligible
Meisner 2006The participants were not eligible
Sidhu 2004The participants were not eligible
TARTThe participants were not eligible
TIDEThere was no subgroup of stroke patients for whom separate results were available
TRIPODThe participants were not eligible
Varghese 2009The participants were not eligible

Characteristics of ongoing studies [ordered by study ID]

IRIS

  1. a

    TIA: transient ischaemic attack

Trial name or titleInsulin Resistance Intervention after Stroke Trial (IRIS)
MethodsA randomised, interventional, placebo-controlled trial
ParticipantsThose aged 40 years or older with ischaemic stroke or TIA no less than 14 days and no more than 6 months before randomisation and insulin resistance as defined by a value over 3.0 on the homeostasis model assessment of insulin sensitivity
InterventionsPioglitazone versus placebo
OutcomesPrimary outcome: time to occurrence of recurrent fatal or non-fatal stroke, or fatal or non-fatal myocardial infarction
Starting dateFebruary 2005
Contact informationWalter N Kernan, MD, Principal Investigator, Yale University School of Medicine, USA
NotesEstimated enrolment: 3936; estimated study completion date: August 2015

Ancillary