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

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References

References to studies included in this review

IRIS {published data only}

Inzucchi SE, Viscoli CM, Young LH, Furie KL, Gorman M, Lovejoy AM, et al. Pioglitazone prevents diabetes in patients with insulin resistance and cerebrovascular disease. Diabetes Care 2016;39:1684‐92. CENTRAL
Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al. Pioglitazone after ischemic stroke or transient ischemic attack. New England Journal of Medicine 2016;374:1321‐31. CENTRAL
Viscoli CM, Brass LM, Carolei A, Conwit R, Ford GA, Furie KL, et al. Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial. American Heart Journal 2014;168:823‐9.e6. CENTRAL

J‐SPIRIT {published data only}

Tanaka R, Okuma Y, Miyamoto N, Tanaka Y, Yamashiro K, Watada H, et al. Effects of pioglitazone in patients with impaired glucose tolerance after stroke; progress report from J‐SPIRIT study. International Journal of Stroke 2010;5:195 (Abst.PO10427). CENTRAL
Tanaka R, Yamashiro K, Tanaka Y, Miyamoto N, Ueno Y, Watanabe M, et al. Effects of pioglitazone in patients with abnormal glucose metabolism after stroke. The J‐SPIRIT study. Stroke 2013;44:Abst.ATP416. CENTRAL

Kernan 2003 {published data only}

Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, et al. Pioglitazone improves insulin sensitivity among nondiabetic patients with a recent transient ischemic attack or ischemic stroke. Stroke 2003;34:1431‐6. CENTRAL

Marfella 2006 {published data only}

Marfella R, D'Amico M, Di Filippo C, Baldi A, Siniscalchi M, Sasso FC, et al. Increased activity of the ubiquitin‐proteasome system in patients with symptomatic carotid disease is associated with enhanced inflammation and may destabilize the atherosclerotic plaque: effects of rosiglitazone treatment. Journal of the American College of Cardiology 2006;47:2444‐55. CENTRAL

PROactive {published data only}

PROactive study shows reduced heart attacks and strokes in type 2 diabetics on pioglitazone HCI (Actos) therapy. Cardiovascular Journal of South Africa 2005;16:286‐7. CENTRAL
Charbonnel B, Dormandy J, Erdmann E, Massi‐Benedetti M, Skene A, on behalf of the PROactive Study Group. The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive). Diabetes Care 2004;27:1647‐53. CENTRAL
Dormandy JA, Betteridge DJ, Schernthaner G, Pirags V, Norgren L, on behalf of the PROactive investigators. Impact of peripheral arterial disease in patients with diabetes ‐ results from PROactive (PROactive 11). Atherosclerosis 2009;202:272‐81. CENTRAL
Dormandy JA, Charbonnel B, Eckland DJA, Erdmann E, Massi‐Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279‐89. CENTRAL
Erdmann E, Dormandy J, Wilcox R, Massi‐Benedetti M, Charbonnel B. PROactive 07: Pioglitazone in the treatment of type 2 diabetes: results of the PROactive study. Vascular Health and Risk Management 2007;3:355‐70. CENTRAL
Erdmann E, Harding S, Lam H, Perez A. Ten‐year observational follow‐up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes, Obesity and Metabolism 2016;18:266‐73. CENTRAL
Erdmann E, Spanheimer R, Charbonnel B. Pioglitazone and the risk of cardiovascular events in patients with type 2 diabetes receiving concomitant treatment with nitrates, renin‐angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20). Journal of Diabetes 2010;2:212‐20. CENTRAL
Wilcox R, Bousser MG, Betteridge J, Schernthaner G, Pirags V, Kupfer S, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke. Results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38:865‐73. CENTRAL
Wilcox R, Kupfer S, Erdmann E. Effects of pioglitazone on major adverse cardiovascular events in high‐risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macro Vascular Events (PROactive 10). American Heart Journal 2008;155:712‐7. CENTRAL

References to studies excluded from this review

CIMT Trial {published data only}

Lundby Christensen L, Almdal T, Boesgaard T, Breum L, Dunn E, Gade‐Rasmussen B, et al. Study rationale and design of the CIMT trial: the Copenhagen Insulin and Metformin Therapy trial. Diabetes, Obesity and Metabolism 2009;11:315‐22. CENTRAL

Erdmann 2015 {published data only}

Erdmann E, Califf R, Gerstein HC, Malmberg K, Ruilope L, Schwartz GG, et al. Effects of the dual peroxisome proliferator‐activated receptor activator aleglitazar in patients with type 2 diabetes mellitus or prediabetes. American Heart Journal 2015;170:117‐22. CENTRAL

Forst 2008 {published data only}

Forst T, Wilhelm B, Pfützner A, Fuchs W, Lehmann U, Schaper F, et al. Investigation of the vascular and pleiotropic effects of atorvastatin and pioglitazone in a population at high cardiovascular risk. Diabetes and Vascular Disease Research 2008;5:298‐303. CENTRAL

Hedblad 2007 {published data only}

Hedblad B, Zambanini A, Nilsson P, Janzon L, Berglund G. Rosiglitazone and carotid IMT progression rate in a mixed cohort of patients with type 2 diabetes and the insulin resistance syndrome: main results from the Rosiglitazone Atherosclerosis Study. Journal of Internal Medicine 2007;261:293‐305. CENTRAL

ISRCTN54951661 {unpublished data only}

ISRCTN54951661. A 52 week double blind randomized controlled trial comparing the effect of rosiglitazone versus placebo on the prevention of progression of atherosclerosis in high risk patients without diabetes. http://www.isrctn.com/ISRCTN54951661 (accessed May 2017). CENTRAL

Koshiyama 2001 {published data only}

Koshiyama H, Shimono D, Kuwamura N, Minamikawa J, Nakamura Y. Inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2001;86:3452‐6. CENTRAL

Lincoff 2014 {published data only}

Lincoff AM, Tardif JC, Schwartz GG, Nicholls SJ, Rydén L, Neal B, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA 2014;311:1515‐25. CENTRAL

Meisner 2006 {published data only}

Meisner F, Walcher D, Gizard F, Kapfer X, Huber R, Noak A, et al. Effect of rosiglitazone treatment on plaque inflammation and collagen content in nondiabetic patients: data from a randomized placebo‐controlled trial. Arteriosclerosis Thrombosis and Vascular Biology 2006;26:845‐50. CENTRAL

NCT00879970 {published data only}

NCT00879970. Thiazolidinedione intervention with vitamin D evaluation (TIDE). https://clinicaltrials.gov/ct2/show/NCT00879970 (accessed May 2017). CENTRAL

Sidhu 2004 {published data only}

Sidhu JS, Kaposzta Z, Markus HS, Kaski JC. Effect of rosiglitazone on common carotid intima‐media thickness progression in coronary artery disease patients with diabetes mellitus. Arteriosclerosis Thrombosis and Vascular Biology 2004;24:930‐4. CENTRAL

Tanaka 2015 {published data only}

Tanaka R, Yamashiro K, Okuma Y, Shimura H, Nakamura S, Ueno Y, et al. Effects of pioglitazone for secondary stroke prevention in patients with impaired glucose tolerance and newly diagnosed diabetes: the J‐SPIRIT Study. Journal of Atherosclerosis and Thrombosis 2015;22:1305‐16. CENTRAL

TART {published data only}

Hodis HN, Mack WJ, Zheng L, Li Y, Torres M, Sevilla D, et al. Effect of peroxisome proliferator‐activated receptor gamma agonist treatment on subclinical atherosclerosis in patients with insulin‐requiring type 2 diabetes. Diabetes Care 2006;29:1545‐53. CENTRAL
Karim R, Buchanan TA, Hodis HN, Li Y, Mack WJ. The association of smoking and subclinical atherosclerosis in type 2 diabetes: modification by duration of diabetes. Diabetic Medicine 2005;22:81‐7. CENTRAL
Zheng L, Buchanan TA, Hodis HN, Li Y, Torres M, Mack WJ. Time from diagnosis of type 2 diabetes to initiation of insulin therapy is related to carotid artery intima‐media thickness. Atherosclerosis 2003;170:293‐9. CENTRAL
Zheng L, Hodis HN, Buchanan TA, Li Y, Mack WJ. Effect of antihypertensive therapy on progression of carotid intima‐media thickness in patients with type 2 diabetes mellitus. American Journal of Cardiology 2007;99:956‐60. CENTRAL

TRIPOD {published data only}

Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang A, Buchanan TA. TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebo‐controlled trial of troglitazone in women with prior gestational diabetes mellitus. Controlled Clinical Trials 1998;19:217‐31. CENTRAL
Xiang AH, Hodis HN, Kawakubo M, Peters RK, Kjos SL, Marroquin A, et al. Effect of pioglitazone on progression of subclinical atherosclerosis in non‐diabetic premenopausal Hispanic women with prior gestational diabetes. Atherosclerosis 2008;199:207‐14. CENTRAL
Xiang AH, Peters RK, Kjos SL, Ochoa C, Marroquin A, Goico J, et al. Effect of thiazolidinedione treatment on progression of subclinical atherosclerosis in premenopausal women at high risk for type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2005;90:1986‐91. CENTRAL

Varghese 2009 {published data only}

Varghese A, Yee MS, Chan CF, Crowe LA, Keenan NG, Johnston DG, et al. Effect of rosiglitazone on progression of atherosclerosis: insights using 3D carotid cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance 2009;11:24. CENTRAL

Collino 2010

Collino M, Aragno M, Castiglia S, Miglio G, Tomasinelli C, Boccuzzi G, et al. Pioglitazone improves lipid and insulin levels in overweight rats on a high cholesterol and fructose diet by decreasing hepatic inflammation. British Journal of Pharmacology 2010;160:1892‐902.

Costa 2005

Costa J, Ferro JM, Matias‐Guiu J, Alvarez‐Sabin J, Torres F. Triflusal for preventing serious vascular events in people at high risk. Cochrane Database of Systematic Reviews 2005, Issue 3. [DOI: 10.1002/14651858.CD004296.pub2]

Dasu 2009

Dasu MR, Park S, Devaraj S, Jialal I. Pioglitazone inhibits toll‐like receptor expression and activity in human monocytes and db/db mice. Endocrinology 2009;150:3457‐64.

De Schryver 2007

De Schryver ELLM, Algra A, van Gijn J. Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD001820.pub3]

De Schryver 2012

De Schryver EL, Algra A, Kappelle LJ, van Gijn J, Koudstaal PJ. Vitamin K antagonists versus antiplatelet therapy after transient ischaemic attack or minor ischaemic stroke of presumed arterial origin. Cochrane Database of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/14651858.CD001342.pub3]

Egger 1997

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple graphical test. BMJ 1997;315:629‐34.

Els 2002

Els T, Klisch J, Orszagh M, Hetzel A, Schulte‐Mönting J, Schumacher M, et al. Hyperglycemia in patients with focal cerebral ischemia after intravenous thrombolysis: influence on clinical outcome and infarct size. Cerebrovascular Diseases 2002;13:89‐94.

Emerging Risk Factors Collaboration 2010

Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta‐analysis of 102 prospective studies. Lancet 2010;375:2215‐22.

Fogg 2009

Fogg C, Kasliwal R, Shakir SA. Risk management and outcomes of adverse events to pioglitazone in primary care in the UK: an observational study. Drug Safety 2009;32:229‐37.

Goldstein 2006

Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke 2006;37:1583‐633.

Graham 2010

Graham DJ, Ouellet‐Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411‐8.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.

Jørgensen 1997

Jørgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Stroke recurrence: predictors, severity, and prognosis. The Copenhagen Stroke Study. Neurology 1997;48:891‐5.

Melikian 2009

Melikian N, Seddon MD, Casadei B, Chowienczyk PJ, Shah AM. Neuronal nitric oxide synthase and human vascular regulation. Trends in Cardiovascular Medicine 2009;19:256‐62.

Mooradian 2002

Mooradian AD, Chehade J, Thurman JE. The role of thiazolidinediones in the treatment of patients with type 2 diabetes mellitus. Treatments in Endocrinology 2002;1:13‐20.

Nakamura 2007

Nakamura T, Yamamoto E, Kataoka K, Yamashita T, Tokutomi Y, Dong YF, et al. Pioglitazone exerts protective effects against stroke in stroke‐prone spontaneously hypertensive rats, independently of blood pressure. Stroke 2007;38:3016‐22.

RevMan 2014 [Computer program]

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Sandercock 2009

Sandercock PA, Gibson LM, Liu M. Anticoagulants for preventing recurrence following presumed non‐cardioembolic ischaemic stroke or transient ischaemic attack. Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/14651858.CD000248.pub2]

Simon 2009

Simon RP, Greenberg DA, Aminoff MJ. Stroke. Clinical Neurology. 7th Edition. New York: McGraw‐Hill, 2009:292‐327.

Sudlow 2009

Sudlow CL, Mason G, Maurice JB, Wedderburn CJ, Hankey GJ. Thienopyridine derivatives versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD001246.pub2]

WHO 2010

World Health Organization. The atlas of heart disease and stroke. www.who.int/cardiovascular_diseases/resources/atlas/en (accessed 12 May 2013).

References to other published versions of this review

Liu 2013

Liu J, Wang LN. Peroxisome proliferator‐activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. Cochrane Database of Systematic Reviews 2013, Issue 8. [DOI: 10.1002/14651858.CD010693]

Liu 2014

Liu J, Wang LN. Peroxisome proliferator‐activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. Cochrane Database of Systematic Reviews 2014, Issue 1. [DOI: 10.1002/14651858.CD010693.pub2]

Liu 2015

Liu J, Wang LN. Peroxisome proliferator‐activated receptor gamma agonists for preventing recurrent stroke and other vascular events in patients with stroke or transient ischaemic attack. Cochrane Database of Systematic Reviews 2015, Issue 10. [DOI: 10.1002/14651858.CD010693.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

IRIS

Methods

A multicentre, double‐blind, placebo‐controlled clinical trial to test the effectiveness of pioglitazone for insulin resistant, non‐diabetic patients with a recent ischaemic stroke or TIA

Participants

People aged at least 40 years with qualifying ischaemic stroke or TIA during the 6 months before randomisation, as well as insulin resistance, defined as a value of more than 3.0 on the homeostasis model assessment of insulin resistance index. 3876 participants were randomised.

Interventions

Pioglitazone or matching placebo. The initial dose was 15 mg of pioglitazone daily or placebo. The dose was increased to 2 pills daily (30 mg of pioglitazone or placebo) at 4 weeks and to 3 pills daily (45 mg of pioglitazone or placebo) at 8 weeks. At 12 weeks, participants were started on 1 x 45 mg pioglitazone tablet or placebo tablet daily.

Outcomes

Fatal or non‐fatal stroke; fatal or non‐fatal myocardial infarction; heart failure resulting in hospitalisation or death; death from any cause; diabetes; and cognitive decline

Notes

Participants were contacted every 4 months with a median follow‐up of 4.8 years.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was performed using a random permuted block design with variable block sizes stratified by site.

Allocation concealment (selection bias)

Low risk

To conceal the allocation sequence, randomisation lists were kept only at the central pharmacy and the statistical centre.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The Investigational Drug Service prepared medication bottles, including starter supplies, which were stored at the research sites. At the baseline visit, a structured interview was administered and the starter bottle with the participant's assigned randomisation number was dispensed.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Reviewers were blinded to treatment allocation.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

During a median follow‐up of 4.8 years, a total of 227 participants (5.9%) withdrew consent and 99 participants (2.6%) were lost to follow‐up.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported.

Other bias

Unclear risk

This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and monitored by an independent data and safety monitoring board appointed by NINDS. Pioglitazone and placebo were provided by Takeda Pharmaceuticals International.

J‐SPIRIT

Methods

A multicentre, randomised, double‐blind, placebo‐controlled trial to test the effect of pioglitazone on the reduction of recurrent stroke in people 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.

Interventions

Pioglitazone or matching placebo

Outcomes

Recurrence of stroke; recurrence of ischaemic stroke

Notes

Mean observation periods were 25 ± 19.9 months in the pioglitazone group and 30 ± 16 months in the control group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation was not described.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment was not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to judge

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to judge

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Insufficient information to judge

Selective reporting (reporting bias)

Unclear risk

Insufficient information to judge

Other bias

Unclear risk

Information about financial support was not provided.

Kernan 2003

Methods

A 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

Participants

Non‐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.

Interventions

Pioglitazone 45 mg per day or placebo was given for 3 months.

Outcomes

Mean proportional changes in insulin sensitivity; mean C‐reactive protein concentration; adverse events

Notes

A repeated oral glucose tolerance test was done at the endpoint of the 3 months of therapy. The mean age was 66 years among participants assigned to pioglitazone and 67 years among participants assigned to placebo.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A 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 risk

After 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 risk

Participants were blinded to treatment assignment throughout the study.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Research staff and investigators were blinded to treatment assignment throughout the study.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No participant permanently discontinued the treatment.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported.

Other bias

Low risk

The study was funded by an investigator‐initiated grant from Takeda Pharmaceuticals North America. Takeda had no involvement in data collection, data analysis, or report composition. By contract, Takeda could not suppress publication of this report.

Marfella 2006

Methods

A randomised, placebo‐controlled trial

Participants

40 people who presented with symptoms of cerebral ischaemic attack were included and randomised as 1:1 into the trial.

Interventions

Rosiglitazone 8 mg per day or placebo was given for 4 months.

Outcomes

Ubiquitin‐proteasome activity

Notes

We did not include 38 people with asymptomatic carotid stenosis in this review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation was not described.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment was not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to judge

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The specimens were analysed by an expert pathologist blinded to the participant's diagnosis.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No participant in either group discontinued the treatment.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported.

Other bias

Unclear risk

Information about financial support was not provided.

PROactive

Methods

A multicentre, randomised, double‐blind, placebo‐controlled trial

Participants

People aged 35 to 75 years with type 2 diabetes and a previous stroke (6 months before randomisation) were included.
984 eligible people were randomised into the trial, with 486 in the pioglitazone group and 498 in the placebo group.

Interventions

Pioglitazone titration from 15 mg to 45 mg per day depending on tolerability or placebo was given until the first occurrence of any of the events described in the 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

Notes

We did not include data for participants without previous stroke.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of random sequence generation was not described.

Allocation concealment (selection bias)

Unclear risk

Allocation concealment was not reported.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Insufficient information to judge

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Insufficient information to judge

Incomplete outcome data (attrition bias)
All outcomes

High risk

882/984 (90%) participants completed the final visit: 439/486 (90%) in the pioglitazone group and 443/498 (89%) in the placebo group. Intention‐to‐treat analysis was used.

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported.

Other bias

Unclear risk

This study was funded by Takeda Pharmaceuticals and Eli Lilly, and designed by the international steering committee, who also approved the protocol and amendments. The sponsors had 2 representatives on the international steering committee; the same 2 were also members of the executive committee. Data analysis, data interpretation, and writing of the report was done by the executive committee, with contributions from the international steering committee, the data and safety monitoring committee, and the endpoint adjudication committee. All the authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

TIA: transient ischaemic attack

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

CIMT Trial

The intervention was not PPAR‐γ agonist.

Erdmann 2015

The participants were not eligible.

Forst 2008

There was no subgroup of stroke patients for whom separate results were available.

Hedblad 2007

The participants were not eligible.

ISRCTN54951661

The participants were not eligible.

Koshiyama 2001

The participants were not eligible.

Lincoff 2014

The participants were not eligible.

Meisner 2006

The participants were not eligible.

NCT00879970

There was no subgroup of stroke patients for whom separate results were available.

Sidhu 2004

The participants were not eligible.

Tanaka 2015

There was no placebo for comparison.

TART

The participants were not eligible.

TRIPOD

The participants were not eligible.

Varghese 2009

The participants were not eligible.

PPAR‐γ: peroxisome proliferator‐activated receptor gamma

Data and analyses

Open in table viewer
Comparison 1. Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Recurrence of stroke Show forest plot

3

4979

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.44, 0.99]

Analysis 1.1

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 1 Recurrence of stroke.

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 1 Recurrence of stroke.

2 Reported adverse events Show forest plot

3

1044

Risk Difference (M‐H, Random, 95% CI)

0.10 [‐0.08, 0.28]

Analysis 1.2

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 2 Reported adverse events.

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 2 Reported adverse events.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

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

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 3

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

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 1 Recurrence of stroke.
Figures and Tables -
Analysis 1.1

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 1 Recurrence of stroke.

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 2 Reported adverse events.
Figures and Tables -
Analysis 1.2

Comparison 1 Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo, Outcome 2 Reported adverse events.

Summary of findings for the main comparison. Peroxisome proliferator‐activated receptor gamma agonists for preventing recurrent stroke and other vascular events in people with stroke or transient ischaemic attack

Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) agonists for preventing recurrent stroke and other vascular events in people with stroke or transient ischaemic attack

Patient or population: people with stroke or transient ischaemic attack

Settings: inpatients

Intervention: PPAR‐γ agonists

Comparison: placebo

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

PPAR‐γ agonists

Recurrence of stroke

Follow‐up: 25 to 57.6 months

85 per 1000

56 per 1000

(37 to 84)

RR 0.66 (0.44 to 0.99)

4979
(3 studies)

⊕⊕⊕⊝
Moderate¹

Reported adverse events

Follow‐up: 3 to 34.5 months

492 per 1000

502 per 1000

(412 to 530)

RD 0.10 (‐0.08 to 0.28)

1044
(3 studies)

⊕⊕⊝⊝
Low²

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 126 of 498 (25%). For the total events of all‐cause death, non‐fatal myocardial infarction or non‐fatal stroke, there were 98 of 498 (20%).

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%). For the total events of all‐cause death, non‐fatal myocardial infarction or non‐fatal stroke, there were 76 of 486 (16%).

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 (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 (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).

984
(1 study)

⊕⊕⊝⊝
Low³

Pioglitazone reduced fatal or non‐fatal stroke and total events of cardiovascular death, non‐fatal myocardial infarction or non‐fatal stroke.

Deaths due to vascular events

Not reported

Not reported

Disability due to vascular events

Not reported

Not reported

Improvement in quality of life

Not reported

Not reported

Insulin sensitivity

Assessed with composite insulin sensitivity index

The change in the composite index was ‐0.1 ± 0.6. The C‐reactive protein concentration increased from 0.41 to 0.45 mg/L.

The change in the composite index was 1.2 ± 0.6. The C‐reactive protein concentration declined from 0.30 to 0.20 mg/L.

The change in the composite index was significantly increased in the pioglitazone group in comparison with the placebo group (P = 0.0003).

20
(1 study)

⊕⊕⊝⊝
Low³

Ubiquitin‐proteasome activity in carotid plaques

Ubiquitin 468.7 ± 89 ng/mg; proteasome 20S 79.8 ± 25 pmol/mg; nitrotyrosine 3.5 ± 0.42 nmol/pg; superoxide anion production 6.26 ± 1.4 pmol/L

Ubiquitin 322 ± 79 ng/mg; proteasome 20S 46.8 ± 10 pmol/mg; nitrotyrosine 2.2 ± 0.21 nmol/pg; superoxide anion production 3.57 ± 1.1 pmol/L

Compared with the placebo group, symptomatic carotid plaques in the rosiglitazone group showed fewer inflammatory cells (P < 0.01) with less ubiquitin (P < 0.01), proteasome 20S (P < 0.01), nuclear factor kappa B (P < 0.01), nitrotyrosine (P < 0.01), superoxide anion production (P < 0.01), and more collagen content (P < 0.01).

40
(1 study)

⊕⊕⊝⊝
Low³

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RD: risk difference; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1Downgraded one level due to risk of bias.
2Downgraded one level due to risk of bias and one level due to inconsistency of results.
3Downgraded one level due to risk of bias and one level due to imprecision (small number of participants).

Figures and Tables -
Summary of findings for the main comparison. Peroxisome proliferator‐activated receptor gamma agonists for preventing recurrent stroke and other vascular events in people with stroke or transient ischaemic attack
Comparison 1. Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Recurrence of stroke Show forest plot

3

4979

Risk Ratio (M‐H, Random, 95% CI)

0.66 [0.44, 0.99]

2 Reported adverse events Show forest plot

3

1044

Risk Difference (M‐H, Random, 95% CI)

0.10 [‐0.08, 0.28]

Figures and Tables -
Comparison 1. Peroxisome proliferator‐activated receptor gamma agonists agonists versus placebo