|Pioglitazone and the risk of myocardial infarction and other major adverse cardiac events: a meta-analysis of randomized, controlled trials
|Nagajothi N, Adigopula S, Balamuthusamy S, Velazquez-Cecena J L, Raghunathan K, Khraisat A, Singh S, Molnar J, Khosla S, Benatar D
The authors concluded that pioglitazone did not appear to increase myocardial infarction (MI) and may reduce stroke and revascularisation. Conclusions regarding myocardial infarction appeared supported by the evidence, but the results for stroke and revascularisation were not statistically significant and may not be reliable.
To evaluate the effect of pioglitazone on cardiovascular outcomes.
MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews and DARE were searched. Some details of the search strategy were reported, but dates were not reported. Ongoing trials were sought in ClinicalTrials.gov, www.act.org.uk and www.controlled-trials.gov. Only studies published in English were included.
Randomised controlled trials (RCTs) that compared the effects of pioglitazone with placebo or other hypoglycaemic agents and assessed myocardial infarction were eligible for inclusion. Secondary review outcomes included stroke, revascularisation, total mortality and cardiovascular mortality.
The included studies compared pioglitazone with placebo, metformin, gliclazide, glyburide and glimepiride. Study duration ranged from six to 18 months.
Two reviewers independently selected studies.
Assessment of study quality
Two reviewers independently assessed treatment allocation, allocation concealment, blinding and analysis on an intention-to-treat (ITT) basis.
For each study, numbers of patients with events of interest were extracted for each treatment group and used to calculate relative risks. Two reviewers independently extracted data onto a standardised form.
Methods of synthesis
For most analyses, pooled relative risks and 95% confidence intervals (CI) were calculated using the fixed-effect Mantel-Haenszel method; a random-effects model was used for the analysis of revascularisation, for which significant heterogeneity was found. Heterogeneity was assessed using Χ2 and I2 statistics.
Results of the review
Five RCTs were included (n approximately 9,965). All studies used intention-to-treat analysis. Four RCTs were double-blind.
There was no statistically significant difference between pioglitazone and control for the primary outcome of myocardial infarction (relative risk 0.86, 95% CI: 0.69 to 1.07, p=0.17) or the secondary outcomes of stroke (relative risk 0.79, 95% CI: 0.61 to 1.02, p=0.07; values reported here because the authors referred to stroke in their conclusion), total mortality (p=0.56) or cardiovascular mortality (p=0.47). No significant heterogeneity was found for any of these analyses (I2=0% for all).
Pioglitazone was associated with a non-statistically significant reduction in coronary revascularisation compared to control, (random-effects model relative risk 0.40, 95% CI: 0.13 to 1.23, p=0.11). Significant heterogeneity was found (p=0.02, I2=74.7%).
Pioglitazone did not appear to increase the risk of myocardial infarction and may reduce the risk of stroke and revascularisation.
The review question was clearly stated and inclusion criteria were appropriately defined. Several relevant sources were searched, but no attempts were made to minimise publication or language biases and so some relevant studies may have been omitted. Appropriate methods were used to minimise reviewer error and bias during the review process. Validity was assessed, but only the level of blinding and use of intention-to-treat analysis was reported which meant that the quality of the evidence could not be judged fully. No information was provided about participants, so the generalisability of results could not be evaluated. Pooling data from studies with different comparators (placebo and active drugs) may not have been appropriate. Having pooled all studies, some examination of effects for the different comparators may have provided additional information. Evidence on the effect of pioglitazone on myocardial infarction appeared supported by the evidence, but the results for stroke and revascularisation were not statistically significant and may not be reliable.
Implications of the review for practice and research
The authors did not state any implications for practice or research.
Nagajothi N, Adigopula S, Balamuthusamy S, Velazquez-Cecena J L, Raghunathan K, Khraisat A, Singh S, Molnar J, Khosla S, Benatar D. Pioglitazone and the risk of myocardial infarction and other major adverse cardiac events: a meta-analysis of randomized, controlled trials. American Journal of Therapeutics 2008; 15(6): 506-511
Subject indexing assigned by NLM
Cardiovascular Diseases /chemically induced /mortality; Diabetes Mellitus, Type 2 /drug therapy; Humans; Hypoglycemic Agents /adverse effects /therapeutic use; Myocardial Infarction /chemically induced; Risk Assessment; Thiazolidinediones /adverse effects /therapeutic use
Database entry date
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.