Individual patient data analysis firms up rosiglitazone safety verdict
medwireNews: An individual patient data meta-analysis confirms the increased heart failure risk associated with rosiglitazone and lends some support to an elevated myocardial infarction risk.
It also reveals the pitfalls of relying on meta-analyses based on summary patient data when addressing medication safety concerns, with Joshua Wallach (Yale School of Public Health, New Haven, Connecticut, USA) and co-researchers finding discrepancies between reported events in the published trials and the individual patient data.
They were able to obtain individual patient data for 33 rosiglitazone clinical trials involving 21,156 participants from rosiglitazone’s manufacturer, GlaxoSmithKline. Twenty-nine of these trials had been included in previous meta-analyses, and among these the team identified 26 that had more myocardial infarctions in the individual patient data than in the published summary data, plus one that had fewer events.
One trial had more cardiovascular deaths in the individual versus the summary data, but five had fewer.
“Therefore, previous meta-analyses of rosiglitazone safety might not have included the data necessary to accurately classify all adverse events,” write the researchers in The BMJ.
They note: “Given the large number of patients treated for diabetes, drugs with even modest cardiovascular risks can have major public health implications.”
Authorization to market rosiglitazone is currently suspended in Europe and although still available in the USA its use has declined in the wake of uncertainties around its safety profile.
Across the 33 trials with individual patient data, there was a significant 33% increased risk for cardiovascular events in the 56% of participants taking rosiglitazone versus control participants. This was largely due to a 54% increased risk for heart failure associated with rosiglitazone use, which the researchers say is in line with previous meta-analyses of summary patient data.
But they add: “Almost 20 years after rosiglitazone was approved, uncertainties still exist among patients, clinicians, and policy makers about the effect of the drug on the risk of myocardial infarction.”
Some meta-analyses have an increased risk with rosiglitazone use whereas others have not.
“Our analysis also suggests an increased risk of myocardial infarction, albeit with less certainty because the 95% confidence interval just crosses 1.0 in most of the analyses,” write Wallach et al.
The potential increased risk ranged from 7% to 30% depending on which statistical method the team used, whether they restricted the analysis to trials with individual patient data or included additional trials with summary data, and whether they included the RECORD trial.
There were 103 trials with only summary-level data, including 23,683 participants of whom 53.3% took rosiglitazone. RECORD was an open-label randomized trial of rosiglitazone versus metformin plus a sulfonylurea, which the researchers say was “widely criticized.”
“Our study suggests that when evaluating drug safety and performing meta-analyses focused on safety, [individual patient data] might be necessary to accurately classify all adverse events,” they conclude.
“By including these data in research, patients, clinicians, and researchers would be able to make more informed decisions about the safety of interventions.”
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