Tejani and colleagues1 point out that further consideration should be given to the merit of serious adverse events as an overall marker of the benefit of any therapy — including statins.
The letter by Tejani and colleagues, in response to our article,2 includes an alternative interpretation of our estimate of the pooled risk of serious adverse events and withdrawals across treatment groups. This interpretation is interesting but is not widely used for several reasons.
First, the definition and reporting of serious adverse events are not typically standardized, nor do they typically include the prespecified primary outcome for the trial. Both of these limitations can introduce error when estimating the effect of treatment on serious adverse events. If the pooled analysis of the primary outcomes of the trial (e.g., nonfatal myocardial infarction or coronary death) suggested no benefit for recipients of statins but showed that serious adverse events were less common in the statin group, would Tejani and colleagues have suggested that we ignored the data if we concluded that statins were ineffective?
Second, the interpretation of Tejani and colleagues assumes that efficacy outcomes, such as myocardial infarction and mortality, are included in the analysis of total serious adverse events observed. Our interpretation is based on a more conventional assumption — that efficacy outcomes are removed from analyses of serious adverse events. We based our assumption on first-hand experience with previous trials as well as on supplementary trial data. For example, the US Food and Drug Administration medical reviewer’s report of the JUPITER trial states “Any adjudicated cardiovascular death was classified as an efficacy endpoint and not an [adverse event].”3 Despite our best efforts, we could not always determine whether efficacy and safety outcomes were analyzed separately, based on available trial reports. Nonetheless, because we agree that serious adverse events are clinically important, we took extra care to identify and report these analyses in our paper.
Third, our definition of serious adverse events also included events that led to withdrawal of assigned treatment, not only those that were life-threatening. Because not all withdrawals from treatment are clinically relevant, some of the concerns raised by Tejani and colleagues may be less applicable than their letter suggests.
Despite these caveats, we acknowledge that properly interpreting how harm was experienced, measured and reported by trialists is of special importance when achievable benefits are low, and that our finding of lower cardiovascular and mortality risk is sensitive to this assumption. We thank Tejani and colleagues for raising this important point.