Outcomes, Outcomes, Every where, nor any Stop to Think?

Abstract

W hen judging clinical evidence from the medical literature, it is not just the results that require evaluation. The outcomes assessed in a study must also be scrutinized. Although ideally outcome selection would not affect study results and their interpretation, this cannot be assumed. 1,2 Hochman and McCormick 3 add to this literature by raising questions about two types of outcomes, surrogate and composite endpoints, reported in recent high-profile randomized trials. They also draw attention to the potentially misleading reporting of relative risks without companion absolute risks, which for uncommon outcomes may lead to an overly optimistic sense of an intervention's benefit or alternatively an overly negative portrayal of harm.The authors extend previous observations that surrogate and composite outcomes appear commonly in the literature. 2,[4][5][6] In addition to reporting the ongoing frequency of these outcome reporting issues, Hochman and McCormick found potentially worrisome associations between surrogate endpoints and both commercial funding and positive results. Surrogate endpoints were more common among commercially funded trials in the present study, in contrast to a previous report limited to cardiovascular trials. 2 Furthermore, trials using surrogate endpoints were more likely to report positive findings.It must be noted that these observations should not be viewed as an indictment of commercially sponsored research. It is possible that results from such studies are more likely to be positive because they stem from more plausible study hypotheses, 7 for example, although literature providing evidence in support of this possibility is lacking. These results are further complicated by the potential subjectivity in existing definitions of surrogate endpoints, and it is possible that there would be disagreement on some of the determinations of surrogate versus clinical endpoints in this study. Therefore, it will be important to validate the current results using a reproducible consensus definition of a surrogate endpoint, a goal perhaps within reach. 8 Even if confirmed, the appropriateness of surrogate endpoints and the accuracy of study conclusions based on surrogate endpoints will need to be further evaluated to determine if positive results from such studies reflect trustworthy findings or provide evidence of systematic bias.Hochman and McCormick also found numerous trials applying composite endpoints comprised of elements of disparate clinical importance, rendering them difficult to interpret in a clinically meaningful manner for patients. This problem has been reported previously, 5,9 but unfortunately appears to persist in the general medical literature. Interestingly, the authors found that composite endpoints were unexpectedly associated with negative study findings, although this result was of borderline statistical significance. The authors note that confounding of composite endpoints with other contributors to negative study outcomes may explain this finding, so further work is needed to...