The challenges of comparing results between placebo controlled randomized trials and non-experimental new user, active comparator cohort studies: the example of olmesartan

One of the challenges of pharmacoepidemiology that is both exciting and frustrating is the replication of findings. It is often easy to frame the question as “does drug X cause side effect Y”, but this ignores subtle differences in the actual contrasts that are being made. This issue is well highlighted by three recent studies of the cardiovascular safety of the medication Olmesartan published in this issue of the Journal 1–3. These non-experimental (observational) studies were motivated by safety signals from two randomized, placebo controlled trials that suggested that Olmesartan increased all-cause mortality in patients with diabetes4–5. Although the absolute number of deaths observed in the randomized trials was small, the possibility of such an effect is a legitimate cause for concern 1–3. The three non-experimental studies are all well designed and placed in independent populations in two different countries (the United States of America and the United Kingdom).