Retrospective analyses for hypothesis generation. A commentary on the PACK trial (prevention of atherosclerotic complications with ketanserin).

Publication of the results of a large-scale randomized control trial (RCT) of the anti-serotonin drug ketanserin in patients with intermittent claudication offers an opportunity to examine the validity of retrospective subgroup analyses to generate hypotheses for further validation. This was prompted by an unanticipated adverse interaction which occurred in a subgroup of patients receiving both ketanserin and potassium-losing diuretics. The quality of the study ranked it in the 99th percentile of over 400 RCTs evaluated by a quality scoring system. The subgroup analysis resulted from the emergence during the study of a highly significant excess mortality in the patients on diuretics (relative risks 0.88 for those on ketanserin alone, 0.95 on potassium-sparing and 2.44 for those on potassium-losing diuretics (P = 0.007). External validity was evident from data in the literature indicating that a rare tendency of the many drugs that prolong the QT interval to cause torsade de pointes and fatal arrhythmias is exacerbated by hypokalemia of the degree caused by potassium losing diuretics. When the ketanserin and placebo treated patients also on potassium-losing diuretics are removed from the analyses there is a 23% reduction in endpoints which the power is no longer sufficient to detect as significant. There is also an apparent lag phase. Further study of the drug is clearly indicated.