Can treatment that is helpful on average be harmful to some patients? A study of the conflicting information needs of clinical inquiry and drug regulation.

Randomized controlled trials are conducted with heterogeneous groups of patients, and the trial results represent an estimate of the average difference in the responses of the treatment groups. Clinicians, however, engage in a process of clinical inquiry, assembling data that will allow an assessment of the appropriate choice of treatment according to more narrowly defined clinical features. We describe a method of clinical inquiry within RCTs that can enhance the applicability of results to clinical decision making. Our methods included the use of data from the Beta-Blocker Heart Attack Trial, which enrolled 3837 subjects in 31 clinical centers. The 31 centers were divided into 21 dominant centers (mortality rates higher for placebo than propranolol) and 10 divergent centers (higher mortality rates for patients randomized to propranolol). Overall, compared to placebo, propranolol reduced the risk of dying for the "average" patient from 9.8 to 7.2%. Results for patients in dominant centers (RR = 0.50) were significantly different from those in divergent centers (RR = 1.33). We identified two cotherapies--aspirin use and coronary artery surgery--that subsequently affected the benefits of propranolol in divergent centers. For patients in divergent centers, propranolol reduced the risk of dying for patients treated with aspirin and/or coronary surgery (RR = 0.39), but not for patients not receiving these therapies (RR = 1.42). We conclude that differences in results across centers of a multicenter RCT may reflect important distinctions in the clinical conditions of enrolled subjects. These distinctions help to identify subgroups of patients in which treatment that has an average overall benefit may be harmful for some patients.