The neglected time factor and antihypertensive therapy. A pitfall in evaluating side effects in a cross-over study

The aim of this study was to examine the influence of a time factor that may lead to inaccurate interpretation of data on the incidence of side effects in a double-blind study with drug cross-over. After a washout period, 58 patients with essential hypertension received either 20 mg of enalapril or 50 mg of atenolol. After two weeks, the dosage was doubled (to 40 mg of enalapril and 100 mg of atenolol) in those patients with diastolic blood pressure higher than 95 mm Hg. After four weeks of active treatment and a second two-week washout period, patients received the alternative antihypertensive agent under the same procedure and time schedule as in the first treatment phase. Four patients dropped out. Side effects were evaluated by questionnaire at weeks 2, 4, 8, and 10. In the 54 patients who completed the study, enalapril and atenolol led to almost identical blood pressure reduction in both treatment phases, indicating that pooling these data is a sound method. However, incidence of side effects was twice as high in phase 1 as in phase 2 and markedly decreased in each treatment phase, with no differences being observed between enalapril and atenolol. These results clearly demonstrate that pooling side effects data from a cross-over study may lead to quite wrong interpretations.