enroll many more patients and followed them for far longer periods of time. A dramatic recent example of the danger of substitute endpoints was found in the evaluation of the usefulness of antiarrhythmic drugs following myocardial infarction. Because such drugs had been shown to reduce abnormal ventricular depolarizations (the substitute endpoints) in the short run, it made sense that they should reduce the occurrence of life-threatening arrhythmias in the long run. A group of investigators performed randomized trials on three agents (encainide, flecainide and moricizine) previously shown to be effective in suppressing the substitute endpoint of abnormal ventricular depolarizations in order to determine whether they reduced mortality in patients with asymptomatic or mildly symptomatic arrhythmias following myocardial infarction. The investigators had to stop the trials when they discovered that mortality was substantially higher in patients receiving antiarrhythmic treatment than in those receiving placebo [27] [28] . Clinicians relying on the substitute endpoint of arrhythmia suppression would have continued to administer the three drugs to the considerable detriment of their patients. Even when investigators report favourable effects ot treatment on one clinically important outcome, clinicians must take care that there are no deleterious effects on other outcomes. For instance, as this series was in preparation the controversy continued over whether reducing lipids unexpectedly increases non-cardiovascular causes of death [29] . Cancer chemotherapy may lengthen life but decrease its quality. Finally, surgical trials often document prolonged life for those who survive the operation (yielding higher 3-year survival in those receiving surgery), but