May we die twice?

To the Editor: The re-analysis of the INSIGHT trial presented by Mancia and associates recently in Hypertension1 is questionable in some aspects and may not have internal validity. Any conclusion based on analysis of subgroups with a small proportion of the participants of the entire trial should be taken as hypothesis generating and may invalidate it if not established a priori.2 This report does not comply with these rules, since the conclusions were based on a secondary analysis of an outcome not defined a priori, in a subgroup of 1/5 of the whole participants of the original trial. Differently from that stated in the present manuscript, the original publication of the INSIGHT trial3 did not include total mortality, cardiovascular mortality and death from a nonvascular cause as a primary or secondary prespecified outcome. Any subgroup analysis should also be limited in view of the nonsignificant 10% higher incidence of the primary endpoint in patients treated with nifedipine GITS in the original trial.3 Independently of these shortcomings, it is difficult to follow the definition of the secondary outcome employed in this re-analysis, the composite of all-cause death, death from a vascular cause, and death from a nonvascular cause (literal). Looking at Table 4, we see that 103 individuals in the diabetic subgroup died during the study (total mortality). In the figure on the same page, however, we may see that 214 individuals with diabetes presented the secondary outcome. In the original report of this trial,3 the sum of partial causes of deaths was 305 (all deaths, first event, Table 4). In the current report, the sum of all deaths, in diabetics and nondiabetic patients (Figure) was 780. In the absence of an alternative explanation, it seems that the secondary outcome employed in this report was the sum of all-cause death, death from cardiovascular cause and death from a nonvascular cause; ie, some participants may have died twice during the trial. The advantage of nifedipine GITS over diuretic in terms of effect on hard outcomes was restricted to this unusual outcome. The higher incidence of coronary heart disease and heart failure in diabetics was similar to that observed in the original trial, despite not being formally significant in view of the small sample size. Based on the findings of this re-analysis, the authors state that nifedipine could be considered as first-line therapy for hypertensive diabetics. Moreover, they state that nifedipine has direct organ-protective properties in addition to the protection provided by the blood pressure lowering effect per se. In view of the recent findings of the ALLHAT trial,4 it is evident that we need to lower blood pressure in order to get cardiovascular protection, and that this may be better accomplished starting treatment with a diuretic, in patients with or without diabetes. It is certainly time to stop fooling us.5