Benefits of antihypertensive pharmacologic therapy and blood pressure reduction in outcome trials

In a quantitative overview of published trials, we investigated whether pharmacologic properties of antihypertensive drugs, as opposed to reduction in blood pressure, explain cardiovascular outcomes in hypertensive or high-risk patients. We used meta-regression to investigate the association between the odds ratios of outcome (experimental vs. reference treatment) and the corresponding blood pressure differences between study groups. Thus, we correlated odds ratios with between-group differences in systolic pressure. We then compared odds ratios of benefit observed in recent trials with those predicted by meta-regression on the basis of the differences in systolic pressure between randomized groups. Among nine actively-controlled trials in hypertension, significant differences in systolic pressure (follow-up minus baseline) between randomized groups (experimental minus reference) were observed in the ALLHAT, CAPPP, MIDAS, and NORDIL trials. Furthermore, the differences in achieved systolic and/or diastolic pressure between study groups were also significant in the hypertension trials and studies in high-risk patients, which involved untreated control patients. The differences between the observed odds ratios and those predicted by meta-regression did not reach statistical significance except for NORDIL and the single-drug therapy subgroup of the PROGRESS trial. In NORDIL, the risk of stroke was lower on diltiazem than on the older drug classes despite a 3.1 mm Hg higher systolic pressure on the calcium channel blocker. In PROGRESS, perindopril alone reduced blood pressure by 5/3 mm Hg, but did not affect the incidence of all cardiovascular events or the recurrence of stroke. In conclusion, the finding that in the reviewed trials blood pressure reduction largely accounted for outcome emphasizes the desirability of tight blood pressure control. The hypothesis that blood pressure-lowering medications might influence cardiovascular prognosis over and beyond their antihypertensive effect remains to a large extent unproved.