Placebo-controlled trials of blood pressure-lowering therapies for primary prevention of dementia.

Placebo-Controlled Trials of Blood Pressure–Lowering Therapies for Primary Prevention of Dementia To the Editor: Hypertension at middle age is a risk factor for vascular and neurodegenerative dementia later in life.1 Because populations are aging, the number of demented patients will grow 2-fold every 20 years, from 24.3 million people in 2000 to 81.1 million by 2040, with 60% living in developing countries.2 The question of whether hypertension is a modifiable risk factor for dementia is therefore of great clinical importance. Our 2007 meta-analysis1 included 4 placebo-controlled trials of blood pressure–lowering therapies for prevention of dementia (18 196 patients and 642 dementia cases).3–6 The common odds ratio was 0.89 (CI, 0.75 to 1.04) and did not reach statistical significance (P 0.15). However, sensitivity analyses revealed a difference (P 0.04) that depended on whether active treatment started with or included a diuretic or dihydropyridine calcium channel blocker compared with an inhibitor of the renin system. The pooled odds ratios were 0.75 (CI, 0.60 to 0.94; P 0.01) for Systolic Hypertension in the Elderly Program (SHEP),3 SystEur,5 and the combination therapy arm of PROGRESS,4 and 1.08 (CI, 0.84 to 1.38; P 0.54) for SCOPE6 and the perindopril-only subgroup of the PROGRESS trial.4 Since our 2007 review,1 4 additional placebo-controlled trials reported on the prevention of dementia by blood pressure– lowering therapies, including ADVANCE,7 HYVET-COG,8 PRoFESS,9 and, most recently, TRANSCEND.10 We therefore updated our meta-analysis (Figure). In all trials combined, blood pressure lowering did not reduce the risk ( 5%). For trials involving a diuretic or dihydropyridine calcium channel blocker as part of active treatment, the reduction was significant ( 18%), whereas this was not the case in trials of renin system inhibitors ( 1). This difference between drug classes might be explained by the amount of blood pressure reduction because in weighted metaregression analysis, lowering of systolic pressure explained 41% (P 0.08) of the risk reduction. However, several quantitative overviews11–13 support the idea that diuretics and dihydropyridine calcium channel blockers have a small (5% to 10%) benefit beyond blood pressure lowering in the prevention of stroke. Moreover, 2 trials, respectively on prevention5 and