Placebo-Controlled Trials of Blood Pressure–Lowering Therapies for Primary Prevention of Dementia
2010; Lippincott Williams & Wilkins; Volume: 57; Issue: 2 Linguagem: Inglês
10.1161/hypertensionaha.110.165142
ISSN1524-4563
AutoresJan A. Staessen, Lutgarde Thijs, Tom Richart, Augustine N. Odili, W. H. Birkenhäger,
Tópico(s)Diet and metabolism studies
ResumoHomeHypertensionVol. 57, No. 2Placebo-Controlled Trials of Blood Pressure–Lowering Therapies for Primary Prevention of Dementia Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBPlacebo-Controlled Trials of Blood Pressure–Lowering Therapies for Primary Prevention of Dementia Jan A. Staessen, Lutgarde Thijs, Tom Richart, Augustine N. Odili and Willem H. Birkenhäger Jan A. StaessenJan A. Staessen , Lutgarde ThijsLutgarde Thijs , Tom RichartTom Richart , Augustine N. OdiliAugustine N. Odili and Willem H. BirkenhägerWillem H. Birkenhäger Originally published28 Dec 2010https://doi.org/10.1161/HYPERTENSIONAHA.110.165142Hypertension. 2011;57:e6–e7Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2010: Previous Version 1 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 Syst-Eur,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.4Since 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 progression14 of dementia, showed positive effects of dihydropyridine calcium channel blockers. Experimental studies, reviewed in this journal,1 also support the hypothesis that inhibiting the inward current of calcium ions in neuronal cells protects against necrosis and apoptosis. In conclusion, the issue of whether blood pressure lowering reverses the risk of Alzheimer's disease remains unsettled. A sufficiently powered trial comparing a diuretic or long-acting dihydropyridine calcium channel blocker with a renin system inhibitor in the primary prevention of dementia is needed, but such an orphan trial will not easily find a sponsor unless public agencies take up the challenge.Download figureDownload PowerPointFigure. Effects of blood pressure lowering on the incidence of dementia in placebo-controlled clinical trials. Solid squares represent the odds ratios in individual trials and have a size proportional to the inverse of the variance. Horizontal lines and diamonds denote the 95% CIs for individual trials and summary statistics, respectively. Pooled estimates of risk were computed from a fixed-effect model and are weighted for the inverse of the variance. The vertical dotted line marks the position of the point estimate of the pooled effect size for all trials combined. The individual studies were: the SHEP;3 the Systolic Hypertension in Europe trial (Syst-Eur);5 the Perindopril Protection Against Recurrent Stroke Study–monotherapy (PROGRESS/Per) and combined therapy (PROGRESS/Com) arms;4 the Hypertension in the Very Elderly substudy on cognition;8 the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE);7 the Study on Cognition and Prognosis in the Elderly (SCOPE);6 the Prevention Regimen for Effectively Avoiding Second Strokes trial (PRoFESS);9 and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND).10 Pooled estimates of the between-group differences in systolic blood pressure (ΔSBP) and median or average follow-up (FU) were weighted for the number of patients. DIU indicates diuretic; CCB, calcium channel blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.Jan A. Staessen University of Leuven, Belgium Maastricht University, the NetherlandsLutgarde ThijsTom RichartAugustine N. OdiliWillem H. Birkenhäger University of Leuven, BelgiumDisclosuresJ.A.S. did consultancies for pharmaceutical companies and received funding for studies, seminars, and travel from manufacturers of blood pressure–lowering drugs. All other coauthors have no conflicts of interest to declare.FootnotesLetters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment. References 1. Staessen JA, Richart T, Birkenhäger WH. Less atherosclerosis and lower blood pressure for a meaningful life perspective with more brain. Hypertension. 2007; 49:389–400.LinkGoogle Scholar2. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M; Alzheimer's Disease International. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005; 366:2112–2117.CrossrefMedlineGoogle Scholar3. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). J Am Med Assoc. 1991; 265:3255–3264.CrossrefMedlineGoogle Scholar4. The PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003; 163:1069–1075.CrossrefMedlineGoogle Scholar5. Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster B, Yodfat Y, Fagard R; Syst-Eur Investigators. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998; 352:1347–1351.CrossrefMedlineGoogle Scholar6. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomised double-blind intervention trial. J Hypertens. 2003; 21:875–886.CrossrefMedlineGoogle Scholar7. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007; 370:829–840.CrossrefMedlineGoogle Scholar8. Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C, Waldman A, Walton I, Poulter R, Ma S, Comsa M, Burch L, Fletcher A, Bulpitt C; HYVET investigators. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008; 7:683–689.CrossrefMedlineGoogle Scholar9. Yusuf S, Diener HC, Sacco RL, Cotton D, Öunpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BPL, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voigt T, Weber M, Yoon BW; PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008; 359:1225–1237.CrossrefMedlineGoogle Scholar10. Anderson C, Teo K, Gao P, Arima H, Dans A, Unger T, Commerford P, Dyal L, Schumacher H, Pogue J, Paolasso E, Holwerda N, Chazova I, Binbrek A, Young J, Yusuf S; for the ONTARGET and TRANCEND Investigators. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol. 2010;1026 [Epub ahead of print].Google Scholar11. Messerli FH, Grossman E, Lever AF. Do thiazide diuretics confer specific protection against strokes?Arch Intern Med. 2003; 163:2557–2560.CrossrefMedlineGoogle Scholar12. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362:1527–1535.CrossrefMedlineGoogle Scholar13. Verdecchia P, Reboldi G, Angeli A, Gattobigio R, Bentivoglio M, Thijs L, Staessen JA, Porcellati C. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension. 2005; 46:386–392.LinkGoogle Scholar14. 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