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Do Thiazide Diuretics Confer Specific Protection Against Strokes?

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Do Thiazide Diuretics Confer Specific Protection Against Strokes? REVIEW ARTICLE Do Thiazide Diuretics Confer Specific Protection Against Strokes? Franz H. Messerli, MD; Ehud Grossman, MD; Anthony F. Lever, MD everal large studies have suggested that therapy with thiazide diuretics confers a particu- lar benefit in reducing the risk of strokes that seem to be, at least to some extent, inde- pendent of the blood pressure–lowering effect. Such a cerebroprotective effect was docu- mented not only with monotherapy but also when diuretics were used in combination with Sother drugs. The cerebroprotective effect does not seem to be shared by other drug classes, such as the ␤-blockers or the angiotensin-converting enzyme inhibitors, in patients without manifest car- diovascular disease. Since stroke is one of the most devastating sequelae of high blood pressure, our data strongly favor the use of low-dose diuretics either as initial therapy or in combination in all hy- pertensive patients at risk for cerebrovascular disease. Arch Intern Med. 2003;163:2557-2560 Lowering blood pressure has been shown stroke risk only by a nonsignificant 5%. to reduce the risk of stroke in patients with In contrast to perindopril, indapamide hypertension by more than one third.1 monotherapy for a similar 5–mm Hg sys- Even in patients with isolated systolic hy- tolic blood pressure reduction lowered pertension, lowering systolic blood pres- the risk of stroke by 29% in the Post- sure reduced the risk of stroke by the same stroke Antihypertensive Treatment Study magnitude.2 In most trials in which a re- (PATS).4 This would indicate that in duction in stroke rates was documented, PROGRESS most of the benefits in pre- antihypertensive therapy was diuretic vention of recurrent strokes were related based. However, it is not known whether to diuretic therapy (Figure). Since the the reduction in strokes was related to the Medical Research Council (MRC) study in fall in blood pressure per se and/or to a spe- 1985,5 there has been some speculation cific effect of diuretic therapy. whether diuretics can confer a specific ce- rebroprotective effect, that is, reduce the EVIDENCE FROM risk of stroke more than was expected from PROSPECTIVE TRIALS their antihypertensive efficacy. In the MRC trial, bendroflumethiazide was docu- In the recent Perindopril Protection mented to be almost 3 times as effica- Against Recurrent Stroke Study cious as the ␤-blocker propranolol hydro- (PROGRESS)3 in patients with cerebro- chloride in preventing strokes.5 In some vascular disease, combination therapy of patient groups, such as male smokers, the a diuretic (indapamide) and angiotensin- difference between the diuretic and the converting enzyme (ACE) inhibitor (per- ␤-blocker was even greater because pro- indopril) reduced the risk of stroke by 43% pranolol, despite lowering blood pres- compared with placebo. However, perin- sure, provided no protection against dopril alone, despite lowering systolic strokes. In the MRC trial in elderly pa- blood pressure by 5 mm Hg, decreased tients,6 when patients were subdivided ac- cording to systolic blood pressure strata, From the Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner the stroke rate for any given systolic blood Clinic Foundation, New Orleans, La (Dr Messerli); Department of Internal Medicine D, pressure was consistently lower in the di- The Chaim Sheba Medical Center, Tel-Hashomer, Israel (Dr Grossman); and uretic group, even compared with pa- Department of Medicine & Therapeutics, Western Infirmary, Glasgow, Scotland tients receiving placebo. Thus, for a given (Dr Lever). The authors have no relevant financial interest in this article. blood pressure, diuretic therapy not only (REPRINTED) ARCH INTERN MED/ VOL 163, NOV 24, 2003 WWW.ARCHINTERNMED.COM 2557 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 seemed to be more efficacious to pre- with no history of cardiovascular dis- diuretic or ␤-blocker therapy (rela- vent strokes than ␤-blockers, but it ease, the adjusted risk of ischemic tive risk, 1.25). Finally, in the An- even had an advantage over placebo. stroke was 2 to 21⁄2 times higher tihypertensive and Lipid-Lowering Several other studies have at- among users of ␤-blockers, cal- Treatment to Prevent Heart Attack tested to the superior efficacy of cium antagonists, or ACE inhibi- Trial (ALLHAT),9,10 patients treated diuretic therapy in reducing the tors than among users of a diuretic with the ␣-blocker doxazosin me- risk for cerebrovascular disease alone. Interestingly, even in pa- sylate and the ACE inhibitor lisin- (Table 1).3-10 In a large meta- tients with cardiovascular disease, di- opril showed an increased risk of analysis, including 48220 patients, uretics still conferred a lower stroke stroke compared with those receiv- Psaty et al11 found that high-dose di- risk than other drugs, although ing chlorthalidone. uretic therapy reduced the risk of the difference was considerably stroke by 51%, whereas therapy with smaller. More recently, the Capto- MONOTHERAPY VS ␤-blockers reduced the risk by only pril Prevention Project (CAPPP)8 COMBINATION THERAPY 29% (P=.02). Klungel et al12 showed showed an increased stroke risk with that among 1237 single-drug users captopril therapy compared with Not only were diuretics in mono- therapy consistently superior to other drug therapies for the preven- PROGRESS PROGRESS PROGRESS tion of cerebrovascular disease, but (Perindopril) (Indapamide) (Perindopril + Indapamide) a similar phenomenon could be ob- (n = 1281) (n = 2841) (n = 1770) 0 served when diuretic monotherapy was compared with combination therapy. In the MRC studies,5,6 the 10 addition of a ␤-blocker to the di- uretic diminished cerebrovascular 20 benefits in both the middle-aged and the older population. In the Sys- Reduction 30 tolic Hypertension in the Elderly Program (SHEP) study,7 patients re- ceiving a combination of a ␤-blocker 40 SBP, mm Hg with a diuretic had a 34% higher risk Stroke, % of stroke than those receiving di- 50 uretic monotherapy. One might ar- gue that it is not surprising for com- In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS),3 a decrease of 5 mm Hg bination therapy to be associated in systolic blood pressure (SBP) reduced strokes by a nonsignificant 5%. In the Post-stroke with smaller benefits, since it was ob- Antihypertensive Treatment Study,4 for the same decrease in blood pressure, indapamide therapy reduced strokes by 29%. The addition of indapamide to perindopril treatment reduced strokes viously given in patients who re- by 43%. quired more blood pressure lower- Table 1. Prospective Studies Showing Superior Stroke Protection by Diuretics Compared With Placebo or Other Antihypertensive Treatment No. of Type of Follow-up, Source Patients Patients y Comparative Treatments Stroke Outcome MRC,5 1985 17 354 Hypertension 5.5 Bendroflumethiazide vs placebo; Diuretics reduced stroke rate by 67%; ␤-blockers propranolol hydrochloride vs placebo reduced stroke rate by only 24% (this reduction was nonsignificant in smokers) SHEP,7 1991 4736 ISH in the elderly 4.5 Chlorthalidone vs placebo Diuretics reduced stroke rate by 36% MRC,6 1992 4396 Hypertension in 5.8 Hydrochlorothiazide–amiloride Diuretics reduced stroke rate by 31%; ␤-blockers the elderly hydrochloride vs placebo; atenolol vs reduced stroke rate by a nonsignificant 18% placebo PATS,4 1995 5665 Post stroke 3 Indapamide vs placebo Diuretics reduced stroke rate by 29% CAPPP,8 1999 10 985 Hypertension 6.1 Captopril vs diuretics or ␤-blockers The rate of stroke was 25% higher in or both captopril-treated patients ALLHAT,9 2000 24 335 Hypertension 3.3 Chlorthalidone vs doxazosin mesylate The rate of stroke was 19% higher in doxazosin-treated patients PROGRESS,3 2001 6105 Post stroke 4 Perindopril vs placebo; The rate of stroke was not reduced by ACE inhibitor perindopril + indapamide vs placebo therapy, but was significantly reduced by 43% with combination therapy of ACE inhibitor and diuretics ALLHAT,10 2002 24 309 Hypertension 4.9 Lisinoprol vs chlorthalidone 15% Higher stroke rate with lisinopril therapy (PϽ.02)—no difference in whites, 30% difference in blacks Abbreviations: ACE, angiotensin-converting enzyme; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; CAPPP, Captopril Prevention Project; ISH, isolated systolic hypertension; MRC, Medical Research Council; PATS, Post-stroke Antihypertensive Treatment Study; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; SHEP, Systolic Hypertension in the Elderly Program. (REPRINTED) ARCH INTERN MED/ VOL 163, NOV 24, 2003 WWW.ARCHINTERNMED.COM 2558 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 Table 2. Prospective Studies Comparing Calcium Antagonists and Diuretics No. of Type of Follow-up, Source Patients Patients y Comparative Treatments Stroke Outcome MIDAS,27 1996 883 Hypertension 3 Hydrochlorothiazide vs isradipine Stroke rate nonsignificantly higher in isradipine arm INSIGHT,28 2000 6321 Hypertension 4 Nifedipine GITS vs amiloride Fatal and nonfatal stroke similarly reduced in both hydrochloride–hydrochlorothiazide treatment arms ALLHAT,10 2002 24 303 Hypertension 4.9 Chlorthalidone vs amiloride hydrochloride Nonsignificant 7% lower stroke risk with amlodipine Abbreviations: ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; GITS, gastrointestinal transport system; INSIGHT, International Nifedipine
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