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 particular benefit in reducing the risk of strokes that seem to be, at least to some extent, independent of the blood pressure–lowering effect. Such a cerebroprotective effect was documented 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 cardiovascular 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 hypertensive 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 cerebroprotective 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

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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 monotherapy 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 diuretic 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 receiving 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.

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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 GITS Study Intervention as a Goal in Hypertension Treatment; MIDAS, Multicenter Isradipine Diuretic Atherosclerosis Study.

ing and, therefore, were at a higher PUTATIVE MECHANISM firmed in 2 different experimental risk than patients receiving mono- OF CEREBROPROTECTION models.24,25 Conceivably, a greater therapy. However, in the MRC trial, stimulation of these non-AT1 rescue the best reduction of cardiovascu- If the answer is yes to the question mechanisms by diuretics (which in- lar risk occurred with diuretic mono- above, what could be the pathophysi- crease the activity of the renin angio- therapy; when a ␤-blocker was ologic mechanism accounting for a tensin system), angiotensin receptor added, efficacy diminished and be- greater cerebroprotective effect of di- blockers,andcalciumantagonistscom- came even weaker with ␤-blocker uretics compared with other antihy- pared with ␤-blockers or ACE inhibi- monotherapy.13 In the study by pertensive drugs? A very bold hypoth- tors would account for a greater pro- Klungel et al,12 nonthiazide combi- esis to explain this phenomenon was tectionagainststrokesinpatientswith- 19 nations had a 21⁄2-fold greater cere- put forward by Brown and Brown af- outcardiovasculardisease.Incontrast, brovascular disease risk than thia- ter the publication of the MRC trial. inpatientswithcardiovasculardisease, zide monotherapy, and the risk was These authors proposed that the acti- a high percentage of strokes probably consistently lower with all thiazide vation of the renin angiotensin system originatesdirectlyfromcardiacdisease combinations (␤-blockers, calcium and increased angiotensin II levels or destabilization of atherosclerotic antagonists, or ACE inhibitors) than could have a protective effect against plaque. In such a population, reduc- with nonthiazide combinations. stroke. Angiotensin II, by predomi- tion of circulating angiotensin II lev- nantly constricting the larger cerebral els by ACE inhibition would more THE PLATEAU blood vessels, would help protect the likely be beneficial by reversing or pre- OF STROKE MORTALITY smaller reticular striate arteries where venting cardiovascular disease. The Charcot-Bouchard aneurysms usually Fournier hypothesis would allow us We should also consider that age- are located, the rupture of which is a to explain the distinctly smaller differ- adjusted mortality of strokes, which common cause of intracerebral hem- ence in ischemic strokes between di- was falling dramatically in the 1970s orrhage in patients with hypertension. uretic and nondiuretic therapy in pa- and 1980s, seems to have pla- Fournier et al20 refined this hypothesis tients with a history of cardiovascular teaued in the United States14 and bysuggestingthattheprotectiveeffects disease compared with those with no western Europe15 and to actually against cerebrovascular disease were cardiovascular disease in the Klungel 12 have increased in eastern Europe. related to the angiotensin II non-AT1 study and the cerebrovascular ben- Cooper et al16 pointed out that the receptors, which are only expressed in efits of the ACE inhibitor used in the annual death rate from stroke de- the ischemic zones of the brain. Non- Heart Outcomes Prevention Evalua- 26 creased by almost 5% in the 1970s, AT1 receptors have been shown to be- tion (HOPE) study, in which more 3.5% in the 1980s, and only 0.7% in come up-regulated after global ische- than 80% of the patients had cardio- the 1990s. It is particularly intrigu- mia in the brain and may serve as me- vascular disease. If this hypothesis ing that this plateau in stroke mor- diators of protective mechanisms by holds true, diuretics, angiotensin re- tality occurred over the period dur- recruitingcollateralcirculationandde- ceptor blockers, and calcium antago- ing which control of blood pressure creasingneuronalapoptosis.21,22 Thus, nists should prove to be more cerebro- 17 ␤ increased from 10% to 29%. Blood blockadeoftheAT1 receptor(andspar- protective than -blockers or ACE in- pressure control in the 1990s was ingthenon-AT1 receptor)byanangio- hibitors in hypertensive patients achieved by using more and more tensin receptor blocker could be more without preexisting heart disease. drugs other than diuretics. In fact, protective against stroke than decreas- the ratio between diuretics and drugs ing angiotensin II by ACE inhibition. CALCIUM ANTAGONISTS that suppress the renin angiotensin In the Losartan Intervention for End- system decreased more than 5-fold pointreductioninhypertension(LIFE) In 3 studies in which calcium an- 18 since 1980. Could it be that diuret- study, AT1 blockade with losartan po- tagonists were compared against ics confer a specific effect on the tassium decreased the stroke risk 25% diuretic therapy, cerebroprotec- cerebrovascular circulation that is better than did atenolol-based therapy tion seemed to be not significantly not shared by any other antihyper- at similar blood pressure levels.23 In- different between treatment arms 10,27,28 tensive drug class and that the de- deed, the superiority of AT1 blockade (Table 2). Of note, in the cline in diuretic use is causing stroke over ACE inhibition at equipotent Multicenter Isradipine Diuretic mortality to plateau? blood pressure reduction was con- Atherosclerosis Study (MIDAS),27

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Downloaded From: https://jamanetwork.com/ on 10/03/2021 a short-acting (twice-a-day) cal- 2. Staessen JA, Gasowski J, Wang JG, et al. Risks 16. Cooper R, Cutler J, Desvigne-Nickens P, et al. cium antagonist was used, whereas of untreated and treated isolated systolic hyper- Trends and disparities in coronary heart disease, tension in the elderly: meta-analysis of outcome stroke, and other cardiovascular diseases in the in Intervention as a Goal in Hyper- trials. Lancet. 2000;355:865-872. United States: findings of the National Confer- 28 tension Treatment (INSIGHT) 3. PROGRESS Collaborative Group. Randomised trial ence on Cardiovascular Disease Prevention. Cir- and ALLHAT,10 once-a-day com- of a perindopril-based blood-pressure lowering culation. 2000;102:3137-3147. pounds were compared against di- regimen among 6105 individuals with previous 17. Lenfant C, Roccella E. A call to action for more uretic therapy. stroke or transient ischaemic attack. Lancet. 2001; aggressive treatment of hypertension. J Hyper- 358:1033-1041. tens Suppl. 1999;17(suppl 1):S3-S7. 4. PATS Collaborating Group. Post-stroke Antihy- 18. Fournier A, Oprisiu R, Mazouz H, et al. Stroke death CONCLUSIONS pertensive Treatment Study. Chin Med J (Engl). rate annual decrease reversal and prescription de- 1995;108:710-717. crease of antihypertensive drugs stimulating the Whatever the exact mechanism, sev- 5. Medical Research Council Working Party. MRC trial angiotensin II formation [abstract]. Am J Hyper- eral large studies suggest that thia- of treatment of mild hypertension: principal re- tens. 2002;15:106A. sults. Br Med J (Clin Res Ed). 1985;291:97-104. zide diuretics confer a particular ben- 19. Brown MJ, Brown J. Does angiotensin-II protect 6. MRC Working Party. Medical Research Council trial against strokes? Lancet. 1986;2:427-429. efit in reducing the risk of stroke that of treatment of hypertension in older adults: prin- 20. Fournier A, Mazouz H, Pruna A, et al. Stroke pre- seems to be, at least to some extent, cipal results. BMJ. 1992;304:405-412. vention and antihypertensive treatment: may an- independent of their blood pressure– 7. KostisJB,BergeKG,DavisBR,HawkinsCM,Probst- giotensin receptor type 1 antagonist (AT1RA) be field J. Effect of atenolol and reserpine on se- more protective than angiotensin converting en- lowering effect. This cerebroprotec- lected events in the Systolic Hypertension in the tive effect does not seem to be shared zyme inhibitor (ACEI)? Nieren Hochblutdruck Elderly Program (SHEP). Am J Hypertens. 1995; Krankheiten. 2000;29:S545-S554. by some other drug classes, such as 8:1147-1153. 21. Fernandez L, Spencer D, Kaczmar T. Angiotensin the ␤-blockers and the ACE inhibi- 8. Hansson L, Lindholm LH, Niskanen L, et al. Effect II decreases mortality rate in gerbils with unilat- tors, in patients without manifest of angiotensin-converting-enzyme inhibition com- eral carotid ligation. 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Car- diovascular events in hypertensive patients ran- diovascular morbidity and mortality in the Losar- astating sequelae of high blood pres- domized to doxazosin vs chlorthalidone: the An- tan Intervention for Endpoint reduction in hyper- sure, and its prevention should be tihypertensive and Lipid-Lowering Treatment to tension study (LIFE): a randomised trial against the utmost goal of antihyperten- Prevent Heart Attack Trial (ALLHAT). JAMA. 2000; atenolol. Lancet. 2002;359:995-1003. 283:1967-1975. sive therapy. These findings, if con- 24. Fernandez LA, Caride VJ, Stromberg C, Naveri L, 10. The ALLHAT Officers and Coordinators for the firmed by currently ongoing stud- Wicke JD. Angiotensin AT2 receptor stimulation ALLHAT Collaborative Research Group. The Anti- increases survival in gerbils with abrupt unilat- ies, strongly favor the use of drugs hypertensive and Lipid-Lowering Treatment to Pre- eral carotid ligation. 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Correction

Error in Table. In the Review Article by Messerli et al titled “Do Thiazide Di- uretics Confer Specific Protection Against Strokes?” published in the Novem- ber 24, 2003, issue of the ARCHIVES (2003;163:2557-2560), in Table 2 on page 2559, the comparative treatment for the ALLHAT Study should have read “Chlorthalidone vs amlodipine.”

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