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1 REVIEW ARTICLE Do Thiazide Diuretics Confer Specific Protection Against Strokes? Franz H. Messerli, MD; Ehud Grossman, MD; Anthony F. Lever, MD Several 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 other 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: Lowering blood pressure has been shown to reduce the risk of stroke in patients with hypertension by more than one third. 1 Even in patients with isolated systolic hypertension, lowering systolic blood pressure reduced the risk of stroke by the same magnitude. 2 In most trials in which a reduction in stroke rates was documented, antihypertensive therapy was diuretic based. However, it is not known whether the reduction in strokes was related to the fall in blood pressure per se and/or to a specific effect of diuretic therapy. EVIDENCE FROM PROSPECTIVE TRIALS In the recent Perindopril Protection Against Recurrent Stroke Study () 3 in patients with cerebrovascular disease, combination therapy of a diuretic (indapamide) and angiotensinconverting enzyme (ACE) inhibitor (perindopril) reduced the risk of stroke by 43% compared with placebo. However, perindopril alone, despite lowering systolic blood pressure by 5 mm Hg, decreased From the Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Clinic Foundation, New Orleans, La (Dr Messerli); Department of Internal Medicine D, The Chaim Sheba Medical Center, Tel-Hashomer, Israel (Dr Grossman); and Department of Medicine & Therapeutics, Western Infirmary, Glasgow, Scotland (Dr Lever). The authors have no relevant financial interest in this article. stroke risk only by a nonsignificant 5%. In contrast to perindopril, indapamide monotherapy for a similar 5 mm Hg systolic blood pressure reduction lowered the risk of stroke by 29% in the Poststroke Antihypertensive Treatment Study (PATS). 4 This would indicate that in most of the benefits in prevention of recurrent strokes were related to diuretic therapy (Figure). Since the Medical Research Council (MRC) study in 1985, 5 there has been some speculation whether diuretics can confer a specific cerebroprotective effect, that is, reduce the risk of stroke more than was expected from their antihypertensive efficacy. In the MRC trial, bendroflumethiazide was documented to be almost 3 times as efficacious as the -blocker propranolol hydrochloride in preventing strokes. 5 In some patient groups, such as male smokers, the difference between the diuretic and the -blocker was even greater because propranolol, despite lowering blood pressure, provided no protection against strokes. In the MRC trial in elderly patients, 6 when patients were subdivided according to systolic blood pressure strata, the stroke rate for any given systolic blood pressure was consistently lower in the diuretic group, even compared with patients receiving placebo. Thus, for a given blood pressure, diuretic therapy not only 2557

2 seemed to be more efficacious to prevent strokes than -blockers, but it even had an advantage over placebo. Several other studies have attested to the superior efficacy of diuretic therapy in reducing the risk for cerebrovascular disease (Table 1) In a large metaanalysis, including patients, Psaty et al 11 found that high-dose diuretic therapy reduced the risk of stroke by 51%, whereas therapy with -blockers reduced the risk by only 29% (P=.02). Klungel et al 12 showed that among 1237 single-drug users Reduction (Perindopril) (n = 1281) SBP, mm Hg Stroke, % with no history of cardiovascular disease, the adjusted risk of ischemic stroke was 2 to times higher among users of -blockers, calcium antagonists, or ACE inhibitors than among users of a diuretic alone. Interestingly, even in patients with cardiovascular disease, diuretics still conferred a lower stroke risk than other drugs, although the difference was considerably smaller. More recently, the Captopril Prevention Project (CAPPP) 8 showed an increased stroke risk with captopril therapy compared with (Indapamide) (n = 2841) (Perindopril + Indapamide) (n = 1770) In the Perindopril Protection Against Recurrent Stroke Study (), 3 a decrease of 5 mm Hg in systolic blood pressure (SBP) reduced strokes by a nonsignificant 5%. In the Post-stroke 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 by 43%. diuretic or -blocker therapy (relative risk, 1.25). Finally, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 9,10 patients treated with the -blocker doxazosin mesylate and the ACE inhibitor lisinopril showed an increased risk of stroke compared with those receiving chlorthalidone. MONOTHERAPY VS COMBINATION THERAPY Not only were diuretics in monotherapy consistently superior to other drug therapies for the prevention of cerebrovascular disease, but a similar phenomenon could be observed when diuretic monotherapy was compared with combination therapy. In the MRC studies, 5,6 the addition of a -blocker to the diuretic diminished cerebrovascular benefits in both the middle-aged and the older population. In the Systolic Hypertension in the Elderly Program (SHEP) study, 7 patients receiving a combination of a -blocker with a diuretic had a 34% higher risk of stroke than those receiving diuretic monotherapy. One might argue that it is not surprising for combination therapy to be associated with smaller benefits, since it was obviously given in patients who required more blood pressure lower- Table 1. Prospective Studies Showing Superior Stroke Protection by Diuretics Compared With Placebo or Other Antihypertensive Treatment Source No. of Type of Follow-up, y Comparative Treatments Stroke Outcome MRC, Hypertension 5.5 Bendroflumethiazide vs placebo; propranolol hydrochloride vs placebo Diuretics reduced stroke rate by 67%; -blockers reduced stroke rate by only 24% (this reduction was nonsignificant in smokers) SHEP, ISH in the elderly 4.5 Chlorthalidone vs placebo Diuretics reduced stroke rate by 36% MRC, Hypertension in the elderly 5.8 Hydrochlorothiazide amiloride hydrochloride vs placebo; atenolol vs Diuretics reduced stroke rate by 31%; -blockers reduced stroke rate by a nonsignificant 18% placebo PATS, Post stroke 3 Indapamide vs placebo Diuretics reduced stroke rate by 29% CAPPP, Hypertension 6.1 Captopril vs diuretics or -blockers or both The rate of stroke was 25% higher in captopril-treated patients ALLHAT, Hypertension 3.3 Chlorthalidone vs doxazosin mesylate The rate of stroke was 19% higher in doxazosin-treated patients, Post stroke 4 Perindopril vs placebo; perindopril + indapamide vs placebo The rate of stroke was not reduced by ACE inhibitor therapy, but was significantly reduced by 43% with combination therapy of ACE inhibitor and diuretics ALLHAT, Hypertension 4.9 Lisinoprol vs chlorthalidone 15% Higher stroke rate with lisinopril therapy (P.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;, Perindopril Protection Against Recurrent Stroke Study; SHEP, Systolic Hypertension in the Elderly Program. 2558

3 Table 2. Prospective Studies Comparing Calcium Antagonists and Diuretics Source No. of Type of Follow-up, y Comparative Treatments Stroke Outcome MIDAS, Hypertension 3 Hydrochlorothiazide vs isradipine Stroke rate nonsignificantly higher in isradipine arm INSIGHT, Hypertension 4 Nifedipine GITS vs amiloride hydrochloride hydrochlorothiazide Fatal and nonfatal stroke similarly reduced in both treatment arms ALLHAT, 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 risk than patients receiving monotherapy. However, in the MRC trial, the best reduction of cardiovascular risk occurred with diuretic monotherapy; when a -blocker was added, efficacy diminished and became even weaker with -blocker monotherapy. 13 In the study by Klungel et al, 12 nonthiazide combinations had a fold greater cerebrovascular disease risk than thiazide monotherapy, and the risk was consistently lower with all thiazide combinations ( -blockers, calcium antagonists, or ACE inhibitors) than with nonthiazide combinations. THE PLATEAU OF STROKE MORTALITY We should also consider that ageadjusted mortality of strokes, which was falling dramatically in the 1970s and 1980s, seems to have plateaued in the United States 14 and western Europe 15 and to actually have increased in eastern Europe. Cooper et al 16 pointed out that the annual death rate from stroke decreased by almost 5% in the 1970s, 3.5% in the 1980s, and only 0.7% in the 1990s. It is particularly intriguing that this plateau in stroke mortality occurred over the period during which control of blood pressure increased from 10% to 29%. 17 Blood pressure control in the 1990s was achieved by using more and more drugs other than diuretics. In fact, the ratio between diuretics and drugs that suppress the renin angiotensin system decreased more than 5-fold since Could it be that diuretics confer a specific effect on the cerebrovascular circulation that is not shared by any other antihypertensive drug class and that the decline in diuretic use is causing stroke mortality to plateau? PUTATIVE MECHANISM OF CEREBROPROTECTION If the answer is yes to the question above, what could be the pathophysiologic mechanism accounting for a greater cerebroprotective effect of diuretics compared with other antihypertensive drugs? A very bold hypothesis to explain this phenomenon was putforwardbybrownandbrown 19 after the publication of the MRC trial. These authors proposed that the activation of the renin angiotensin system and increased angiotensin II levels could have a protective effect against stroke. Angiotensin II, by predominantly constricting the larger cerebral blood vessels, would help protect the smaller reticular striate arteries where Charcot-Bouchard aneurysms usually are located, the rupture of which is a common cause of intracerebral hemorrhage in patients with hypertension. Fournieretal 20 refinedthishypothesis bysuggestingthattheprotectiveeffects against cerebrovascular disease were related to the angiotensin II non-at 1 receptors, which are only expressed in the ischemic zones of the brain. Non- AT 1 receptors have been shown to become up-regulated after global ischemia in the brain and may serve as mediators of protective mechanisms by recruitingcollateralcirculationanddecreasingneuronalapoptosis. 21,22 Thus, blockadeoftheat 1 receptor(andsparingthenon-at 1 receptor)byanangiotensin receptor blocker could be more protective against stroke than decreasing angiotensin II by ACE inhibition. In the Losartan Intervention for Endpointreductioninhypertension(LIFE) study, AT 1 blockade with losartan potassium decreased the stroke risk 25% better than did atenolol-based therapy at similar blood pressure levels. 23 Indeed, the superiority of AT 1 blockade over ACE inhibition at equipotent blood pressure reduction was confirmed in 2 different experimental models. 24,25 Conceivably, a greater stimulation of these non-at 1 rescue mechanisms by diuretics (which increase the activity of the renin angiotensin system), angiotensin receptor blockers,andcalciumantagonistscompared with -blockers or ACE inhibitors would account for a greater protectionagainststrokesinpatientswithoutcardiovasculardisease. Incontrast, inpatientswithcardiovasculardisease, a high percentage of strokes probably originatesdirectlyfromcardiacdisease or destabilization of atherosclerotic plaque. In such a population, reduction of circulating angiotensin II levels by ACE inhibition would more likely be beneficial by reversing or preventing cardiovascular disease. The Fournier hypothesis would allow us to explain the distinctly smaller difference in ischemic strokes between diuretic and nondiuretic therapy in patients with a history of cardiovascular disease compared with those with no cardiovascular disease in the Klungel study 12 and the cerebrovascular benefits of the ACE inhibitor used in the Heart Outcomes Prevention Evaluation (HOPE) study, 26 in which more than 80% of the patients had cardiovascular disease. If this hypothesis holds true, diuretics, angiotensin receptor blockers, and calcium antagonists should prove to be more cerebroprotective than -blockers or ACE inhibitors in hypertensive patients without preexisting heart disease. CALCIUM ANTAGONISTS In 3 studies in which calcium antagonists were compared against diuretic therapy, cerebroprotection seemed to be not significantly different between treatment arms (Table 2). 10,27,28 Of note, in the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS),

4 a short-acting (twice-a-day) calcium antagonist was used, whereas in Intervention as a Goal in Hypertension Treatment (INSIGHT) 28 and ALLHAT, 10 once-a-day compounds were compared against diuretic therapy. CONCLUSIONS Whatever the exact mechanism, several large studies suggest that thiazide diuretics confer a particular benefit in reducing the risk of stroke that seems to be, at least to some extent, independent of their blood pressure lowering effect. This cerebroprotective effect does not seem to be shared by some other drug classes, such as the -blockers and the ACE inhibitors, in patients without manifest cardiovascular disease. However, calcium antagonists seem to confer similar cerebroprotection as diuretics. Stroke is one of the most devastating sequelae of high blood pressure, and its prevention should be the utmost goal of antihypertensive therapy. These findings, if confirmed by currently ongoing studies, strongly favor the use of drugs that stimulate the AT 2 receptor such as thiazide diuretics either as initial therapy or in combination in hypertensive patients at risk for cerebrovascular disease. Accepted for publication January 8, Corresponding author: Franz H. Messerli, MD, Ochsner Clinic Foundation, 1514 Jefferson Hwy, New Orleans, LA ( REFERENCES 1. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease, I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335: Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355: Collaborative Group. Randomised trial of a perindopril-based blood-pressure lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. 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5 tein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998;279: Danesh J, Whincup P, Walker M, et al. Fibrin D-dimer and coronary heart disease: prospective study and meta-analysis. Circulation. 2001;103: Jousilahti P, Salomaa V, Rasi V, Vahtera E, Palosuo T. The association of C- reactive protein, serum amyloid A and fibrinogen with prevalent coronary heart disease: baseline findings of the PAIS project. Atherosclerosis. 2001;156: Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation. 1998;97: Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285: Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347: Chew DP, Bhatt DL, Robbins MA, et al. Incremental prognostic value of elevated baseline C-reactive protein among established markers of risk in percutaneous coronary intervention. Circulation. 2001;104: Hjalmarson A, Elmfeldt D, Herlitz J, et al. Effect on mortality of metoprolol in acute myocardial infarction: a double-blind randomised trial. Lancet. 1981;2: Pedersen TR. Six-year follow-up of the Norwegian Multicenter Study on Timolol After Acute Myocardial Infarction. N Engl J Med. 1985;313: Gottlieb SS, McCarter RJ, Vogel RA. Effect of -blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998; 339: Smith RS, Warren DJ. Effect of -blocking drugs on peripheral blood flow in intermittent claudication. J Cardiovasc Pharmacol. 1982;4: Hiatt WR, Stoll S, Nies AS. Effect of -adrenergic blockers on the peripheral circulation in patients with peripheral vascular disease. Circulation. 1985;72: Radack K, Deck C. -Adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease: a meta-analysis of randomized controlled trials. Arch Intern Med. 1991;151: Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345: Correction Error in Table. In the Review Article by Messerli et al titled Do Thiazide Diuretics Confer Specific Protection Against Strokes? published in the November 24, 2003, issue of the ARCHIVES (2003;163: ), in Table 2 on page 2559, the comparative treatment for the ALLHAT Study should have read Chlorthalidone vs amlodipine. (REPRINTED) ARCH INTERN MED/ VOL 164, FEB 23, American Medical Association. All rights reserved.

In the Literature 1001 BP of 1.1 mm Hg). The trial was stopped early based on prespecified stopping rules because of a significant difference in cardi

In the Literature 1001 BP of 1.1 mm Hg). The trial was stopped early based on prespecified stopping rules because of a significant difference in cardi Is Choice of Antihypertensive Agent Important in Improving Cardiovascular Outcomes in High-Risk Hypertensive Patients? Commentary on Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators.