Do Thiazide Diuretics Confer Specific Protection Against Strokes?

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 β-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.

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.

In the recent Perindopril Protection Against Recurrent Stroke Study (PROGRESS)³ in patients with cerebrovascular disease, combination therapy of a diuretic (indapamide) and angiotensin-converting 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 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 Post-stroke Antihypertensive Treatment Study (PATS).⁴ This would indicate that in PROGRESS most of the benefits in prevention of recurrent strokes were related to diuretic therapy (Figure 1). 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 β-blocker propranolol hydrochloride in preventing strokes.⁵ In some patient groups, such as male smokers, the difference between the diuretic and the β-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 seemed to be more efficacious to prevent strokes than β-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).^3-10 In a large meta-analysis, including 48 220 patients, Psaty et al¹¹ found that high-dose diuretic therapy reduced the risk of stroke by 51%, whereas therapy with β-blockers reduced the risk by only 29% (P = .02). Klungel et al¹² showed that among 1237 single-drug users with no history of cardiovascular disease, the adjusted risk of ischemic stroke was 2 to 2½ times higher among users of β-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 diuretic or β-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 α-blocker doxazosin mesylate and the ACE inhibitor lisinopril showed an increased risk of stroke compared with those receiving chlorthalidone.

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 β-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 β-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 lowering 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 β-blocker was added, efficacy diminished and became even weaker with β-blocker monotherapy.¹³ In the study by Klungel et al,¹² nonthiazide combinations had a 2½-fold greater cerebrovascular disease risk than thiazide monotherapy, and the risk was consistently lower with all thiazide combinations (β-blockers, calcium antagonists, or ACE inhibitors) than with nonthiazide combinations.

We should also consider that age-adjusted mortality of strokes, which was falling dramatically in the 1970s and 1980s, seems to have plateaued in the United States¹⁴ and western Europe¹⁵ and to actually have increased in eastern Europe. Cooper et al¹⁶ 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 1980.¹⁸ 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?

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 put forward by Brown and Brown¹⁹ 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. Fournier et al²⁰ refined this hypothesis by suggesting that the protective effects against cerebrovascular disease were related to the angiotensin II non-AT₁ receptors, which are only expressed in the ischemic zones of the brain. Non-AT₁ receptors have been shown to become up-regulated after global ischemia in the brain and may serve as mediators of protective mechanisms by recruiting collateral circulation and decreasing neuronal apoptosis.^21,22 Thus, blockade of the AT₁ receptor (and sparing the non-AT₁ receptor) by an angiotensin receptor blocker could be more protective against stroke than decreasing angiotensin II by ACE inhibition. In the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study, AT₁ 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 AT₁ 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-AT₁ rescue mechanisms by diuretics (which increase the activity of the renin angiotensin system), angiotensin receptor blockers, and calcium antagonists compared with β-blockers or ACE inhibitors would account for a greater protection against strokes in patients without cardiovascular disease. In contrast, in patients with cardiovascular disease, a high percentage of strokes probably originates directly from cardiac disease 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 study¹² 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 β-blockers or ACE inhibitors in hypertensive patients without preexisting heart disease.

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),²⁷ 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.

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 β-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 AT₂ receptor such as thiazide diuretics either as initial therapy or in combination in hypertensive patients at risk for cerebrovascular disease.

Corresponding author: Franz H. Messerli, MD, Ochsner Clinic Foundation, 1514 Jefferson Hwy, New Orleans, LA 70121 (e-mail: fmesserli@aol.com).

Accepted for publication January 8, 2003.