Preventing stroke in hypertensive patients at risk

Journal of the American Society of Hypertension 2(4) (2008) S38 –S45

Original Article

Preventing stroke in hypertensive patients at risk Björn Dahlöf, MD Department of Medicine, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden

Abstract Stroke is a leading cause of death and disability worldwide, and despite improvements in healthcare, its incidence is still rising. Elevated blood pressure (BP) is the single most important modifiable risk factor for stroke, doubling stroke risk for each 20 mm Hg increase in systolic blood pressure (SBP). Although BP reduction can lower stroke risk by 30% to 40%, there is mounting evidence that different antihypertensive classes do not provide equal stroke prevention for the same reductions in BP. In comparison with other antihypertensive agents, angiotensin receptor blockers (ARB) provide additional protection against stroke and other cardiovascular outcomes, beyond that explained by reductions in BP alone. One ARB, telmisartan, exhibits properties that may prove especially useful in the prevention of stroke. To this day, telmisartan is being evaluated in a series of large-scale studies, including the Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) Trial, the world’s largest secondary stroke prevention trial. Results from this study will clarify the benefits of telmisartan in secondary stroke prevention and help to determine the most effective approaches for stroke recurrence in high-risk patients. J Am Soc Hypertens 2008;2(4): S38 –S45. © 2008 American Society of Hypertension. All rights reserved. Keywords: Telmisartan; angiotensin receptor blocker; antihypertensive; cerebrovascular.

Introduction According to figures compiled for the World Health Organization, cardio- and cerebrovascular disease (mainly ischemic heart disease and stroke) are a leading cause of mortality.1 There are more than 15 million cases of clinical stroke each year, accounting for around 5 million deaths.1 Stroke also carries a heavy financial burden in terms of costs of care for society as well as severely impaired quality of life and independence for individuals. Silent or subclinical stroke is likely to occur with even greater frequency than clinical stroke and increases the risk for a subsequent cerebrovascular event by up to three-fold in the elderly.2

Stroke Risk Factors — The Importance of Hypertension

male gender, and family history, as well as modifiable ones, such as hypertension, atrial fibrillation, smoking, and obesity (Table 1).3,4 Hypertension is by far the single most important controllable risk factor for stroke, by virtue of its prevalence and the increased risk that it confers.3–5 Hypertension is pandemic — in 2000, a quarter of the worldwide population, almost a billion people, had elevated blood pressure (BP), and by 2025 this number is expected to be nearer to 1.6 billion.6 The presence of hypertension increases the risk of stroke in all age groups, such that between the ages of 40 and 70 years, each 20 mm Hg increase in systolic blood pressure [SBP] (or 10 mm Hg increase in diastolic pressure) is associated with an approximate doubling of stroke mortality.7 Furthermore, the relationship between BP and stroke mortality is strong, linear, and continuous right down to “normal” BPs of 115/75 mm Hg (Figure 1).7

The risk factors for stroke are well documented and include both nonmodifiable factors, such as increasing age,

Antihypertensive Treatment Based on material presented at a Boehringer Ingelheim-Sponsored Meeting held in Madrid, Spain, May 4 –5, 2007. Conflict of interest: none. Corresponding author: Björn Dahlöf, MD, Department of Medicine, Sahlgrenska University Hospital/Östra, SE-416 85 Gothenburg, Sweden. Tel: ⫹46 31 343 5305 / 703 1853; fax: ⫹46 31 217 008. E-mail: [email protected]

Lowering BP with antihypertensive treatment reduces stroke risk by 30% to 40%.8 –11 The Blood Pressure Lowering Trialists’ Collaboration, which reviewed 29 randomized controlled trials evaluating the effects of different antihypertensive treatments on major cardiovascular outcomes, found that the largest reductions in BP produced the largest reductions in stroke.11 Indeed, the benefits of BP control

1933-1711/08/$ – see front matter © 2008 American Society of Hypertension. All rights reserved. doi:10.1016/j.jash.2008.03.008

B. Dahlöf / Journal of the American Society of Hypertension 2(4) (2008) S38 –S45 Table 1 Risk factors for stroke3,4 Nonmodifiable Risk Factors

Modifiable Risk Factors

Older age Male gender Nonwhite ethnicity Family history Previous stroke

Elevated blood pressure Diabetes mellitus Atrial fibrillation Carotid artery disease Hyperlipidemia Cigarette smoking Obesity High alcohol consumption

were more pronounced for stroke risk than for any other cardiovascular outcome or death. While the benefits of BP control on stroke reduction (and cardiovascular disease outcomes) are undisputed, the question of whether specific classes of antihypertensive agents offer special protection against stroke is still debated. In a meta-analysis of 18 long-term, randomized trials of older antihypertensives against placebo, diuretics reduced stroke risk by 51% (relative risk [RR], 0.49; 95% confidence interval [CI], 0.39 to 0.62) and beta-blockers by 29% (RR, 0.71; 95% CI, 0.59 to 0.86) compared with placebo.9 However, a more recent analysis of controlled trials comparing beta-blockers with other antihypertensive treatments found the RR of stroke to be 16% higher with beta-blockers (RR, 1.16; 95% CI, 1.04% to 1.30%; P ⫽ .009) than with other drugs, raising questions about the real value of these agents in stroke prevention.12

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In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which randomized 19,257 hypertensive patients to amlodipine-, atenolol-, and/or atorvastatin-based regimens (factorial design), the risk of the primary endpoint (nonfatal myocardial infarction and fatal coronary heart disease [CHD] events) was further reduced by the combination of atorvastatin and amlodipine.13 Atorvastatin reduced the risk of CHD events by 53% in the amlodipinebased group and by 16% in the atenolol-based group. The ASCOT Study also showed that statin therapy substantially reduced stroke in patients with well-controlled BP and with “normal” cholesterol.14 In addition, an amlodipine-based therapy more effectively reduced stroke than an atenololbased therapy even after adjustment for a small difference in BP.15 In the Blood Pressure Lowering Trialists’ Collaboration analysis, reduction in stroke risk was 38% (95% CI, 18 to 53) with calcium antagonist-based regimens and 28% (95% CI, 19 to 36) with angiotensin-converting enzyme (ACE) inhibitor-based regimens compared with placebo.11 Angiotensin receptor blocker (ARB)-based regimens reduced stroke risk by 21% (95% CI, 10 to 31) compared with active control.11 This evidence, together with data from numerous randomized controlled studies, suggests that some agents that target the renin-angiotensin system (RAS) may be particularly effective in stroke prevention compared with other drug classes.16 –21 The RAS pervades all aspects of the cardiovascular disease continuum through the actions of its most important mediator, angiotensin II.22 Angiotensin II is implicated in

Figure 1. Stroke mortality rate in each decade of age vs. (A) SBP or (B) DBP at the start of that decade, based on meta-analysis of individual data from 1 million adults in 62 prospective studies. CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure. Reprinted with permission from Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective studies collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13.7

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Figure 2. Reduction in stroke among hypertensive adults with LVH treated once daily with losartan-based or atenolol-based antihypertensive treatment for ⬎4 years in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study. (A) mean BP during the study. (B) Kaplan-Meier curve of the proportion patients with stroke (fatal and nonfatal) in each treatment group. BP, blood pressure; LVH, left ventricular hypertrophy. Reprinted with permission from Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.17

almost all of the pathological processes that lead to and perpetuate cardiovascular disease including endothelial dysfunction, vasoconstriction, cardiac, and vascular remodeling, inflammation, and thrombosis, and is, therefore, an important therapeutic target for the prevention of cardiovascular disease and stroke.22 Currently, angiotensin II activity can be interrupted with ACE inhibitors, which block ACErelated production of angiotensin II, or by ARBs, which prevent the actions of angiotensin II by selective blockade of its type 1 receptor (AT1). Both of these antihypertensive drug classes have demonstrated cardio- and cerebrovascular protective effects, but with different profiles; ACE inhibitors are more protective against CHD, and ARBs are more protective for stroke.

ACE Inhibitors and Stroke Prevention In clinical studies, ACE inhibitors provide better protection against cerebrovascular disease and stroke than placebo. For example, the placebo-controlled Heart Outcomes Prevention Evaluation (HOPE) Trial in high-risk patients with vascular disease or diabetes demonstrated that ACE inhibition with ramipril significantly reduced the rates of stroke (3.4% vs. 4.9% with placebo; RR, 0.68; 95% CI, 0.56 to 0.84; P ⬍ .001), cardiovascular death (6.1% vs. 8.1% for placebo; RR, 0.74; 95% CI, 0.64 to 0.87; P ⬍ .001), and myocardial infarction (9.9% vs. 12.3% for placebo; RR, 0.80; 95% CI, 0.70 to 0.90; P ⬍ .001), despite only a small 2- to 3 mm Hg reduction in BP; however, this reduction was considerably larger in the 24-hour ambulatory BP monitoring substudy, and it was not taken at trough or peak.16 Nevertheless, this effect was not observed when ACE inhibitors were compared against other antihypertensives: in a meta-analysis of older vs. newer antihypertensive agents in

cardiovascular prevention, ACE inhibitors gave 10% less protection against primary stroke for the same level of BP control than older drugs (RR, 1.10; 95% CI, 1.01 to 1.20; P ⫽ .03), while the opposite trend was observed for ARBs (RR, 0.76; 95% CI, 0.65 to 0.88; P ⫽ .0002).23

ARBs and Stroke Prevention The evidence supporting ARBs in stroke prevention is the strongest and most consistent.17–21,24 ARBs appear to provide better primary and secondary stroke prevention than any other antihypertensives and exhibit a protective effect that cannot be fully accounted for by BP reduction alone. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) Study was the first large controlled trial to demonstrate this effect in primary stroke prevention. In the LIFE Study, high-risk adults aged 55 to 80 years with essential hypertension (sitting BP 160 to 200/95 to 115 mm Hg) and left ventricular hypertrophy (LVH) were randomized to a losartan-based or atenolol-based antihypertensive treatment for at least 4 years. Despite almost identical BP reduction (losartan, ⫺30.2/16.6 mm Hg [standard deviation 18.5/10.1 mm Hg]; atenolol, ⫺29.1/16.8 mm Hg [19.2/10.1 mm Hg]), the losartan-based regimen reduced the RR of fatal or nonfatal stroke by 25% (RR, 0.75; 95% CI, 0.63 to 0.89; P ⫽ .001) more than the atenolol-based regimen (Figure 2).17 ARB-based treatment was also associated with a 13% lower RR of the primary composite endpoint of cardiovascular death, myocardial infarction, and stroke compared with the atenolol-based regimen (RR, 0.87; 95% CI, 0.77 to 0.98; P ⫽ .021), and a 25% lower incidence of new-onset diabetes (RR, 0 .75; 95% CI, 0.63 to 0.88; P ⫽ .001). In addition, the losartan-based regimen produced better regression of LVH, intima-media thickness, and mi-

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croalbuminuria, and better prevention of new-onset atrial fibrillation than atenolol-based therapy, for the same reduction in BP. Indeed, for patients with new-onset atrial fibrillation in whom the risk of stroke is increased manifold,25 losartan-based treatment resulted in a significant 51% reduction in stroke compared with atenolol-based treatment (RR, 0.49; 95% CI, 0.29 to 0.86; P ⫽ .01).25 In the Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) Study, ARB-based treatment with eprosartan gave better protection against future strokes and cardiovascular events in high-risk hypertensive stroke survivors than calcium-channel blocker (CCB) based treatment with nitrendipine, despite identical reductions in BP over 24 hours.20 The relative reduction in recurrent stroke risk with eprosartan was 25% (RR, 0.75; 95% CI, 0.58 to 0.97; P ⫽ .026) and in the primary combined endpoint of cerebrovascular and cardiovascular events and noncardiovascular death was 21% (RR, 0.79; 95% CI, 0.66 to 0.96; P ⫽ .014) lower compared with nitrendipine.20 Additional benefits are also achievable when an ARB is added to an already aggressive BP-lowering treatment regimen. This was shown in the recent Jikei Heart Study, in which 3,081 high-risk Japanese patients (mean age 65 years) with hypertension, CHD, and/or heart failure who already had well-controlled BP (mean 139/81 mm Hg) with conventional antihypertensive treatments were randomized either to additional treatment with valsartan, or adjustment of conventional treatment, to achieve a more aggressive BP goal of less than 130/80 mm Hg. After 3 years’ follow-up, both treatment regimens had achieved a mean BP of 131/77 mm Hg, but patients receiving valsartan-based treatment had a 39% greater reduction in the composite endpoint of cardiovascular or cerebrovascular event or cardiovascular death (RR, 0.61; 95% CI, 0.47 to 0.79; P ⫽ .00021) and a 40% greater reduction in the risk of new or recurrent stroke events (RR, 0.60; 95% CI, 0.38 to 0.95; P ⫽ .028), compared with patients on non-ARB-based therapy.21 The addition of an ARB to conventional antihypertensive therapy in these high-risk patients not only improved BP control and reduced cardiovascular risk but also provided better target organ protection and reduction in stroke risk than could be accounted for by the effects of BP reduction alone.21

The Importance of Selective AT1 Receptor Blockade The cerebrovascular protective benefits of ARBs have been ascribed to BP-lowering and the pleiotropic effects of angiotensin II at the AT2 receptor.26 Current evidence suggests that the pathological effects of angiotensin II are mediated through the AT1 receptor while a second angiotensin receptor, AT2, mediates more favorable actions that promote normal endothelial and vascular function,27 and increase neuronal survival and neurite outgrowth.28 Exper-

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imental data suggest that ARBs prevent stroke by selectively blocking the actions of angiotensin II at AT1 receptors in the brain,29 thus preventing brain ischemia, while simultaneously allowing angiotensin II to stimulate unoccupied AT2 receptors, encouraging a cerebrovascular protective effect.28,30,31 In a recent meta-analysis of 200,000 patients treated for hypertension, it was strongly indicated that antihypertensive drugs that potentially could stimulate the AT2 receptor in the brain through more endogenous angiotensin II (i.e., ARBs, CCBs, and diuretics) were more stroke protective than other antihypertensive drugs.32

Telmisartan Certain ARBs, like telmisartan, exhibit additional properties that may play a more beneficial role in stroke prevention.26 Compared with other ARBs, telmisartan also has a longer half-life and provides more sustained 24-hour and early morning BP control.33 This may be particularly relevant in view of the documented circadian increase in stroke incidence that occurs during the early morning BP surge.34,35 Animal studies show that telmisartan has higher bloodbrain barrier penetration than other ARBs,36,37 and – uniquely among ARBs – is a modulator of peroxisome proliferator-activated receptor-gamma (PPAR-␥) in clinically relevant doses.38 PPAR-␥ is a nuclear receptor that influences the expression of multiple genes involved in carbohydrate and lipid metabolism and is a well-known target for the treatment of insulin resistance, type 2 diabetes, and atherosclerosis. From the few published studies in the area, telmisartan improves insulin sensitivity and markers of atherosclerosis in patients with insulin resistance or type 2 diabetes, results that could be attributed to its effects on PPAR-␥.39 – 41 The full clinical significance of this activity, however, is yet to be determined. Pre-clinical studies suggest that PPAR-␥ expression is elevated following ischemia, which suggests that it plays a role, and may actually be involved in the post-ischemic anti-inflammatory response.42,43

Telmisartan in Stroke Prevention There are currently no prospective published studies of the effects of telmisartan on stroke prevention, although its effects on markers of stroke risk are promising. For instance, in a small-scale clinical trial in hypertensive patients with LVH, telmisartan produced significantly greater (P ⬍ .001) regression in left ventricular mass (21.97 ⫾ 5.84 g/m2; 15.7%) than the beta-blocker carvedilol (12.31 ⫾ 3.14 g/m2; 9.1%) despite comparable reductions in BP (Figure 3).44 This finding has important implications for stroke prevention, because the presence and severity of LVH correlates closely with the risk of stroke and transient ischemic attack in patients with hypertension.45,46 Importantly, regression of

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Figure 3. Change in LVMI and SBP following treatment with telmisartan or carvedilol. LVMI, left ventricular mass index; MRI, magnetic resonance imaging; SBP, systolic blood pressure. Reproduced with permission from Galzerano D, Tammaro P, del Viscovo L, Lama D, Galzerano A, Breglio R, et al. Three-dimensional echocardiographic and magnetic resonance assessment of the effect of telmisartan compared with carvedilol on left ventricular mass a multicenter, randomized, longitudinal study. Am J Hypertens 2005;18: 1563–9.44

LVH was validated in the LIFE Study to have independent value for risk reduction for stroke among other cardiovascular events.46 There are currently three ongoing large-scale international randomized controlled trials designed to evaluate the cardioprotective, BP-independent effects of telmisartan on cardiovascular endpoints including stroke. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) Study will compare the effects of an ARB (telmisartan), an ACE inhibitor (ramipril), or a combination of both on BP-independent cardioprotection in high-risk hypertensive patients with both asymptomatic and symptomatic cardiovascular disease but well-controlled BP.47 A parallel trial – the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Study – has the same endpoints but will compare telmisartan with placebo in similarly high-risk hypertensive patients intolerant to ACE inhibitors. The primary endpoints for both trials are the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Recruitment is now complete, with 25,620 patients randomized in the ONTARGET Study and 5,926 in the TRANSCEND Study,47 and results are expected in 2008. The third study, the Prevention Regimen For Effectively avoiding Second Strokes (PRoFESS) Trial, is the world’s largest secondary stroke prevention trial.48 This randomized, double-blind trial will evaluate the benefits of two treatment approaches for the prevention of second stroke in patients with recent ischemic stroke: firstly, it will compare the efficacy of two standard antiplatelet regimens (acetylsalicylic acid [aspirin] plus extended-release dipyridamole vs. clopidogrel), and in a second analysis the efficacy of telmisartan added to standard antiplatelet therapy vs. stan-

dard antiplatelet therapy alone. The primary outcome for the trial is recurrent stroke (target ⫽ 2,280 strokes), with the composite endpoint of stroke, myocardial infarction, or vascular death the most important secondary outcome. Recruitment completed in July 2006 with 20,333 patients randomized to treatment, with a follow-up period of up to 4 years. A summary of selected baseline characteristics is shown in Table 2.48,49 Results from this study, which are expected in the second quarter of 2008, will clarify the benefits of telmisartan in secondary stroke prevention and help to determine the most effective approaches for stroke recurrence in high-risk patients.

Conclusion Hypertension has a strong, linear, and continuous relationship with stroke risk and is the single most important modifiable risk factor for stroke prevention. BP-lowering reduces stroke risk substantially. Meta-analyses suggest that BP reduction, per se, is the important determinant in stroke risk reduction. However, the magnitude and effect of different antihypertensive drug classes on stroke prevention does differ, even in the presence of identical BP reduction. While the level of stroke protection conferred by different antihypertensive drug classes is still under debate, there is evidence to suggest that beta-blockers may be a less favorable option, while ARBs appear to offer additional protection. In large-scale clinical studies, ARBs are more protective against both primary and secondary stroke than control antihypertensive regimens, despite virtually identical reductions in BP. Telmisartan exhibits properties that may prove to be especially useful in the prevention of stroke. The value of this ARB is currently being evaluated in some of the

B. Dahlöf / Journal of the American Society of Hypertension 2(4) (2008) S38 –S45 Table 2 Summary of selected baseline characteristics of patients enrolled in the PRoFESS trial Total patients Mean age, years Gender, % female Median time from index stroke to randomization, days Time groups, % ⱕ10 days 11 to 30 days ⱖ31 days Stroke subtypes by TOAST classification, %49 Large-artery atherosclerosis Small-artery occlusion (lacune) Cardioembolism Acute stroke of other determined etiology Stroke of undetermined etiology Medical history, % Previous stroke (prior to qualifying stroke)/TIA Hypertension Diabetes mellitus Hyperlipidemia Ischemic coronary artery disease Atrial fibrillation Valvular disease Deep vein thrombosis Physical examination (mean) Blood pressure, mm Hg Body mass index Waist circumference, cm

20,333 66.1 ⫾ 8.6 36.0 15

39.9 29.0 31.1 28.5 52.1 1.8 2.0 15.5 26.9 73.8 28.1 46.6 16.2 2.6 1.7 1.5 144/84 26.8 96.5

PRoFESS, Prevention Regimen For Effectively avoiding Second Strokes Trial; TIA, transient ischemic attack; TOAST, Trial of Org 10,172 in Acute Stroke Treatment. Reproduced with permission from Diener HC, Sacco R, Yusuf S. Rationale, design and baseline data of a randomized, doubleblind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS). Cerebrovasc Dis 2007;23:368 – 80.48

largest and most comprehensive studies on stroke prevention ever conducted. In conclusion, BP-lowering is one of the most effective strategies for stroke prevention. While BP reduction alone is an essential goal, antihypertensive treatments that confer additional cerebrovascular protection surely represent an even more desirable choice.

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