Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention

Reviews

Role of antihypertensive therapy with angiotensinconverting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention Robert L. Talbert

Received December 16, 2009, and in revised form June 18, 2010. Accepted for publication July 9, 2010.

Abstract Objective: To review the available literature on the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients. Data sources: A Medline search was conducted using the search terms stroke and antihypertensives, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers from 1985 to August 17, 2009. Study selection: Randomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients. Data synthesis: The prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a renin–angiotensin–aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies. Conclusion: A growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention. Keywords: Hypertension, antihypertensive agents, stroke prevention and treatment, pharmacotherapy, blood pressure. J Am Pharm Assoc. 2010;50:e116–e125. doi: 10.1331/JAPhA.2010.09234

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Robert L. Talbert, PharmD, FCCP, BCPS, FAHA, is Professor, College of Pharmacy, University of Texas at Austin. Correspondence: Robert L. Talbert, PharmD, FCCP, BCPS, FAHA, Professor, College of Pharmacy, University of Texas at Austin College of Pharmacy, Pharmacotherapy Education and Research Center, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Fax: 210-5678328. E-mail: [email protected] Disclosure: Dr. Talbert has served on the Novartis Pharmaceuticals Corporation speaker’s bureau and received an honorarium for preparing this manuscript. Acknowledgments: The preparation of this manuscript was supported by Novartis Pharmaceuticals Corporation. The author contributed to the development of concepts and was involved in writing and revising the manuscript at each development stage. The author wishes to thank Nancy Sheridan and John Decker of Complete Healthcare Communications, Inc., for editorial support and research assistance. Funding: Novartis Pharmaceuticals Corporation provided funding for editorial support in the development of this manuscript and provided an honorarium to Dr. Talbert.

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T

he prevalence of stroke is high in the United States and carries a tremendous burden that can include disability or death. Annual rates for new and recurrent stroke among adults 20 years or older are estimated at approximately 610,000 and 185,000, respectively,1,2 with the prevalence of stroke being approximately 6.5 million in 2006.2 For 2008, total direct and indirect costs of cardiovascular diseases and stroke in the United States were estimated at $448.5 billion.3 For stroke alone, lost productivity resulting from morbidity and mortality totaled $21.8 billion, with direct costs (hospitalization and nursing home services, physicians and other professionals, and medical durables and home health care) accounting for an additional $43.7 billion.3 Stroke accounted for approximately 1 of every 16 deaths in the United States in 2004 (150,000 deaths/ year)4 and, when considered separately from other cardiovascular diseases, ranked third among all causes of death following heart disease and cancer.3 Despite these sobering statistics, evidence of progress also exists. From 1994 to 2004, the stroke death rate decreased 24.2% and the actual number of stroke deaths declined by 6.8%.3 However, there is considerable room for improvement. In general, stroke incidence rates are greater for men than for women, but this difference disappears with age.3 Stroke incidence varies greatly according to geographic location and ethnicity.3 For example, the overall prevalence of stroke across the

At a Glance

Synopsis: Hypertension is a major risk factor for stroke that often requires treatment with two or more drugs to reach goal blood pressure in most patients. The literature was reviewed to determine the effects of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients. Identifying hypertension quickly and aggressively lowering blood pressure to goal with combination therapy, including a renin– angiotensin–aldosterone system (RAAS) blocker and CCB, may be critical to reducing stroke incidence. Analysis: Estimates from 2005 showed that blacks were twice as likely to experience a first-ever stroke compared with whites. Evidence from ALLHAT suggests that a diuretic should be part of the antihypertensive regimen in black patients. Activation of RAAS is a major contributor to hypertension development in about two-thirds of patients; therefore, suppression of RAAS is a rational initial target for blood pressure control. Fixed-dose combination therapy may improve patient adherence to therapy compared with multiple-drug combination therapy, but potential disadvantages of fixed-dose combination therapy include low numbers of combination products, most of which are branded and therefore more expensive, and limited ability to titrate individual component doses.

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United States has decreased from 1994 to 2004 in every state by 5.7% (Alabama) to 34.5% (Minnesota).3 The southeastern region of the United States is often referred to as the “stroke belt” because of the high rates of stroke mortality in the region. However, five states elsewhere in the country (Illinois, Michigan, Missouri, Nevada, Texas, and West Virginia) also have prevalence estimates of 3.0% or higher.3 Recent estimates (2005) for ethnicity showed that blacks were twice as likely to incur a firstever stroke compared with whites.3 At ages 45 to 84 years, the age-adjusted stroke incidence for black men and women is 6.6 and 4.9 per 1,000 population, respectively. The prevalence of stroke among blacks was 3.4% compared with 2.3% for whites and 2.0% for Asians.3 In a 20-year follow-on study initiated in 1965 comparing risk of hospitalized stroke in American men from the Framingham study with Japanese American men in the Honolulu Heart Study, it was demonstrated (after adjusting for age and other risk factors) that Framingham men (62 of 1,000) had a 40% excess of thrombotic stroke compared with Japanese American men (45 of 1,000, P < 0.001).5 Among American Indians 65 to 74 years of age, new and recurrent strokes occur at a similar frequency for men and women (6.1 vs. 6.6 per 1,000).3 According to the BASIC (Brain Attack Surveillance in Corpus Christi) project, Mexican Americans (16.8 of 1,000) have an increased incidence of stroke compared with non-Hispanic whites (13.6 of 1,000).3 Stroke can be categorized into two broad types: ischemic stroke, which accounts for approximately 88% of all stroke, and hemorrhagic stroke, which accounts for 12% of all stroke4,6; each of these types of stroke can be subcategorized by mechanism, which, in the case of ischemic stroke, may include atherosclerotic cerebrovascular disease, penetrating artery disease (lacunes), and cardiogenic embolism (Figure 1).7,8 Clinical management of stroke is guided by evaluation of patient risk factors. Risk factors for stroke are categorized as (1) nonmodifiable risk factors, including factors such as age, gender, or race; (2) modifiable risk factors, the improvement of which has documented benefit in reducing cerebrovascular risk such as hypertension, cardiac disease, diabetes, or obesity; and (3) potentially modifiable but less well-documented risk factors, including oral contraceptive use, migraine, and sleepdisordered breathing.8,9 Recent estimates (2005) suggested that more than 70 million Americans (1 in 3 adults) have the modifiable risk factor hypertension1,3,10—up from 43.1 million in 1991.11 Hypertension correlates with an increase in cardiovascular events,12 including stroke, for which it is the greatest risk factor.3 For every 20–mm Hg increase in systolic blood pressure (SBP) or 10–mm Hg increase in diastolic blood pressure (DBP), stroke mortality doubles (Figure 2).13,14 In one analysis of data from the Framingham Heart Study, it was estimated that an average reduction in DBP by 2 mm Hg among white men aged 35 to 64 years would reduce risk of stroke by 14%, prevalence of hypertension (DBP ≥90 mm Hg) by 17%, and risk of coronary artery disease by 6%.15 For those 49 to 69 years, each 20–mm Hg reduction in usual SBP is associated with a twofold reduction in stroke mortality without any evidence of a plateau at least to 115/75 mm www.japha.org

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Stroke 12%

Primary hemorrhage

• Intraparenchymal • Subarachnoid

88% Ischemic stroke 20%

25%

Atherosclerotic cerebrovascular disease

Hypoperfusion

20%

Penetrating artery disease (”lacunes”)

30%

Cardiogenic embolism • • • •

5%

Cryptogenic stroke

Atrial brillation Valve disease Ventricular thrombi Many others

Other, unusual causes

• • • • • •

Prothrombic states Dissections Arteritis Migraine/vasospasm Drug abuse Many more

Arteriogenic emboli

Figure 1. Classification of stroke incidence by mechanism with estimates of stroke.

Reprinted with permission from Fagan S, Hess D. Stroke. In: Pharmacotherapy: a pathophysiological approach. 8th ed. New York: McGraw-Hill; 2008:373–84.

B 256

256

128

128

64

64

Stroke mortality ( oating absolute risk and 95% CI)

Stroke mortality ( oating absolute risk and 95% CI)

A

32 16 8 4 2

Age at risk: 80–89 years 70–79 years 60–69 years 50–59 years

32 16 8 4 2 1

1

0

0 120

140

160

180

200

70

80

90

100

Usual systolic blood pressure

Usual diastolic blood pressure

(mm Hg)

(mm Hg)

110

Figure 2. Stroke mortality rate in each decade versus usual systolic (A) and diastolic (B) blood pressure at the start of that decade.

Reprinted with permission from Lewington S, Clarke R, Qizilbash N, et al. 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.

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Hg; for individuals 40 to 49 years of age, stroke mortality was reduced by 60%.1,13 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended diuretic monotherapy or combination therapy for initial treatment of hypertension, even in patients with stage 1 hypertension (blood pressure 140– 159/90–99 mm Hg)14 without compelling indications; patients who have SBP more than 20 mm Hg above goal or DBP more than 10 mm Hg above goal should receive initial therapy with two or more drugs.14 JNC 7 recommends diuretics and angiotensin-converting enzyme inhibitors (ACEIs) as first-line therapy for stroke prevention, but these guidelines are more than 7 years old and do not consider contemporary trials. The European Society of Hypertension/European Society of Cardiology guidelines recommend monotherapy for initial treatment in patients who have mildly elevated blood pressure and low to moderate total cardiovascular risk; initial treatment with low-dose combination therapy is recommended for patients with stage 2 (blood pressure ≥160/≥100 mm Hg) or stage 3 hypertension or with high or very high total cardiovascular risk.16

Objectives We sought to (1) review the pathophysiologic rationale for the demonstrated clinical efficacy of antihypertensive therapy with calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), or other renin–angiotensin–aldosterone system (RAAS) blockers for prevention of stroke; (2) provide an overview of the outcomes obtained for stroke prevention in clinical trials that use ARBs, CCBs, and ACEIs as aggressive antihypertensive therapy; and (3) examine the merit of the use of CCB/ ARB fixed-dose antihypertensive therapy for stroke prevention.

Therapy with RAAS blockers/CCBs Optimizing a therapeutic approach to stroke prevention requires consideration of both the underlying pathophysiology of stroke and the differing mechanisms of action used by available antihypertensive agents. Further, consideration should be given to ways to improve adherence to therapy, including fixed-dose combination antihypertensive therapy. Early identification and treatment of hypertension with combination therapy to quickly achieve goal blood pressure rates is critical in the prevention of stroke. Activation of RAAS is a major contributor to development of hypertension in about two-thirds of patients; thus, suppression of RAAS is a rational initial target for blood pressure control.17,18 Angiotensin II, and in particular the angiotensin II type 1 receptor (AT1), is suspected to be an important but likely not the only “final common pathway” for many of the pathophysiologic sequelae of an upregulated RAAS. A direct renin inhibitor inhibits the enzymatic activity of renin, which prevents the formation of angiotensin I from its inactive precursor, angiotensinogen. ACEIs, in turn, prevent or reduce the formation of angiotensin II from angiotensin I,17 and ARBs inhibit angiotensin II activity by blocking the AT1 receptor,17 which is the primary effector of angiotensin II activity. Journal of the American Pharmacists Association

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Antihypertensive agents that block the action of RAAS can provide benefit beyond blood pressure reduction. For example, use of RAAS blockers has been shown to reverse left ventricular hypertrophy associated with hypertension19 and to decrease insulin resistance.20,21 In addition, RAAS blockers have been shown to reduce oxidative stress, improve endothelial function, and decrease inflammation.22 RAAS blockers have demonstrated renoprotective and vasoprotective effects (reducing growth of vascular smooth muscle, inhibiting progression of atherosclerotic plaques, and stabilizing plaques) that may be independent of blood pressure reduction.20,22,23 These actions can help interrupt the mechanisms involved in the development of cardiovascular disease and offer an opportunity to prevent disease progression. The ARBs valsartan and losartan (but not olmesartan, telmisartan, irbesartan, or candesartan) significantly reduced beta-amyloid protein levels, and this effect occurred in the absence of any evident cell toxicity.24 Although the reason for differing effects occurring among ARBs is unclear, valsartan and losartan significantly reduced the beta-amyloid levels; this is thought to be the result of differing effects on beta-amyloid oligomerization in vivo. Among seven antihypertensive drugs tested, valsartan was the only one found to inhibit beta-amyloid peptide oligomerization into soluble high–molecular weight species in vivo. Given that beta-amyloid may influence the pathological response to cerebral ischemia, ARBs that inhibit beta-amyloid accumulation, and in particular their oligomerization, could be of particular value in limiting vascular injury in patients with stroke.24,25 Other classes of antihypertensive drugs that were tested were much less potent in preventing oligomerization. Preclinical evidence supports a greater reduction of stroke with ARBs than with ACEIs. Use of ARBs (e.g., candesartan, olmesartan) for improving outcome in stroke is supported by preclinical studies in rodent models showing protective and superior effects of these agents in experimental acute cerebral ischemia, reducing stroke volume, and improving neurologic outcome compared with ramipril, without reducing blood pressure.26,27 Further, in mice, the ARB valsartan, at a nonhypotensive dose, decreased the neurological deficit and ischemic area after middle cerebral artery occlusion. Treatment with valsartan for 4 weeks induced increases in capillary density and attenuated ischemic brain damage.28 Dihydropyridine CCBs have antioxidant and anti-inflammatory effects that may be independent of their blood pressure– lowering effects and result in synergistic vasoprotective activity with RAAS blockers.21,23,29 In addition, CCBs are known to reduce the carotid intima-media thickening that is associated with an increased risk for stroke30 and are more effective in this regard than ACEIs.31

Role of CCBs in hypertension management and stroke prevention Many landmark trials have investigated the effect of blood pressure control on stroke prevention, some of which demonstrated an association between aggressive treatment of hypertension and stroke rate reduction with evidence that CCBs may provide www.japha.org

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0.052 0.023 0.033 0.036 Placebo HCTZ (12.5–25) Placebo Placebo FEVER (n = 9,800)35 ACCOMPLISH (n = 5,744)52 Syst-Eur (n = 4,695)64 NORDIL (n = 10,916)65

0.014 0.034 0.042, 0.051 0.037 0.019 0.019 0.029 Felodipine (5–10) Amlodipine (5–10) Amlodipine (2.5–10), lisinopril (10–40) Felodipine (5) Amlodipine (5–10) Nitrendipine (10−40) Diltiazem (180−360) HOT (n = 6,262)12 ASCOT-BPLA (n = 19,257)29 ALLHAT (n = 9,048)32

Abbreviations used: ACCOMPLISH, Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ACTION, A Coronary disease Trial Investigating Outcome with Nifedipine Gastrointestinal Therapeutic System; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm; BPLTT, Blood Pressure Lowering Treatment Trialists’ Collaboration; CAMELOT, Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis; CAPPP, Captopril Prevention Project; CCB, calcium channel blocker; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular Endpoints; DIABHYCAR, Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril; FEVER, Felodipine Event Reduction; HCTZ, hydrochlorothiazide; HOPE, Heart Outcomes Prevention Evaluation; HOT, Hypertension Optimal Treatment; HYVET, Hypertension in the Very Elderly Trial; IDNTZ, Irbesartan Diabetic Nephropathy Trial; INSIGHT, Intervention as a Goal in Hypertension Treatment; LIFE, Losartan Intervention For Endpoint reduction in hypertension;

≤26 ≤69 ≤36 ≤95

≤45 ≤45 ≤36

≤99 0c ≤64 ≤95 ≤73

0.10 0.93 0.60 0.15 0.18, 0.165 0.74 0.0003 0.28, 0.02 0.0019 0.17 0.003 0.04 −0.006 −0.007 0 −0.024 −0.020, −0.022 NA −0.01 −0.002, 0.007 −0.015 −0.004 −0.014 −0.007 0.026 0.017 0.012 0.079 0.046, 0.048 NA 0.044 0.044 Placebo Placebo Placebo Placebo Placebo, irbesartan (300) Placebo Atenolol (50–100) Chlorthalidone (25) 0.020 0.01 0.012 0.055 0.026 Nifedipine (30–60) Nisoldipine (20–40) Amlodipine (5–10) Amlodipine (5–10) Amlodipine (5–10)

P Comparator 2 Change in Stroke rate absolute riska Comparator 2 Dosage (mg/day) Comparator 1 Stroke rate Comparator 1 Dosage (mg/day)

Trial CCBs ACTION (n = 7,665)59 NICOLE (n = 819)60 PREVENT (n = 825)61 CAMELOT (n = 1,318)62 IDNTZ (n = 1,136)63

slightly better protection for stroke than ACEIs (Table 1). In the Hypertension Optimal Treatment (HOT) study (N = 18,790 patients),12 overall DBP was reduced by an average of more than 20 mm Hg. Antihypertensive therapy, with the long-acting calcium antagonist felodipine at a dose of 5 mg once a day, was given to all patients. Additional therapy and dose increments in four further steps were prescribed to reach the randomized target blood pressure. ACEIs or beta-blockers were added at step 2, and dosage titrations were used at steps 3 (felodipine 10 mg once a day) or 4 (doubling the dose of either the ACEI or the beta-blocker), with the possibility of adding a diuretic at step 5. The lowest risk for stroke was seen at the lowest blood pressure cutpoint (≤80 mm Hg DBP; 3.8 events/1,000 patientyears), although the correlation between tight blood pressure control and prevention of stroke was not significant (P for trend = 0.74). However, risk of stroke was reduced within certain subgroups. In patients with diabetes at baseline (n = 1,501), total stroke showed a declining rate with lower target blood pressure groups, with a risk reduction of about 30% in the DBP 80 mm Hg or less target group versus the DBP 90 mm Hg or less target group. In the HOT study, among patients with ischemic heart disease at baseline (n = 3,080), total stroke showed a significant reduction (P for trend = 0.046; 35, 30, and 20 events/1,000 patient-years, respectively, in the three target groups [DBP ≤90, DBP ≤85, and DBP ≤80 mm Hg]).12 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), patients were randomized to the CCB amlodipine (n = 9,048), the ACEI lisinopril (n = 9,054), or the diuretic chlorthalidone (n = 15,255).32 The 6-year event rate for stroke was higher (P = 0.02) in the lisinopril treatment arm (6.3 events/100 patients) compared with the chlorthalidone treatment arm (5.6 events/100 patients). Stroke rates were similar (P = 0.28) in the chlorthalidone treatment arm and the amlodipine treatment arm (5.4 events/100 patients).32 However, although the treatment effect on stroke for lisinopril and amlodipine was consistent across all subgroups by age and diabetes status, it was not by race and gender. The 6-year event rate for stroke was 52% higher for lisinopril than for amlodipine in black men (9.71 vs. 6.74 events/100 patients) and 48% higher in black women (7.04 vs. 4.86 events/100 patients). Female nonblack patients also suffered more strokes (+41%), but male nonblack patients had 10% fewer strokes on lisinopril than on amlodipine. Statistically, the three-way interaction (treatment–gender–race) was not significant (P = 0.112), and treatment–gender was not significant for the full model (P = 0.110); however, the interaction for treatment–race was significant (P = 0.025). The interaction for treatment–gender was significant for nonblack patients (P = 0.02) but not for black patients (data not shown).33 The VALUE (Valsartan Antihypertensive Long-Term Use Evaluation) trial showed that more events of fatal and nonfatal stroke (as a single category) occurred in the valsartan (ARB) arm versus the amlodipine (CCB) arm (10.0 vs. 8.7/1,000 patient-years), but this difference did not reach statistical significance (P < 0.08). When examining responses over the course of the trial, higher odds ratios were noted in favor of the amlo-

“Adjunct therapy” patients (%)b

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Table 1. Secondary prevention trials demonstrating stroke rate reduction/prevention with aggressive treatment of hypertension

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0.016 0.017 0.006 0.035 0.042 0.150 0.05 0.036 0.087 0.016 0.047

Valsartan (80–160) Eprosartan (600) Losartan (50–100) Candesartan (8–16) Telmisartan (80) Valsartan (80–160)

Ramipril (10)

Placebo

0.036 0.009, 0.017 0.059 0.101

Amlodipine (5–10) Nitrendipine (10) Atenolol (50–100) Placebo Placebo Non-ARB Telmisartan (80) Ramipril + telmisartan (10 + 80)

Placebo Placebo Placebo Placebo

Placebo Placebo Placebo

Placebo

(25/2.5–50/5.0) Atenolol (50−100) Atenolol or HCTZ (50−100 or 12.5)

0.034

0.012 0.016

Ramipril (10) Ramipril (5–10) Ramipril (1.25) Enalapril (5–20), simvastatin (10–40) Enalapril (10–20) Perindopril (4) Perindopril (4) + indapamide (2.5) Perindopril (4–8) Trandolapril (2–4) Indapamide (1.5) Captopril (50−200)

Verapamil (240−360) Verapamil (180−360)

0.037 0.200 0.067 0.047 0.092 0.030 0.043 0.044

0.017 0.022 0.009 0.027

0.034 0.039, 0.030 0.039 0.138

0.049

0.013 0.014

0.005 −0.05 −0.017 −0.011 −0.005 -0.014 0.004 0.003

−0.001 −0.005 −0.003 0.008

0.002 −0.03, −0.013 −0.02 −0.037

−0.015

−0.001 0.002

0.08 0.026 0.001 0.056 0.23 0.015 NA NA

0.83 0.09 0.06 0.04

<0.001 0.18 0.70 0.063, 0.544 0.36 <0.001 0.83

0.33 0.26

≤81

≤93 ≤80 ≤27 ≤66 100 100

≤93 ≤91 0c NA

≤91 ≤95 ≤51

≤48

≤77

≤43 ≤74

Abbreviations used: ACCOMPLISH, Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ACTION, A Coronary disease Trial Investigating Outcome with Nifedipine Gastrointestinal Therapeutic System; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm; BPLTT, Blood Pressure Lowering Treatment Trialists’ Collaboration; CAMELOT, Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis; CAPPP, Captopril Prevention Project; CCB, calcium channel blocker; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular Endpoints; DIABHYCAR, Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril; FEVER, Felodipine Event Reduction; HCTZ, hydrochlorothiazide; HOPE, Heart Outcomes Prevention Evaluation; HOT, Hypertension Optimal Treatment; HYVET, Hypertension in the Very Elderly Trial; IDNTZ, Irbesartan Diabetic Nephropathy Trial; INSIGHT, Intervention as a Goal in Hypertension Treatment; LIFE, Losartan Intervention For Endpoint reduction in hypertension; NICOLE, Nisoldipine in Coronary artery disease in Leuven; MOSES, Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention; NA, not available; NORDIL, the Nordic Diltiazem study; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; PREVENT, Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; SCAT, Simvastatin/Enalapril Coronary Atherosclerosis Trial; SCOPE, Study on Cognition and Prognosis in the Elderly; Syst-Eur, Systolic Hypertension in Europe Trial; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation. a Comparator 1 stroke rate – comparator 2 stroke rate. b Percent of patients taking concomitant medications. c No other calcium-channel blocker was allowed.

EUROPA (n = 12,218)71 PEACE (n = 8,290)72 HYVET (n = 1,933)42 CAPPP (n = 10,985)73 ARBs VALUE (n = 7,649)34 MOSES (n = 681)44 LIFE (n = 4,605)48 SCOPE (n = 2,477)46 PRoFESS (n = 20,332)74 KYOTO HEART75 ACEIs/ARBs ONTARGET (n = 8576)76

CAMELOT (n = 1,332)62 PROGRESS (n = 3,051)38 (n = 3,054)38

ACEIs HOPE (n = 9,297)39 PART2 (n = 617) DIABHYCAR (n = 4,912)69 SCAT (n = 460)70

INVEST (n = 22,576)67 CONVINCE (n = 16,476)68

NICOLE, Nisoldipine in Coronary artery disease in Leuven; MOSES, Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention; NA, not available; NORDIL, the Nordic Diltiazem study; ONTARGET, Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; PREVENT, Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; SCAT, Simvastatin/Enalapril Coronary Atherosclerosis Trial; SCOPE, Study on Cognition and Prognosis in the Elderly; Syst-Eur, Systolic Hypertension in Europe Trial; VALUE,trials Valsartan Antihypertensive Long-Term Use Evaluation. Table 1. Secondary prevention demonstrating stroke rate reduction/prevention with aggressive treatment of hypertension a Comparator 1 stroke rate – comparator 2 stroke rate. b 66 Percent of patients taking concomitant medications. INSIGHT (n = 6,321) Nifedipine (30–60) 0.017 HCTZ/amiloride 0.020 −0.003 0.52 ≤31 c No other calcium-channel blocker was allowed.

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dipine arm for all endpoints, including stroke, during the first 6 months, during which time differences in blood pressure between treatment groups were the greatest.34 Hypertensive Chinese patients (n = 9,800) in the FEVER (Felodipine Event Reduction) study who achieved blood pressure values of 138/82 mm Hg with low-dose felodipine (CCB) and hydrochlorothiazide (vs. 142/84 mm Hg with placebo) had a 27% reduction in the primary endpoint of fatal and nonfatal stroke. In addition, coronary events were reduced by 32% and cardiovascular mortality by 33%.35 A recent meta-analysis of 147 randomized trials of blood pressure–lowering drugs found few differences between different classes of agents, concluding that risk reduction was mostly dependent on blood pressure lowering and that all classes of agents were similarly effective in this regard.36 The authors also reported that combination therapy with three standard agents at one-half dose reduced risk of stroke by 62%, whereas use of standard monotherapy (with any agent) provided about one-half this benefit. The analysis also showed, however, that CCBs had a superior effect in preventing stroke compared with other classes of agents (relative risk 0.91 [95% CI 0.85–0.98], P = 0.01)). ARBs also showed a trend toward benefit in stroke, but this difference was not statistically significant (0.90 [0.71–1.13]).

Role of ACEIs for hypertension management and stroke prevention In the HOPE (Heart Outcomes Prevention Evaluation) trial, patients (n = 9,541) were randomized to the ACEI ramipril or placebo. Treatment with ramipril was associated with a 22% reduction in relative risk for a combined endpoint of stroke, myocardial infarction, and cardiovascular death and a 32% risk reduction for stroke without further reduction in blood pressure.37,38 A meta-analysis conducted by BPLTT (Blood Pressure Lowering Treatment Trialists’ Collaboration) provided an overview of five placebo-controlled trials of ACEIs (n = 18,229 patients mostly with cerebrovascular and/or coronary heart disease) and four placebo-controlled trials of calcium antagonists (CCBs) (n = 7,482 patients mostly with hypertension or coronary heart disease). Both CCBs and ACEIs showed reductions in stroke (28–38% [95% CI 18–53]).39 PROGRESS (Perindopril Protection Against Recurrent Stroke Study) assessed treatment of patients (n = 6,105) with a history of cerebrovascular disease. Active treatment with the ACEI perindopril as monotherapy or in combination with the diuretic indapamide reduced blood pressure from 147/86 mm Hg to 138/82 mm Hg and showed an overall 28% risk reduction in stroke recurrence versus placebo. However, in this study, combination therapy with the two agents reduced stroke risk by 43% (blood pressure reduced by 12/5 mm Hg), whereas singledrug therapy with perindopril (blood pressure reduction of 5/3 mm Hg) produced no risk reduction. The authors suggested that this dramatic difference in risk reduction was associated with greater levels of blood pressure reduction produced by combination therapy.16,40,41 In HYVET (Hypertension in the Very Elderly Trial), hypertensive patients 80 years or older (n = 3,845) with sustained blood e122 • JAPhA • 50 : 5 • S e p /O c t 2010

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pressure more than 160 mm Hg were randomly assigned to a diuretic (indapamide) or placebo with ACEI add-on therapy provided when necessary to achieve a blood pressure goal of less than 150/80 mm Hg.42 Active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% CI −1 to 51, P = 0.06) and a 39% reduction in the rate of death from stroke (1–62, P = 0.05), and fewer serious adverse events were reported in the active-treatment group (358 vs. 448 in the placebo group, P = 0.001). The study found that active treatment was highly effective for preventing stroke death in elderly patients.

Role of ARBs in hypertension management and stroke prevention The following studies suggested that ARBs were at least as effective as and possibly more effective than ACEIs in reducing risk for stroke and may exert an effect on stroke independent of an effect on blood pressure. A meta-analysis of six trials involving 49,924 patients revealed no significant differences between the effects of ARBs and ACEIs on the risk of myocardial infarction, cardiovascular mortality, and total mortality; however, the risk of stroke was slightly but significantly lower in those treated with ARBs compared with ACEIs (8% [odds ratio 0.92, P = 0.036]).43 The benefit of therapy with ARBs beyond an effect on blood pressure was seen in the Study on Cognition and Prognosis in the Elderly (SCOPE), which compared candesartan and noncandesartan open-label add-on antihypertensive control in elderly hypertensive patients46 and in a subgroup of patients with isolated systolic hypertension.47 The benefits were also seen in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which compared losartan with the beta-blocker atenolol in hypertensive patients.48,49 The adjusted relative risk of stroke was reduced by 23% (9.7 vs. 12.8/1,000 patientyears, P = 0.056) in SCOPE46 and by 25% (10.8 vs. 14.5/1,000 patient-years, P = 0.001) in LIFE48 using ARBs, indicating that ARBs may be superior to beta-blockers and perhaps to the other treatments used in these studies in reducing risk for stroke.48–51 The MOSES (Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention) study44 of hypertensive patients at high cardiovascular risk (n = 1,405) demonstrated a superior protective effect of the blood pressure–lowering treatment of eprosartan (ARB) versus nitrendipine (CCB) on mortality and morbidity after stroke without a difference in blood pressure–lowering effect.45

CCB/RAAS combination therapy for stroke prevention RAAS inhibition can be achieved through the several means described above; however, combination therapy usually leads to improved blood pressure reduction, and theoretically other pleiotropic actions may contribute. CCBs, such as amlodipine, prevent the influx of calcium ions into the smooth muscle cells of blood vessel walls, causing vasodilation and decreasing peripheral vascular resistance, and the resulting decrease in blood pressure induces compensatory activation of RAAS. Journal of the American Pharmacists Association

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Thus, the mechanism of CCB action is complementary with that of RAAS blockers, such as ACEIs and ARBs, and may account for the additive effects of these two classes. For example, the ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension) trial examined time to first event of cardiovascular morbidity and mortality (including but not limited to nonfatal stroke). High-risk hypertensive patients (n = 11,506) were treated with a fixed-dose CCB/ACEI combination versus ACEI/ diuretic combination,52,53 and the CCB/ACEI combination demonstrated reduction in risk of cardiovascular morbidity and mortality by 20% compared with ACEI/diuretic (primary event rate per 1,000 patient-years 32.3 vs. 39.7, P < 0.001). Stroke (fatal plus nonfatal) tended to be lower in the ACEI/CCB combination versus the ACEI/diuretic combination, but this difference was not significant (hazard ratio 0.84 [95% CI 0.65–1.08], P = 0.17).

Fixed-dose combination therapy versus multiple drug combinations In recent years, considering issues of patient nonadherence to antihypertensive therapy regimens and evidence that improved adherence has been associated with improved outcomes in numerous studies, the importance of simplified dosing regimens has been emphasized. Dosing frequency is one important consideration, especially for chronic conditions such as hypertension. A comparison of 20 studies showed that patients receiving once-daily dosing had 22% to 41% more adherent days than patients receiving thrice-daily dosing and 2% to 44% more adherent days than patients receiving twice-daily dosing.54 Fixeddose combination therapy may improve patient adherence to therapy, specifically compared with multiple-drug combination therapy, and many fixed-dose combinations are available.55,56 A retrospective analysis of pharmacy claims showed that adherence was significantly higher in patients prescribed a fixed-dose combination agent of CCB/ACEI than in those prescribed similar drugs as individual agents (88% ± 17% vs. 69% ± 28%, P < 0.0001).57 Increased adherence with fixed-dose regimens may be attributable in part to the fact that they are generally simpler and more convenient (fewer medications) and can be less costly (only one copay) than multiple agents taken separately.14,58 Potential disadvantages include limited numbers of combination products available, with most being branded and therefore more expensive, and limited ability to titrate individual component doses.

Conclusion Stroke ranks third among all causes of death following heart disease and cancer and is associated with a large burden in health care cost. Stroke is prevalent in a wide variety of ethnic groups. Hypertension is a major risk factor for stroke that often requires treatment with two or more drugs to reach goal blood pressure in most patients. In black patients, a diuretic should be part of the antihypertensive regimen based on the outcome of ALLHAT. Early identification of hypertension along with aggresJournal of the American Pharmacists Association

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