Long-term Anti-hypertensive Therapy and Stroke Prevention
Long-term Anti-hypertensive Therapy and Stroke Prevention
We conducted a systematic search using MEDLINE, and included only randomized controlled trials (RCT) in adults that included antihypertensive therapy and stroke outcomes. Medical Subject Heading (MeSH) terms used included stroke, hypertension, randomized controlled trial (publication type), and antihypertensive agents, adrenergic β-antagonists (β-blockers), ARBs, CCBs, thiazide diuretics, and placebo.
Studies were included if they were an RCT with published manuscripts between 1999 and 2014 and compared one of five active antihypertensive regimens (thiazide or thiazide-like diuretic [T-TLD], CCB, β-adrenoceptor antagonist [β-blocker], ACEI, ARB) with placebo or with any of the active antihypertensive regimens. Studies were also included if they provided outcome data on stroke. We excluded studies with abstracts only, those with sample sizes<500 subjects, or those with <6 months of median follow-up. Figure 1 is a flow diagram showing the selection of trials included in this review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
(Enlarge Image)
Figure 1.
Flow diagram for the selection of studies examining effects of different antihypertensive therapies on long-term stroke outcome. ARB angiotensin receptor blocker, CCB calcium channel blocker
Approximately 202 manuscripts were reviewed, with 17 meeting criteria for inclusion. Some included studies compared an active antihypertensive regimen with placebo and/or with another active antihypertensive regimen. The active antihypertensive regimens included four studies in the ACEI group, six in the ARB group, ten in the ACEI/ARB group, ten in the CCB group, six in the β-blocker group, and five in the T-TLD comparison group.
A total of 17 RCTs were selected for this meta-analysis, with 31 derived comparative groups. All extracted data were entered into the Comprehensive Meta-Analysis (CMA) version 2.0 program. The extracted sample size and number of stroke occurrences in each trial were used to calculate an independent risk ratio for stroke with a 95 % confidence interval (CI). Heterogeneity was assessed using the I statistic. The summary effect size was determined using a fixed- or random-effect model based on the presence or absence of heterogeneity. We assumed heterogeneity among the studies when the degree of inconsistency (using I statistics) was >50 % with or without an associated p-value ≤0.05.
We used the DerSimonian and Liard random-effect model and the Mantel–Haenszel fixed-effect model to calculate the summary effect size based on the presence and absence of heterogeneity among studies respectively. Funnel plots were used to visually assess for publication bias, while the Begg and Mazumdar test was used to quantify the amount of publication bias. The Orwin failsafe N test was used to determine the number of missing studies would be required to make the summary effect trivial.
The 17 RCTs included in this meta-analysis accounted for 31 comparative arms ( Table 1 ). The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial was designed to test the hypothesis that treatment with an ACEI (benazepril 20–40 mg daily) combined with amlodipine would result in better cardiovascular outcomes than treatment with the same ACEI combined with a thiazide diuretic. In this trial, amlodipine 5–10 mg daily was compared with hydrochlorothiazide 12.5–25 mg daily. The addition of other antihypertensive agents (except CCBs, T-TLDs, ACEIs, or ARBs) was required to achieve a BP target of<140/90 mmHg or<130/80 (diabetic subjects). In ACCOMPLISH, 41 % of subjects had one or more drug added to hydrochlorothiazide, while 42 % of subjects received additional medications in the amlodipine arm.
ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) compared three antihypertensive agents (chlorthalidone 12.5–25 mg daily, amlodipine 2.5–10 mg daily, and lisinopril 10–40 mg daily) with a BP goal of<140/90 mmHg. Approximately 80.4 % of subjects were receiving amlodipine or another CCB, while 39.5 % were receiving a step 2 (atenolol, reserpine, or clonidine) or step 3 drug (hydralazine) at 5 years in the amlodipine arm. Likewise, 80.5 % (40.7 % step 2 or 3 drugs) and 72.6 % (43 % step 2 or 3 drugs) of subjects were receiving chlorthalidone and lisinopril, respectively, at 5 years.
The ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm) was a prospective, randomized, open-label, blinded-endpoint design that compared amlodipine-based regimens with atenolol-based regimens. Perindopril and bendroflumethiazide in the amlodipine-based and atenolol-based regimens, respectively, were added if BP was not at goal. At 5 years, 52 versus 38 % of patients were receiving additional drugs in the atenolol versus amlodipine arm.
The CTHPCE (Combination Therapy of Hypertension to Prevent Cardiovascular Events) trial was a prospective, randomized, open-label, blinded-endpoint trial that compared a regimen based on benidipine 4–8 mg daily added to either a β-blocker, ARB, or thiazide diuretic. Additional antihypertensive agents (ARB 21.7 %; β-blocker 26.3 %; and thiazide 29.8 %, respectively) were provided to achieve a BP goal of<140/90 mmHG.
The FEVER (Felodipine Event Reduction) trial was a randomized, prospective double-blind, placebo-controlled trial that compared incidence of stroke in hypertensive patients receiving felodipine 5 mg daily or matched placebo treated to a goal BP of ≤160/95 mmHg. All patients were receiving baseline hydrochlorothiazide 12.5 mg daily. Approximately 33.9 and 42.3 % of patients received add-on therapy (α-blocker, β-blocker, ACEI, ARB, and 12 % CCB) in the felodipine and placebo group, respectively.
HYVET (Hypertension in the Very Elderly) was a randomized, double-blind, placebo-controlled trial to assess the benefit of antihypertensive therapy in the very old population (aged ≥80 years). It compared active treatment with indapamide sustained release (SR) 1.5 with placebo to a target BP of<150/80 mmHg. At 2 years, 25.8, 23.9, and 49.5 % of subjects in the active-treatment group were receiving indapamide alone, indapamide and perindopril (2 mg), and indapamide and perindopril (4 mg), respectively. Meanwhile, in the control arm, 14.2, 13.4, and 71.8 % of subjects, respectively, were receiving the corresponding placebos.
INVEST (INternational VErapamil SR-Trandolapril) was a prospective, randomized, open-label trial. A sub-study of INVEST assessed the effects of a verapamil SR versus an atenolol-based regimen in subjects with prior myocardial infarction (MI). The target BP was <140/90 mm Hg, or<130/85 mm Hg in the presence of diabetes and/or renal impairment. At 2 years, 62.3 and 57.4 % were taking add-on therapy with trandolapril and hydrochlorothiazide, respectively.
LIFE (Losartan Intervention for Endpoint reduction in hypertension) was a prospective, randomized, double-blinded parallel-group study that evaluated the effect of losartan versus atenolol in hypertensive patients with left ventricular hypertrophy (LVH) to a BP goal of <140/90 mmHg. A sub-study of LIFE in patients with isolated systolic hypertension (ISH) was used in this meta-analysis. Approximately 58 % of subjects in both groups received additional therapy with hydrochlorothiazide. At 4.7 years, 83.7 and 74.9 % of subjects continued to take losartan and atenolol, respectively.
In the sub-analysis of the NHS (NAGOYA HEAT Study), the cardiovascular protective effect of valsartan versus amlodipine was assessed in diabetic hypertensive patients without previous documented CVD. The NHS was a prospective, randomized, open-labeled, blinded-endpoint trial. Patients were allocated to either valsartan 80–160 mg or amlodipine 5–10 mg daily to a BP target of ≤130/80 mmHg. At 36 months, 54 % of subjects were receiving the studied drugs in both arms. Add-on drugs included β-blockers (24 vs. 29 %), α-blockers (6 vs. 4 %), aldosterone blockers (3 vs. 2 %), thiazides (17 vs. 8 %), and other diuretics (4 vs. 5 %) for the valsartan versus the amlodipine group, respectively.
NORDIL (Nordic Diltiazem) was a prospective, randomized, open-labeled, blinded-endpoint study that compared the effects of a diltiazem-based (180–360 mg) regimen with the effects of regimens based on a thiazide diuretic, β-blocker, or both. The target BP was a diastolic of <90 mmHg. In the diltiazem group, an ACEI followed by a thiazide diuretic or a β-blocker could be added to achieve the target BP. Likewise, in the thiazide diuretic and β-blocker group, both drugs could be combined and then followed by an ACEI or α-blocker to achieve target BP. At the end of the trial, 50 % of patients in the diltiazem versus 45 % in the diuretic and β-blocker group were still taking the assigned randomized monotherapy.
ORIENT (Olmesartan Reducing Incidence of End stage Renal Disease in Diabetic Nephropathy Trial) was a randomized, placebo-controlled study that examined the renoprotective benefit of olmesartan medoxomil. Patients were allocated to receive olmesartan 10–40 mg daily (or placebo) to a target BP <130/85 mmHg. In order to achieve target BP, a diuretic, β-blocker, CCB, or α-blocker could be added. At 144 weeks, 63.4 % of patients were receiving olmesartan 40 mg (or placebo) daily.
PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study) was a prospective, randomized, placebo-controlled trial designed to determine the risk of recurrent stroke in both hypertensive and non-hypertensive patients with cerebrovascular disease. Patients were assigned either perindopril 4 mg daily or matching placebo, with addition of indapamide 2.0 or 2.5 mg daily at the discretion of the treating physician to achieve target BP. A total of 86 % of patients in the active group continued randomized therapy, while 87 % continued therapy in the placebo group. Indapamide was added in 58 % of patients in both groups.
SCAST (Scandinavian Candesartan Acute Stroke Trial) compared candesartan 4–16 mg with matching placebo in patients with recent stroke and a systolic BP ≥140 mmHg. Approximately 97 % of patients received the allocated study drug in both arms, while 28 and 26 % received an ACEI in the candesartan and placebo groups, respectively.
SCOPE (Study on Cognition and Prognosis in the elderly) was a double-blind randomized candesartan or matching placebo trial. In this sub-analysis, candesartan 8–16 mg daily was compared with matching placebo in a sub-group of elderly patients with ISH. Hydrochlorothiazide was the add-on regimen of choice if systolic BP remained ≥160 mmHg. Only 26 and 18 % of patients received monotherapy with candesartan or matching placebo, respectively. A total of 21 % of subjects in the candesartan group and 15 % in the placebo group received double therapy with hydrochlorothiazide. A total of 53 and 68 % received add-on therapy (diuretic, β-blocker, CCB, ACEI, and ARB) in the candesartan and placebo groups, respectively.
SHEP (Systolic Hypertension in the Elderly Program) was a double-blinded, randomized, chlorthalidone–placebo trial that evaluated the effect of this antihypertensive agent on stroke reduction in an elderly population with ISH to a goal systolic BP of<160 mmHg. The active study drug was chlorthalidone 12.5–25 mg daily or matching placebo; add-on therapy with β-blocker or low-dose reserpine could be added if target BP was not met. At the end of the trial, 46 % of participants were receiving only the active study drug, while 23 % were receiving a combination of active study drug plus add-on drug.
STOP-HTN-2 (Swedish Trial in Old Patients with Hypertension-2) was an RCT designed to investigate the benefit of newer antihypertensive agents (enalapril, lisinopril, felodipine, and isradipine) compared with older agents (atenolol, metoprolol, pindolol, and hydrochlorothiazide plus amiloride) on cardiovascular mortality. In this meta-analysis, we isolated and compared stroke incidence in the ACEI (enalapril 10–20 mg and lisinopril 10–20 mg daily) versus CCB (felodipine 2.5–5 mg and isradipine 2.5–5 mg daily) groups.
VART (Valsartan Amlodipine Randomized Trial) was a prospective open-labeled, blinded-endpoint study that compared the effects of valsartan 80–160 mg daily with those of amlodipine 5–10 mg daily on cardiovascular events in patients with BP ≥140/90 mmHg. Add-on therapy included α-blockers, β-blockers, or diuretics if target BP <140/90 mmHg was not achieved with active treatment. At 36 months, 81.7 versus 69.2 % of patients were receiving monotherapy with amlodipine and valsartan, respectively.
Methods
Search Method
We conducted a systematic search using MEDLINE, and included only randomized controlled trials (RCT) in adults that included antihypertensive therapy and stroke outcomes. Medical Subject Heading (MeSH) terms used included stroke, hypertension, randomized controlled trial (publication type), and antihypertensive agents, adrenergic β-antagonists (β-blockers), ARBs, CCBs, thiazide diuretics, and placebo.
Inclusion/Exclusion Criteria
Studies were included if they were an RCT with published manuscripts between 1999 and 2014 and compared one of five active antihypertensive regimens (thiazide or thiazide-like diuretic [T-TLD], CCB, β-adrenoceptor antagonist [β-blocker], ACEI, ARB) with placebo or with any of the active antihypertensive regimens. Studies were also included if they provided outcome data on stroke. We excluded studies with abstracts only, those with sample sizes<500 subjects, or those with <6 months of median follow-up. Figure 1 is a flow diagram showing the selection of trials included in this review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
(Enlarge Image)
Figure 1.
Flow diagram for the selection of studies examining effects of different antihypertensive therapies on long-term stroke outcome. ARB angiotensin receptor blocker, CCB calcium channel blocker
Approximately 202 manuscripts were reviewed, with 17 meeting criteria for inclusion. Some included studies compared an active antihypertensive regimen with placebo and/or with another active antihypertensive regimen. The active antihypertensive regimens included four studies in the ACEI group, six in the ARB group, ten in the ACEI/ARB group, ten in the CCB group, six in the β-blocker group, and five in the T-TLD comparison group.
Statistical Analysis
A total of 17 RCTs were selected for this meta-analysis, with 31 derived comparative groups. All extracted data were entered into the Comprehensive Meta-Analysis (CMA) version 2.0 program. The extracted sample size and number of stroke occurrences in each trial were used to calculate an independent risk ratio for stroke with a 95 % confidence interval (CI). Heterogeneity was assessed using the I statistic. The summary effect size was determined using a fixed- or random-effect model based on the presence or absence of heterogeneity. We assumed heterogeneity among the studies when the degree of inconsistency (using I statistics) was >50 % with or without an associated p-value ≤0.05.
We used the DerSimonian and Liard random-effect model and the Mantel–Haenszel fixed-effect model to calculate the summary effect size based on the presence and absence of heterogeneity among studies respectively. Funnel plots were used to visually assess for publication bias, while the Begg and Mazumdar test was used to quantify the amount of publication bias. The Orwin failsafe N test was used to determine the number of missing studies would be required to make the summary effect trivial.
Studies Included
The 17 RCTs included in this meta-analysis accounted for 31 comparative arms ( Table 1 ). The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial was designed to test the hypothesis that treatment with an ACEI (benazepril 20–40 mg daily) combined with amlodipine would result in better cardiovascular outcomes than treatment with the same ACEI combined with a thiazide diuretic. In this trial, amlodipine 5–10 mg daily was compared with hydrochlorothiazide 12.5–25 mg daily. The addition of other antihypertensive agents (except CCBs, T-TLDs, ACEIs, or ARBs) was required to achieve a BP target of<140/90 mmHg or<130/80 (diabetic subjects). In ACCOMPLISH, 41 % of subjects had one or more drug added to hydrochlorothiazide, while 42 % of subjects received additional medications in the amlodipine arm.
ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) compared three antihypertensive agents (chlorthalidone 12.5–25 mg daily, amlodipine 2.5–10 mg daily, and lisinopril 10–40 mg daily) with a BP goal of<140/90 mmHg. Approximately 80.4 % of subjects were receiving amlodipine or another CCB, while 39.5 % were receiving a step 2 (atenolol, reserpine, or clonidine) or step 3 drug (hydralazine) at 5 years in the amlodipine arm. Likewise, 80.5 % (40.7 % step 2 or 3 drugs) and 72.6 % (43 % step 2 or 3 drugs) of subjects were receiving chlorthalidone and lisinopril, respectively, at 5 years.
The ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm) was a prospective, randomized, open-label, blinded-endpoint design that compared amlodipine-based regimens with atenolol-based regimens. Perindopril and bendroflumethiazide in the amlodipine-based and atenolol-based regimens, respectively, were added if BP was not at goal. At 5 years, 52 versus 38 % of patients were receiving additional drugs in the atenolol versus amlodipine arm.
The CTHPCE (Combination Therapy of Hypertension to Prevent Cardiovascular Events) trial was a prospective, randomized, open-label, blinded-endpoint trial that compared a regimen based on benidipine 4–8 mg daily added to either a β-blocker, ARB, or thiazide diuretic. Additional antihypertensive agents (ARB 21.7 %; β-blocker 26.3 %; and thiazide 29.8 %, respectively) were provided to achieve a BP goal of<140/90 mmHG.
The FEVER (Felodipine Event Reduction) trial was a randomized, prospective double-blind, placebo-controlled trial that compared incidence of stroke in hypertensive patients receiving felodipine 5 mg daily or matched placebo treated to a goal BP of ≤160/95 mmHg. All patients were receiving baseline hydrochlorothiazide 12.5 mg daily. Approximately 33.9 and 42.3 % of patients received add-on therapy (α-blocker, β-blocker, ACEI, ARB, and 12 % CCB) in the felodipine and placebo group, respectively.
HYVET (Hypertension in the Very Elderly) was a randomized, double-blind, placebo-controlled trial to assess the benefit of antihypertensive therapy in the very old population (aged ≥80 years). It compared active treatment with indapamide sustained release (SR) 1.5 with placebo to a target BP of<150/80 mmHg. At 2 years, 25.8, 23.9, and 49.5 % of subjects in the active-treatment group were receiving indapamide alone, indapamide and perindopril (2 mg), and indapamide and perindopril (4 mg), respectively. Meanwhile, in the control arm, 14.2, 13.4, and 71.8 % of subjects, respectively, were receiving the corresponding placebos.
INVEST (INternational VErapamil SR-Trandolapril) was a prospective, randomized, open-label trial. A sub-study of INVEST assessed the effects of a verapamil SR versus an atenolol-based regimen in subjects with prior myocardial infarction (MI). The target BP was <140/90 mm Hg, or<130/85 mm Hg in the presence of diabetes and/or renal impairment. At 2 years, 62.3 and 57.4 % were taking add-on therapy with trandolapril and hydrochlorothiazide, respectively.
LIFE (Losartan Intervention for Endpoint reduction in hypertension) was a prospective, randomized, double-blinded parallel-group study that evaluated the effect of losartan versus atenolol in hypertensive patients with left ventricular hypertrophy (LVH) to a BP goal of <140/90 mmHg. A sub-study of LIFE in patients with isolated systolic hypertension (ISH) was used in this meta-analysis. Approximately 58 % of subjects in both groups received additional therapy with hydrochlorothiazide. At 4.7 years, 83.7 and 74.9 % of subjects continued to take losartan and atenolol, respectively.
In the sub-analysis of the NHS (NAGOYA HEAT Study), the cardiovascular protective effect of valsartan versus amlodipine was assessed in diabetic hypertensive patients without previous documented CVD. The NHS was a prospective, randomized, open-labeled, blinded-endpoint trial. Patients were allocated to either valsartan 80–160 mg or amlodipine 5–10 mg daily to a BP target of ≤130/80 mmHg. At 36 months, 54 % of subjects were receiving the studied drugs in both arms. Add-on drugs included β-blockers (24 vs. 29 %), α-blockers (6 vs. 4 %), aldosterone blockers (3 vs. 2 %), thiazides (17 vs. 8 %), and other diuretics (4 vs. 5 %) for the valsartan versus the amlodipine group, respectively.
NORDIL (Nordic Diltiazem) was a prospective, randomized, open-labeled, blinded-endpoint study that compared the effects of a diltiazem-based (180–360 mg) regimen with the effects of regimens based on a thiazide diuretic, β-blocker, or both. The target BP was a diastolic of <90 mmHg. In the diltiazem group, an ACEI followed by a thiazide diuretic or a β-blocker could be added to achieve the target BP. Likewise, in the thiazide diuretic and β-blocker group, both drugs could be combined and then followed by an ACEI or α-blocker to achieve target BP. At the end of the trial, 50 % of patients in the diltiazem versus 45 % in the diuretic and β-blocker group were still taking the assigned randomized monotherapy.
ORIENT (Olmesartan Reducing Incidence of End stage Renal Disease in Diabetic Nephropathy Trial) was a randomized, placebo-controlled study that examined the renoprotective benefit of olmesartan medoxomil. Patients were allocated to receive olmesartan 10–40 mg daily (or placebo) to a target BP <130/85 mmHg. In order to achieve target BP, a diuretic, β-blocker, CCB, or α-blocker could be added. At 144 weeks, 63.4 % of patients were receiving olmesartan 40 mg (or placebo) daily.
PROGRESS (Perindopril pROtection aGainst REcurrent Stroke Study) was a prospective, randomized, placebo-controlled trial designed to determine the risk of recurrent stroke in both hypertensive and non-hypertensive patients with cerebrovascular disease. Patients were assigned either perindopril 4 mg daily or matching placebo, with addition of indapamide 2.0 or 2.5 mg daily at the discretion of the treating physician to achieve target BP. A total of 86 % of patients in the active group continued randomized therapy, while 87 % continued therapy in the placebo group. Indapamide was added in 58 % of patients in both groups.
SCAST (Scandinavian Candesartan Acute Stroke Trial) compared candesartan 4–16 mg with matching placebo in patients with recent stroke and a systolic BP ≥140 mmHg. Approximately 97 % of patients received the allocated study drug in both arms, while 28 and 26 % received an ACEI in the candesartan and placebo groups, respectively.
SCOPE (Study on Cognition and Prognosis in the elderly) was a double-blind randomized candesartan or matching placebo trial. In this sub-analysis, candesartan 8–16 mg daily was compared with matching placebo in a sub-group of elderly patients with ISH. Hydrochlorothiazide was the add-on regimen of choice if systolic BP remained ≥160 mmHg. Only 26 and 18 % of patients received monotherapy with candesartan or matching placebo, respectively. A total of 21 % of subjects in the candesartan group and 15 % in the placebo group received double therapy with hydrochlorothiazide. A total of 53 and 68 % received add-on therapy (diuretic, β-blocker, CCB, ACEI, and ARB) in the candesartan and placebo groups, respectively.
SHEP (Systolic Hypertension in the Elderly Program) was a double-blinded, randomized, chlorthalidone–placebo trial that evaluated the effect of this antihypertensive agent on stroke reduction in an elderly population with ISH to a goal systolic BP of<160 mmHg. The active study drug was chlorthalidone 12.5–25 mg daily or matching placebo; add-on therapy with β-blocker or low-dose reserpine could be added if target BP was not met. At the end of the trial, 46 % of participants were receiving only the active study drug, while 23 % were receiving a combination of active study drug plus add-on drug.
STOP-HTN-2 (Swedish Trial in Old Patients with Hypertension-2) was an RCT designed to investigate the benefit of newer antihypertensive agents (enalapril, lisinopril, felodipine, and isradipine) compared with older agents (atenolol, metoprolol, pindolol, and hydrochlorothiazide plus amiloride) on cardiovascular mortality. In this meta-analysis, we isolated and compared stroke incidence in the ACEI (enalapril 10–20 mg and lisinopril 10–20 mg daily) versus CCB (felodipine 2.5–5 mg and isradipine 2.5–5 mg daily) groups.
VART (Valsartan Amlodipine Randomized Trial) was a prospective open-labeled, blinded-endpoint study that compared the effects of valsartan 80–160 mg daily with those of amlodipine 5–10 mg daily on cardiovascular events in patients with BP ≥140/90 mmHg. Add-on therapy included α-blockers, β-blockers, or diuretics if target BP <140/90 mmHg was not achieved with active treatment. At 36 months, 81.7 versus 69.2 % of patients were receiving monotherapy with amlodipine and valsartan, respectively.
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