Long-term Anti-hypertensive Therapy and Stroke Prevention
Long-term Anti-hypertensive Therapy and Stroke Prevention
There is a strong, graded, and continuous relationship between BP and stroke risk, with higher BP associated with greater stroke risk. Primary prevention studies in pre-hypertensive patients have shown a statistically significant stroke risk reduction with active antihypertensive therapy when compared with placebo. In a metaanalysis of 23 trials, any antihypertensive drugs versus no treatment were associated with a statistically significant 32 % relative risk reduction in stroke. Like primary prevention stroke studies, secondary prevention studies have also shown benefit for antihypertensive drugs versus no treatment in stroke risk reductions. In a meta-analysis of 25 trials of antihypertensive drugs versus no treatment in patients with history of stroke but without hypertension, the treatment group was associated with a significant 23 % pooled relative risk reduction of strokes.
The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial was a multicenter randomized open-label trial of 3020 participants that investigated the benefit of a BP target 130–149 versus<130 mmHg in patients with recent lacunar stroke. At 1 year, mean systolic BP was 138 mmHg in the higher-target group and 127 mmHg in the lower-target group. The lower-target group had nonsignificant rates of reduction in the primary endpoint of all stroke (including ischemic strokes and intracranial hemorrhages).
The BPLTTC was a systematic review that included 29 randomized antihypertensive trials that investigated the effects of different BP-lowering regimens on major cardiovascular events, including stroke. This review also showed a stroke risk reduction with intensive BP target (−4/−3 mmHg BP difference).
Similar to the BPLTTC, our meta-analysis showed that ACEIs were the least effective in BP reduction ( Table 3 ). In terms of the different antihypertensive drugs used in the BPLTTC, ACEIs and CCBs reduced stroke risk by 30 and 39 %, respectively, when compared with placebo. However, no significant differences in stroke outcome were observed among the different antihypertensive drug classes. Other studies have suggested that ACEIs and ARBs are more effective in reducing recurrent stroke, but the evidence is sparse. Despite evidence of reduced BP reduction with reduced stroke rates, which antihypertensive medication is most effective for long-term stroke prevention is unclear. In this review, we assessed the effectiveness of individual antihypertensive agents in reducing stroke risk.
The PROGRESS trial was a prospective, randomized, placebo-controlled trial designed to determined the risk of recurrent stroke in both hypertensive and non-hypertensive patients with cerebrovascular disease. Patients were assigned to 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. BP was lowered by 9/4 mmHg in the perindopril-based group, with a statistically significant 28 % relative risk reduction for total stroke. The PROGRESS trial suggested a linear relationship between BP reduction and stroke. In a meta-analysis of 28 trials in hypertensive or high-risk patients, ACEIs did not show a significant reduction in the prevention of stroke when compared with placebo/diuretics/β-blockers (odds ratio 0.94 [95 % CI 0.83–1.08], p = 0.41). A network meta-analysis of first-line antihypertensive drug treatment showed a significant reduction in stroke of 14 % with low-dose diuretics versus ACEIs. In our systematic review, no statistically significant difference was observed in longterm stroke occurrence with ACEIs when compared with non-ACEI antihypertensive agents. The summary risk ratio for stroke occurrence in the ACEI group compared with non-ACEI antihypertensive agents was 1.01 (95 % CI 0.81–1.27).
MOSES (Morbidity and Mortality after Stroke, and Eprosartan compared with Nitrendipine for Secondary Prevention study) enrolled 1405 patients to a target BP <140/90 mmHg. No difference in BP reduction was observed in either group; however, t a statistically significant reduction was seen in fatal and nonfatal cerebrovascular events favoring the eprosartan group. SCOPE showed a similar reduction in stroke (42 % risk reduction) with candesartan compared with placebo in elderly patients with ISH despite little difference in BP reduction. In patients with acute stroke and increased BP, candesartan did not improve cognitive function, quality of life, or vascular endpoints but instead may be harmful in this setting. In a network meta-analysis of first-line antihypertensive drug treatment, a non-statistically significant reduction in stroke of 20 % was observed with ARBs versus low-dose diuretics.
Our analysis shows a 15 % non-statistically significant reduction in stroke rate with ARB compared with non-ARB antihypertensive drugs, which suggests that ARBs could be better at reducing stroke rate than ACEIs in hypertensive patients without an otherwise compelling indication to be receiving an ACEI. The reduction in stroke could be explained by the observed difference in BP (−)21.2/8.5 mmHg versus (−)16.3/9.6 mmHg with ARBs versus ACEIs, respectively. Whether an ARB is a better antihypertensive agent than an ACEI remains to be seen.
In a recent study by Bangalore et al., β-blocker use in patients with prior MI but no HF was associated with a lower composite cardiovascular outcome. These findings were driven by lower recurrent MI with no difference in mortality. On the other hand, in patients without MI, β-blocker use was not associated with fewer cardiovascular events but instead was associated with increased stroke risk. Evidence is mounting that β-blocker use in patients without MI is not associated with fewer cardiovascular events; however, they are associated with increased stroke risk. In our analysis, β-blocker use was associated with a 42 % statistically significant increase in stroke rate compared with non-β-blocker antihypertensive drugs. The observed changes in BP noted in our study suggest that β-blockers are more effective in reducing BP than other antihypertensive drugs. However, the reduction in BP in the β-blocker groups did not translate to a reduction in stroke occurrence. The increased risk of stroke seen with β-blockers could therefore be explained by its metabolic effects (insulin resistance, lipid disturbance).
CCBs have been shown to reduce the incidence of stroke in patients with hypertension. The BPLTTC showed a statistically significant 38 % relative risk reduction in stroke when CCBs were compared with placebo. However, a trend was observed towards an increased risk of HF with CCBs. FEVER also showed a statistically significant reduction in stroke when a CCB-based regimen was compared with placebo. Likewise, in the ALLHAT trial, a CCB (amlodipine) was similar to a TLD (chlorthalidone) in stroke risk reduction despite a trend in favor of the CCB. An increased rate of HF and HF hospitalization was noted in the pre-specified subgroup analysis of the ALLHAT trial. A meta-analysis of 28 trials in hypertensive or high-risk patients showed that CCBs were statistically superior to placebo/diuretics/β-blockers in stroke prevention. This meta-analysis is different from our review study in that it did not include an ACEI or an ARB in the control arm.
In this meta-analysis, CCBs were associated with a statistically significant reduction in stroke rate when compared with all non-CCB antihypertensive drugs. Our findings are in accordance with those of the BPLTTC, which also showed that CCBs were more effective than thiazide diuretics/β-blockers and ACEIs in stroke risk reduction. Our study is different in that it compared CCBs with all four classes of antihypertensive drugs.
T-TLDs have been maintained as one of the preferred first-line antihypertensive agents for more than a decade. The support for their use comes from the landmark ALLHAT, which showed chlorthalidone (TLD) to be as effective as amlodipine (CCB) in reducing the specified endpoints (non-fatal MI plus coronary heart disease death and all-cause mortality); however, chlorthalidone was superior in the reduction of HF occurrence. Similarly, chlorthalidone was shown to be superior to lisinopril (ACEI) in reducing the occurrence of both stroke and HF events.
Our study showed a non-statistically significant reduction in stroke rates with T-TLD compared with other antihypertensive drugs. Despite being an effective antihypertensive drug, T-TLDs have significant metabolic adverse effects, especially at higher doses. In a recently published meta-analysis of ten trials (~17,000 patients), Mukete and Rosendorff found that even lower doses of T-TLD were significantly associated with a higher odds of elevated plasma glucose and reduced potassium. Despite being recommended as preferred first-line antihypertensive drug because of BP effectiveness and lower cost, caution should be used when prescribing to at-risk populations (those with occlusive coronary artery disease, LVH on electrocardiogram, the elderly with ISH, and those with an increased risk for developing diabetes).
The ASCOT-BPLA was a multicenter randomized controlled trial that assessed the antihypertensive effects of a CCB-based (amlodipine) versus a β-blocker-based (atenolol) regimen on the prevention of cardiovascular events. The ASCOT-BPLA BP target was achieved in the two groups. The difference in BP between the two groups was 2.7/1.9 mmHg lower in favor of the CCB-based group. No significant differences were observed in the primary endpoints (non-fatal MI and fatal coronary heart disease) despite a trend in favor of the CCB-based group. Nonetheless, a significant difference in stroke prevention was observed in favor of the CCB-based regimen.
The BPLTTC study suggested that the relative effects on total cardiovascular events was affected by the absolute BP reduction rather than the antihypertensive drug of choice. However, this conclusion was challenged by the life trial, in which a losartan-based regimen was better in stroke prevention than the atenolol-based regimen despite only achieving a 1 mmHg difference in systolic BP reduction in favor of the losartan-based regimen.
CAFÉ (Conduit Artery Function Evaluation) was a sub-study of the ASCOT trial that examined the difference in central aortic BP using the radial artery applanation tonometry method between a CCB-based versus a β-blocker-based regimen. In the CAFÉ trial, no significant difference was found in brachial systolic BP between the two groups; however, a substantial reduction was observed in central aortic systolic BP with the CCB-based regimen compared with the β-blocker-based regimen. The difference in central aortic systolic BP was significantly associated with a reduction in total cardiovascular events and procedures.
The differential outcome in stroke could be explained by the degree of central aortic systolic BP lowering with CCBs versus β-blockers. Furthermore, evidence is mounting that suggests an increased incidence of diabetes associated with β-blocker use. The increased incidence in diabetes could explain the increased stroke risk with β-blockers when compared with CCBs.
Discussion
There is a strong, graded, and continuous relationship between BP and stroke risk, with higher BP associated with greater stroke risk. Primary prevention studies in pre-hypertensive patients have shown a statistically significant stroke risk reduction with active antihypertensive therapy when compared with placebo. In a metaanalysis of 23 trials, any antihypertensive drugs versus no treatment were associated with a statistically significant 32 % relative risk reduction in stroke. Like primary prevention stroke studies, secondary prevention studies have also shown benefit for antihypertensive drugs versus no treatment in stroke risk reductions. In a meta-analysis of 25 trials of antihypertensive drugs versus no treatment in patients with history of stroke but without hypertension, the treatment group was associated with a significant 23 % pooled relative risk reduction of strokes.
The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial was a multicenter randomized open-label trial of 3020 participants that investigated the benefit of a BP target 130–149 versus<130 mmHg in patients with recent lacunar stroke. At 1 year, mean systolic BP was 138 mmHg in the higher-target group and 127 mmHg in the lower-target group. The lower-target group had nonsignificant rates of reduction in the primary endpoint of all stroke (including ischemic strokes and intracranial hemorrhages).
The BPLTTC was a systematic review that included 29 randomized antihypertensive trials that investigated the effects of different BP-lowering regimens on major cardiovascular events, including stroke. This review also showed a stroke risk reduction with intensive BP target (−4/−3 mmHg BP difference).
Similar to the BPLTTC, our meta-analysis showed that ACEIs were the least effective in BP reduction ( Table 3 ). In terms of the different antihypertensive drugs used in the BPLTTC, ACEIs and CCBs reduced stroke risk by 30 and 39 %, respectively, when compared with placebo. However, no significant differences in stroke outcome were observed among the different antihypertensive drug classes. Other studies have suggested that ACEIs and ARBs are more effective in reducing recurrent stroke, but the evidence is sparse. Despite evidence of reduced BP reduction with reduced stroke rates, which antihypertensive medication is most effective for long-term stroke prevention is unclear. In this review, we assessed the effectiveness of individual antihypertensive agents in reducing stroke risk.
Angiotensin-converting Enzyme Inhibitor (ACEI) Versus Non-ACEI Antihypertensive Drugs
The PROGRESS trial was a prospective, randomized, placebo-controlled trial designed to determined the risk of recurrent stroke in both hypertensive and non-hypertensive patients with cerebrovascular disease. Patients were assigned to 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. BP was lowered by 9/4 mmHg in the perindopril-based group, with a statistically significant 28 % relative risk reduction for total stroke. The PROGRESS trial suggested a linear relationship between BP reduction and stroke. In a meta-analysis of 28 trials in hypertensive or high-risk patients, ACEIs did not show a significant reduction in the prevention of stroke when compared with placebo/diuretics/β-blockers (odds ratio 0.94 [95 % CI 0.83–1.08], p = 0.41). A network meta-analysis of first-line antihypertensive drug treatment showed a significant reduction in stroke of 14 % with low-dose diuretics versus ACEIs. In our systematic review, no statistically significant difference was observed in longterm stroke occurrence with ACEIs when compared with non-ACEI antihypertensive agents. The summary risk ratio for stroke occurrence in the ACEI group compared with non-ACEI antihypertensive agents was 1.01 (95 % CI 0.81–1.27).
Angiotensin Receptor Blocker (ARB) Versus Non-ARB Antihypertensive Drugs
MOSES (Morbidity and Mortality after Stroke, and Eprosartan compared with Nitrendipine for Secondary Prevention study) enrolled 1405 patients to a target BP <140/90 mmHg. No difference in BP reduction was observed in either group; however, t a statistically significant reduction was seen in fatal and nonfatal cerebrovascular events favoring the eprosartan group. SCOPE showed a similar reduction in stroke (42 % risk reduction) with candesartan compared with placebo in elderly patients with ISH despite little difference in BP reduction. In patients with acute stroke and increased BP, candesartan did not improve cognitive function, quality of life, or vascular endpoints but instead may be harmful in this setting. In a network meta-analysis of first-line antihypertensive drug treatment, a non-statistically significant reduction in stroke of 20 % was observed with ARBs versus low-dose diuretics.
Our analysis shows a 15 % non-statistically significant reduction in stroke rate with ARB compared with non-ARB antihypertensive drugs, which suggests that ARBs could be better at reducing stroke rate than ACEIs in hypertensive patients without an otherwise compelling indication to be receiving an ACEI. The reduction in stroke could be explained by the observed difference in BP (−)21.2/8.5 mmHg versus (−)16.3/9.6 mmHg with ARBs versus ACEIs, respectively. Whether an ARB is a better antihypertensive agent than an ACEI remains to be seen.
β-blocker Versus Non-β-blocker Antihypertensive Drugs
In a recent study by Bangalore et al., β-blocker use in patients with prior MI but no HF was associated with a lower composite cardiovascular outcome. These findings were driven by lower recurrent MI with no difference in mortality. On the other hand, in patients without MI, β-blocker use was not associated with fewer cardiovascular events but instead was associated with increased stroke risk. Evidence is mounting that β-blocker use in patients without MI is not associated with fewer cardiovascular events; however, they are associated with increased stroke risk. In our analysis, β-blocker use was associated with a 42 % statistically significant increase in stroke rate compared with non-β-blocker antihypertensive drugs. The observed changes in BP noted in our study suggest that β-blockers are more effective in reducing BP than other antihypertensive drugs. However, the reduction in BP in the β-blocker groups did not translate to a reduction in stroke occurrence. The increased risk of stroke seen with β-blockers could therefore be explained by its metabolic effects (insulin resistance, lipid disturbance).
Calcium Channel Blocker (CCB) Versus Non-CCB Antihypertensive Drugs
CCBs have been shown to reduce the incidence of stroke in patients with hypertension. The BPLTTC showed a statistically significant 38 % relative risk reduction in stroke when CCBs were compared with placebo. However, a trend was observed towards an increased risk of HF with CCBs. FEVER also showed a statistically significant reduction in stroke when a CCB-based regimen was compared with placebo. Likewise, in the ALLHAT trial, a CCB (amlodipine) was similar to a TLD (chlorthalidone) in stroke risk reduction despite a trend in favor of the CCB. An increased rate of HF and HF hospitalization was noted in the pre-specified subgroup analysis of the ALLHAT trial. A meta-analysis of 28 trials in hypertensive or high-risk patients showed that CCBs were statistically superior to placebo/diuretics/β-blockers in stroke prevention. This meta-analysis is different from our review study in that it did not include an ACEI or an ARB in the control arm.
In this meta-analysis, CCBs were associated with a statistically significant reduction in stroke rate when compared with all non-CCB antihypertensive drugs. Our findings are in accordance with those of the BPLTTC, which also showed that CCBs were more effective than thiazide diuretics/β-blockers and ACEIs in stroke risk reduction. Our study is different in that it compared CCBs with all four classes of antihypertensive drugs.
Thiazide Diuretics Versus Other Antihypertensive Drugs
T-TLDs have been maintained as one of the preferred first-line antihypertensive agents for more than a decade. The support for their use comes from the landmark ALLHAT, which showed chlorthalidone (TLD) to be as effective as amlodipine (CCB) in reducing the specified endpoints (non-fatal MI plus coronary heart disease death and all-cause mortality); however, chlorthalidone was superior in the reduction of HF occurrence. Similarly, chlorthalidone was shown to be superior to lisinopril (ACEI) in reducing the occurrence of both stroke and HF events.
Our study showed a non-statistically significant reduction in stroke rates with T-TLD compared with other antihypertensive drugs. Despite being an effective antihypertensive drug, T-TLDs have significant metabolic adverse effects, especially at higher doses. In a recently published meta-analysis of ten trials (~17,000 patients), Mukete and Rosendorff found that even lower doses of T-TLD were significantly associated with a higher odds of elevated plasma glucose and reduced potassium. Despite being recommended as preferred first-line antihypertensive drug because of BP effectiveness and lower cost, caution should be used when prescribing to at-risk populations (those with occlusive coronary artery disease, LVH on electrocardiogram, the elderly with ISH, and those with an increased risk for developing diabetes).
Differential Outcome in Stroke Seen With CCBs and β-Blockers
The ASCOT-BPLA was a multicenter randomized controlled trial that assessed the antihypertensive effects of a CCB-based (amlodipine) versus a β-blocker-based (atenolol) regimen on the prevention of cardiovascular events. The ASCOT-BPLA BP target was achieved in the two groups. The difference in BP between the two groups was 2.7/1.9 mmHg lower in favor of the CCB-based group. No significant differences were observed in the primary endpoints (non-fatal MI and fatal coronary heart disease) despite a trend in favor of the CCB-based group. Nonetheless, a significant difference in stroke prevention was observed in favor of the CCB-based regimen.
The BPLTTC study suggested that the relative effects on total cardiovascular events was affected by the absolute BP reduction rather than the antihypertensive drug of choice. However, this conclusion was challenged by the life trial, in which a losartan-based regimen was better in stroke prevention than the atenolol-based regimen despite only achieving a 1 mmHg difference in systolic BP reduction in favor of the losartan-based regimen.
CAFÉ (Conduit Artery Function Evaluation) was a sub-study of the ASCOT trial that examined the difference in central aortic BP using the radial artery applanation tonometry method between a CCB-based versus a β-blocker-based regimen. In the CAFÉ trial, no significant difference was found in brachial systolic BP between the two groups; however, a substantial reduction was observed in central aortic systolic BP with the CCB-based regimen compared with the β-blocker-based regimen. The difference in central aortic systolic BP was significantly associated with a reduction in total cardiovascular events and procedures.
The differential outcome in stroke could be explained by the degree of central aortic systolic BP lowering with CCBs versus β-blockers. Furthermore, evidence is mounting that suggests an increased incidence of diabetes associated with β-blocker use. The increased incidence in diabetes could explain the increased stroke risk with β-blockers when compared with CCBs.
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