Blood Pressure and Stroke Prevention Evidence Tables and Reference List
Hypertension Increases the Risk of Stroke
There is a well-established association between hypertension and increased risk of stroke. In fact, it is regarded as the most important modifiable risk factor. Results from Phases 1 and 2 of the INTERSTROKE study (O’Donnell et al. 2010, O’Donnell et al. 2016), a case-controlled study examining the contribution of specific risk factors to the burden of stroke across, indicated that five risk factors account for more than 80% of the risk for stroke. Among others, including current smoking, abdominal obesity, diet, and physical activity, hypertension was found to be the most significant. In phase 1 of the study, which included a sample size of 6,000, a self-reported history of hypertension or measured blood pressure ≥160/90 mm Hg was associated with an increased risk of all stroke (OR=2.98, 99% CI 2.72-3.28), but was highest for hemorrhagic stroke (OR=9.18, 99% CI 6.80-12.39). The same risk pattern was reported in phase 2 of the study, which included a larger sample size (n=26,919), and used a self-reported history of hypertension or measured blood pressure ≥140/90 mm Hg to define hypertension (O’Donnell et al. 2016). The risk of hemorrhagic stroke was significantly increased (OR=4.09, 99% CI 3.51-4.77). In another case-control study, Du et al. (2000) reported the risk of stroke was significantly higher among subjects who were hypertensive (OR=2.45, 95% CI 1.62 to 3.71, p< 0.001) and the risk of stroke increased with additional risk factors including smoking and diabetes. The authors suggested that at least three-quarters of strokes in hypertensive patients are preventable given appropriate treatment. The authors further emphasized that strokes are caused not by a single risk factor, but by the interaction of multiple risk factors, with some having a stronger independent relationship with stroke than others. A meta-analysis (Lewington et al. 2002) that included the results of one million adults from 61 prospective studies found that an increase of 20 mm Hg in systolic and 10 mm Hg in diastolic blood pressure led to a two-fold increase in stroke mortality in persons aged 40 – 69 years, without any evidence of a threshold down to at least 115/75 mm Hg for all vascular deaths. Age-specific associations were found to be similar for men and women, and for cerebral hemorrhage and cerebral ischemia. Bestehorn et al. (2008) included the results from 47,394 patients diagnosed with hypertension who were under the care of 2,482 general physicians and reported an overall 10-year stroke rate of 26%. The risk increased to 50% with the addition of other co-morbidities. Data from 1.25 million people without a history of cardiovascular disease, included in the CALIBER database were used to estimate lifetime risks and years of life lost to cardiovascular disease (Rapsomanki et al. 2014). During a median follow-up of 5.2 years, for each 20/10 mm Hg increase, the risks of TIA, ischemic stroke and ICH increased across age cohorts (30-59, 60-79 and ≥80 years), with the highest risks noted in the youngest patients. The lifetime risk of ischemic stroke (from index age of 30 years) in persons with hypertension, defined as ≥140/90 mm Hg, was 7.6% (95% CI 7.3%-7.8%) compared with 6.5% (95% CI 6.2%-6.9%) for persons without hypertension. The years of life lost to ischemic stroke for those with hypertension was approximately a half a year.
Pharmacological Treatment of Hypertension Reduces Stroke Risk
Description of many of the non-pharmacological approaches exist to reduce/manage blood pressure, including following a healthy diet, engaging in regular physical activity, consuming modest amounts of alcohol, reducing dietary sodium, avoiding tobacco exposure and managing high stress levels, are presented in other sections. The current recommendations to the pharmacological treatment of hypertension do not advise any particular dose/agent or combinations of agents to meet target blood pressures of <140/90 mg/Hg, (or <130/80 in persons with diabetes and kidney disease), while suggesting that angiotensin-converting enzyme (ACE) inhibitor/diuretic combination is preferred. While the Canadian Hypertension Education program (CHEP) suggests a more conservative systolic blood pressure target for the elderly (≥80 years, 150 mm Hg) due to their increased risk for falls, the present Canadian Best Practice Recommendations for Stroke Care does not differentiate based on age.
Numerous large, randomized controlled trials examining the effectiveness of a variety of antihypertensive agents, used alone, or in combination with other agents, have been published over the past 30 years. Many aimed to establish the superiority of one treatment regimen, or approach over another. These trials are characterized by large sample sizes, and are of high methodological quality. The Losartan Intervention For Endpoint reduction in hypertension (LIFE, Dahlof et al. 2002) and Study on Cognition and Prognosis in the Elderly (SCOPE, Lithell et al. 2003) studies demonstrated the efficacy of angiotensin receptor blockers (ARBs) for both primary and secondary prevention of stroke. Treatment with ARBs was superior to either placebo or atenolol-based antihypertensive regimen. The risk of cardiovascular mortality, stroke and myocardial infarction (combined) was reduced by 13% and 11%, respectively. The results of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial (Jameson et al. 2008) suggested that a higher proportion of persons achieved adequate blood pressure control (defined as< 140/90 mm Hg), using a combination of benazepril–amlodipine compared with benazepril + hydrochlorothiazide (75.4% vs.72.4%). There were fewer cardiovascular events/deaths associated with the addition of amlodipine (HR= 0.80, 95% CI, 0.72 to 0.90, p<0.001), with non-significant reductions in the risk of death from cardiovascular causes between groups or fatal/nonfatal stroke. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) compared: (1) ACE inhibitor ramipril; (2) the angiotensin-receptor blocker telmisartan; and (3), and the combination of the 2 drugs in patients who could not tolerate ACE inhibitors, among patients with vascular disease or high-risk diabetes (Yusef et al. 2008a). The researchers reported that telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes, and was associated with less angioedema. The combination of the 2 drugs was associated with more adverse events without an increased benefit. In the Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) Trial (Yusef et al. 2008b), the additional of telmisartan was not associated with a significant reduction in the risk of recurrent stroke within a median of 2.5 years follow up (HR=0.95, 95% CI 0.86 to 1.04, p= 0.23). Most recently, in the blood-pressure lowering arm of the Heart Outcomes Prevention Evaluation (HOPE) 3 trial (Lonn et al. 2016), patients at intermediate risk of cardiovascular disease (i.e. those without a history of CVD but with at least one or two risk factors, depending on age) were randomized to treatment with candesartan + hydrochlorothiazide or placebo. Although blood pressures were significantly lower in the active treatment group at the end of follow-up (median of 5.6 years), the risks of the primary and secondary outcomes, as well as fatal and nonfatal stroke, were not reduced significantly. In sub group analysis, patients in the highest blood pressure group benefited from active treatment. In the statin + blood pressure lowering arm of the HOPE-3 trail (Yusuf et al. 2016), the addition of rosuvastatin to the combination antihypertensive agents did result in a significantly reduced risk of cardiovascular events, including fatal or nonfatal stroke (HR=0.56, 95% CI 0.36-0.87).
The Secondary Prevention of Small Subcortical Strokes (SPS3 Trial) examined the effectiveness of medical management to reduce recurrent stroke. Lowering systolic blood pressure (SBP) to a target of < 130 mm Hg resulted in a non-significant reduction on all stroke, disabling stroke, myocardial infarction and vascular death compared with target SBP levels of 130-149 mm Hg (Benavente et al. 2013). In the Systolic Blood Pressure Intervention Trial (SPRINT), the potential benefit of a more aggressive blood pressure target was examined (Wright et al. 2015) among patients who were at increased risk of cardiovascular disease, without a history of diabetes. Persons with a history of previous stroke were excluded. Patients with an increased SBP (>130-180 mm Hg) were randomized to receive intensive treatment with a goal of SBP <120 mm Hg using 2-drug therapy, if required or standard treatment with a goal of SBP <140 mm Hg, for up to 6 years. The study was terminated early when the superiority of intensive therapy was demonstrated during interim analysis. The risk of the primary outcome (first occurrence of myocardial infarction, acute coronary syndrome, heart failure or cardiovascular death) was significantly lower for patients in the intensive group (HR=0.75, 95% CI 0.64-0.89, p<0.001); however, the risk of stroke was not (HR=0.89, 95% CI 0.63-1.25, p=0.50). The risks of serious adverse events including episodes of hypotension, syncope, electrolyte abnormality, and acute renal failure were all significantly higher in the intensive group. The potential benefit of achieving a lower diastolic BP was examined in the Hypertension Optimal Treatment (HOT) Trial (Hanssen et al. 1998). This trial included 18,790 patients, aged 50 to 80 years with DBP between 100 mm Hg and 115 mm Hg, of who a small number of participants (~1.2%) had experienced a previous stroke. Participants were randomly allocated to receive antihypertensive treatment to achieve diastolic BP targets of ≤ 90 m Hg, ≤ 85 mm Hg or ≤ 80 mm Hg, using a 5-step treatment program. There were no differences among groups for the risks of major cardiovascular events, all stroke or total mortality. Among the 1,501 participants with diabetes at baseline, the risk of major cardiovascular events was significantly increased in the highest target blood pressure group, compared with the lowest (RR=2.06, 95% CI 1.24-3.44), but without an increase in stroke risk (RR=1.43, 95% CI 0.68-2.99).
Studies examining the benefits versus risks of hypertension management in the very elderly (≥80 years) have emerged in the past few years. In the Hypertension in the Very Elderly Trial (HYVET), elderly patients were randomly assigned to receive either antihypertensive therapy, using indapamide as a first-line agent or matching placebo. Lowering mean blood pressure by 15.0/6.1 mm Hg was associated with a 30% reduction in the rate of fatal or nonfatal stroke (95% CI –1% to 51%, p = 0.06), a 39% reduction in the rate of death from stroke (95% CI 1% to 62%, p = 0.05), a 21% reduction in the rate of death from all causes (95% CI 4% to 35%, p = 0.02), and a 23% reduction in the rate of death from cardiovascular causes (95% CI –1% to 40%, p = 0.06) over a (median) follow-up period of 1.8 years (Beckett et al. 2008). The authors concluded that antihypertensive treatment in patients 80 years of age or older was beneficial. The open-label active treatment extension of the HYVET study included 1682 patients in both arms of the trial (Beckett et al 2012) with same target blood pressure levels <150/80 mm Hg. While there were no significant between-group differences in the incidence of fatal/nonfatal stroke, heart failure, or all cardiovascular events (12 vs. 13, HR= 0.78, 95% CI 0.36 to 1.72, p=0.55), the risks of all-cause mortality and cardiovascular mortality were significantly lower in patients previously receiving active treatment. There was a significant reduction in the risk of fatal/nonfatal stroke and stroke mortality associated with active treatment in the per-protocol analysis (HR=0.63, 95% CI 0.44-0.92, p<0.016 and HR=0.55, 95% CI 0.33-0.92, p<0.021, respectively) (Reisin et al. 2014).
The evidence for the beneficial effect of pharmacological treatment for hypertension in reducing stroke risk and mortality from stroke is strengthen from the results of several meta-analyses. Lee et al. (2012) included the results of 11 RCTs representing data from 42,572 participants (794 with previous stroke) who were at high risk for cardiovascular disease and compared treatment of tight blood pressure control (SBP <130 mmHg) with usual control (SBP 130 to 139 mmHg) on subsequent stroke risk. Tight SBP target was associated with reduced risks of future stroke, and major vascular events, and major coronary events, but was not associated with a significantly lower risk of death. Among patients with diabetes, those without a history of CVD, and younger than 65 years experienced the greatest stroke risk reduction. Law et al (2009) included the results of 147 RCTs (n=464,000) comparing: i) blood pressure lowering medications vs. placebo or usual care; and ii) trials compared different types of blood pressure medications. A blood pressure treatment-associated reduction of 10 mm Hg systolic and 5 mm Hg diastolic was associated with a reduced risk of stroke (RR=0.59, 95% CI 0.52-0.67). The risk of stroke was significantly reduced in trials that included persons with no prior history of stroke, a history of CHD, and a history of stroke. A Cochrane meta-analysis authored by Musini et al. (2009) included 15 trials, (24,055 subjects ≥ 60 years) with moderate to severe hypertension who were treated primarily with first-line thiazide diuretic therapy for a mean duration of treatment of 4.5 years. Treatment was associated with reduced total mortality, (RR= 0.90, 95% CI 0.84-0.97), and reduced total cardiovascular morbidity and mortality (RR=0.72, 95% CI 0.68-0.77). In the three trials restricted to persons with isolated systolic hypertension, the benefit was similar. In very elderly patients, ≥ 80 years the reduction in total cardiovascular mortality and morbidity was similar; however, there was no reduction in total mortality, (RR=1.01, 95% CI 0.90, 1.13). Withdrawals due to adverse effects were increased with treatment (RR= 1.71, 95% CI 1.45, 2.00).