Abstract
For hypertensive patients without prior stroke, TIA, or other symptomatic vascular disease, anti-hypertensive therapy reducing SBP by 10 mm Hg, is associated with reductions in recurrent stroke (by about one-quarter) and of combined stroke, MI, and vascular death (by about one-fifth). Benefit extends across all ages, race-ethnicities, and pathological stroke subtypes. Combined pharmacological and non-pharmacological therapy to lower blood pressure is indicated in all individuals with SBP> 140 or DBP> 90, and in individuals with SBP 130–139 or DBP 80–89 who have additional vascular risk factors. Non-pharmacological blood pressure lowering is indicated in individuals with SBP 130–139 or DBP 80–89 without important additional vascular risk factors. After an ischaemic stroke or TIA, treatment may be gradually started as early as 24–72 hours after onset. The absolute benefits of antihypertensive therapy increase with greater reductions in BP, and are higher for preventing recurrent stroke than for preventing MI, in both primary and secondary prevention. The degree of BP reduction more greatly influences vascular event prevention than does pharmacological agent class. Nonetheless, unless otherwise indicated, beta-blockers are not a preferred agent, as they show less efficacy for stroke prevention. Calcium channel antagonists, ACE inhibitors, and thiazide diuretics are particularly well-studied.
By the year 1990, it was established that there is a direct log-linear relationship between usual blood pressure levels and risk of any stroke (MacMahon et al., 1990). Moreover, it was shown to be a causal relationship when a systematic review of randomized clinical trials demonstrated that lowering BP in hypertensive individuals significantly reduced the risk of first-ever stroke (Collins et al., 1990). Subsequently, additional clinical trials extended these findings to show that blood pressure reduction among individuals with elevated pressure prevented recurrent stroke (Liu et al., 2009).
More recently, blood pressure lowering among individuals with blood pressures in a range then designated as ‘pre-hypertensive’, systolic blood pressure (SBP) 130–139 mm Hg or diastolic blood pressure (DBP) 80–89 mm Hg, was also shown to reduce stroke occurrence (Lee et al., 2011; Sipahi et al., 2012; Huang et al., 2014). The benefit of detecting and treating blood pressures in lower ranges led to redefinition of high blood pressure, with normal being less than 120/80; elevated being SBP between 120–129 and DBP less than 80; stage 1 hypertension being SBP between 130 and 139 or DBP between 80 and 89; stage 2 hypertension being SBP being 140–180 or DBP 90–120; hypertensive crisis being SBP above 180 or DBP above 120 (Whelton et al., 2018).
Though a risk factor for both cerebral and coronary ischaemia, hypertension has a heightened association with cerebrovascular compared with cardiovascular events. Modest reductions in blood pressure by about 10 mm Hg systolic and 5 mm Hg diastolic reduced the relative risk (RR) of stroke by about 41% and the RR of coronary heart disease by about 22% within a few years of beginning the treatment (Blood Pressure Lowering Treatment Trialists’ Collaboration, 2003; Law et al., 2009).
However, despite tremendous advances in our understanding and ability to prevent stroke through treatment of elevated blood pressure, concerns linger about whether a differential approach is warranted for lowering blood pressure in patients with known cerebrovascular disease, and especially those with significant occlusive cerebrovascular disease, because doing so may compromise cerebral perfusion and perhaps even increase the rate of recurrent ischaemic stroke due to haemodynamic insufficiency (Boan et al., 2014).
Evidence
Broad Patient Populations
A systematic review collated 123 randomized controlled trials (RCTs), enrolling 613,815 patients, of blood pressure lowering performed in diverse populations, including cerebrovascular primary prevention (patients without a history of stroke or transient ischaemic attack [TIA]), vascular primary prevention (patients without a history of symptomatic cardiac, cerebral, or peripheral events), cerebrovascular secondary prevention (patients who have already had had one or more strokes/TIAs), and vascular secondary prevention (patients who have had one or more symptomatic vascular events in any circulatory bed) (Ettehad et al., 2016). For the occurrence of stroke, in 54 RCTs enrolling 265,323 individuals, every 10 mm Hg reduction in SBP significantly reduced the risk of stroke occurrence (RR 0.73, 95% confidence interval [CI]: 0.68–0.77). In addition, blood pressure lowering also reduced coronary heart disease (RR 0.83, 95% CI: 0.78–0.88), heart failure (RR 0.72, 95% CI: 0.67–0.78), the composite of all major cardiovascular disease events (RR 0.80, 95% CI: 0.77–0.83), and all-cause mortality (RR 0.87, 95% CI: 0.84–0.91).
The same meta-analysis also investigated the relative effectiveness of the five main classes of anti-hypertensive drugs: angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARB), beta-blockers, calcium channel blockers, and diuretics (Ettehad et al., 2016). Two class differences were noted in averting stroke. Compared with pooled effects of the other drug classes, calcium channel blockers were superior for stroke prevention (RR 0.90, 95% CI: 0.85–0.95) and beta-blockers were inferior for stroke prevention (RR 1.24, 95% CI: 1.14–1.35). In contrast, all classes performed comparably in averting myocardial infarcts. The reduced effectiveness of beta-blockers may reflect off-target effects promoting dyslipidaemia, glucose intolerance, and atrial fibrillation (Sardana et al., 2017; Whelton et al., 2018).
Primary Stroke Prevention
For patients without a history of symptomatic cardiovascular disease, a systematic review of 8 large RCTs showed that every 10 mm Hg reduction in SBP significantly reduced first-ever stroke (RR 0.75, 95% CI: 0.63–0.89). Blood pressure reduction also reduced first-ever heart failure (RR 0.77, 95% CI: 0.59–1.00) and all-cause mortality (RR 0.84, 95% CI: 0.75–0.93), though not first-ever coronary artery events (RR 0.85, 95% CI: 0.55–1.32) (Ettehad et al., 2016). Another systematic review specifically evaluated blood pressure lowering therapy in primary prevention patients who had mildly elevated blood pressure at entry (SBP 140–159 or DBP of 90–99), pooling individual participant level data from 14,906 patients enrolled in 10 trials (Sundstrom et al., 2015). Though the average reduction in blood pressure was modest, at 3.6 mm Hg systolic and 2.4 mm Hg diastolic, the risk of first-ever stroke was reduced importantly (RR 0.72, 95% CI: 0.55–0.92), with projected effects in a primary care cohort of reducing first-ever stroke events over 5 years from occurring in 4.2% to 3.0% of patients
Among primary prevention patients with an indication for blood pressure lowering, failure to prescribe is common and failure to adhere to antihypertensive therapy is associated with increased stroke rates. A UK study showed that among 7008 patients presenting with a first-ever stroke or TIA, 25% had not been prescribed blood pressure lowering agents despite have a clinical indication for antihypertensive therapy (Turner et al., 2016). Moreover, in a Korean study of 33,748 hypertensive patients, those with poor antihypertensive medication adherence had elevated rates of fatal cerebral haemorrhage (hazard ratio [HR] 2.19, 95% CI: 1.28–3.77) and fatal cerebral infarction (HR 1.92, 95% CI: 1.25–2.96) (Kim et al., 2016).
Recent investigations have explored the relative benefits and risks of intensive blood pressure lowering to levels beyond the prior conventional target of SBP at or below 140 mm Hg. Among individuals with starting blood pressures in the 130–139 range and who have prediabetes, diabetes, or subclinical renal impairment (but not symptomatic cardiovascular disease), systematic reviews of trials testing lowering SBP to below 130 mm Hg have found suggestions of additional benefit (Lee et al., 2012; Brunstrom and Carlberg, 2018). Among 11 trials enrolling 62,751 patients, there was a non-significant trend towards reduced stroke incidence (RR 0.85, 95% CI: 0.68–1.06) (Brunstrom and Carlberg, 2018). Among individuals with starting SBPs over a broader range, 130–180 mm Hg, two large RCTs compared the strategies of blood pressure lowering to an aggressive <120 mm Hg target versus a standard <140 mm Hg target, in patients with diabetes (ACCORD Study Group et al, 2010) and without diabetes (SPRINT Research Group et al., 2015). Combined analysis of the 14,094 patients from the two trials showed that allocation to aggressive blood pressure lowering targets was associated with fewer incident strokes (RR 0.75, 95% CI: 0.58–0.97) (Perkovic and Rodgers, 2015) (Figure 15.1). In addition, in the SPRINT trial, over a median 5-year follow-up, allocation to intensive blood pressure treatment to a SBP goal of <120 mm Hg was associated with reduced mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR 0.81, 95% CI: 0.69–0.94) and a trend towards reduced dementia (7.2 vs 8.6 cases per 1000 person-years; HR 0.83, 95% CI: 0.67–1.04) (SPRINT MIND Investigators, 2019).
Figure 15.1 Forest plots showing the effects on outcome of blood pressure lowering to an intensive target of <120 mm Hg vs a less-intensive target of <140 mm Hg, among patients with vascular risk factors but no history of stroke, TIA, or symptomatic vascular disease.
Implications for Practice
This evidence supports a tailored, primary prevention approach to blood pressure reduction across the range of presenting levels of SBP to prevent first stroke and other cardiovascular events (Whelton et al., 2018). Individuals with elevated blood pressure within the normal range (SBP 120–129 and DBP < 80) may be treated with nonpharmacological management, including healthy diet, weight loss, physical activity, and moderate alcohol intake. Individuals with stage 1 hypertension (SBP 130–139 or DBP 80–89) who have no major risk factors for cardiovascular disease may also be treated with nonpharmacological management; those with stage 1 hypertension with age, diabetes, tobacco, cholesterol, or other risk factors placing them at a 10-year risk of cardiovascular events of 10% or more are best also treated with start of single-agent pharmacological antihypertensive therapy. Individuals with stage 2 hypertension (SBP ≥ 140 or DBP ≥ 90) should be treated with a combination of nonpharmacological management plus antihypertensive drug therapy, using 2 agents of different pharmacological classes. When pharmacological therapy is indicated, consideration should be given to including a calcium channel antagonist and to avoiding a beta-blocker to maximize stroke reduction.
Secondary Stroke Prevention
A systematic review in the Cochrane Library identified 11 RCTs enrolling 38,742 participants assessing long-term blood pressure lowering to prevent recurrent stroke and major cardiovascular events after an initial stroke or TIA (Zonneveld et al., 2018). Eight of the trials (35,110 participants) compared antihypertensive therapy with no antihypertensive therapy and three of the trials (3632 participants) compared different SBP targets.
Recurrent Stroke
Among 35,110 patients with prior stroke or TIA who were randomized in eight RCTs to pharmacological blood pressure lowering or control, the frequency of recurrent stroke was reduced (8.7% versus 10.1%, RR 0.81, 95% CI: 0.70–0.93) (Figure 15.2).
Figure 15.2 Forest plot showing the effects of antihypertensive drugs vs control for patients with an index stroke or TIA on recurrent stroke, by pharmacological agent class.
Related posts:
Chapter 5 – Supportive Care during Acute Cerebral Ischaemia
Chapter 12 – Neuroprotection for Acute Brain Ischaemia
Chapter 9 – Acute Antiplatelet Therapy for the Treatment of Ischaemic Stroke and Transient Ischaemic Attack
Chapter 19 – Long-term Antithrombotic Therapy for Large and Small Artery Occlusive Disease
Chapter 25 – Using Pharmacotherapy to Enhance Stroke Recovery
Chapter 26 – Electrical and Magnetic Brain Stimulation to Enhance Post-stroke Recovery
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