Blood pressure and stroke: From incidence to outcome

Stroke is a major public health concern and a growing determinant of health expenditures. According to the World Health Organization, 15 million people suffer stroke worldwide each year. With a mortality rate of approximately one-third, stroke is the second leading cause of death for people older than 60 years and the fifth cause in people aged from 15 to 59.1 Stroke also represents one of the main causes of long-term physical and cognitive disability.1 Evidence-based approaches to plan stroke prevention and management are the best strategy to curb the growing disease burden and costs of care. There is, hence, a continued need to identify the factors that may increase the incidence as well as influence the clinical outcome; blood pressure (BP) and BP dysregulation look like optimal candidates to be thoroughly investigated. High BP is the single most important culprit behind cerebrovascular diseases and the most prevalent modifiable risk factor.2 The risk of stroke increases continuously for BP levels above approximately 115/75 mm Hg and more than 60% of global stroke burden is attributable to nonoptimal BP.,3 A series of changes induced or favored by hypertension, including vascular remodeling, promotion of arteriolo- and atherosclerotic processes, impairment of cerebral hemodynamics, oxidative stress, and inflammation, are thought to contribute to the pathogenesis of brain infarcts and hemorrhages.2 There is also strong evidence that antihypertensive therapy can be crucial for prevention. A 10-mm Hg reduction in systolic BP is associated with a decrease in stroke risk of around one-third.3 The association is consistent across sexes, regions, stroke subtypes, fatal events, and nonfatal events, and the relative benefits appear similar by baseline BP levels and history of cardiovascular disease.3 Far from being a random phenomenon, variability in BP is reproducible within individuals over time.4, 5 Visit-to-visit variability in systolic BP is increased in cohorts at high risk of stroke, and it can predict stroke independently of average BP levels.6 In addition, increased residual variability in systolic BP in patients with treated hypertension is associated with a raised risk of vascular events, and the association seems to be continuous in the same way as the relationship with mean BP.6 Clinical benefits in stroke risk reduction were shown for all classes of antihypertensive drugs. Nonetheless, class-specific effects are suggested to exist, with calcium-channel blockers reducing the hazard to a greater and β-blockers to a smaller extent than expected from reduction in mean SBP alone. Recent meta-analyses showed that such differences between antihypertensive drugs might be related to their effects on within-individual BP variability.6, 7 Furthermore, the effects of BP-lowering agents on BP stability are dose-dependent and persist when used in combinations.8 Accordingly, stabilization of BP may be a novel therapeutic target with practical implications in routine management of hypertension and drug development. The raise in BP levels is found in about three-quarters of the patients with acute stroke, and about half of them have a history of hypertension.9, 10 In the natural course of stroke, BP values decline spontaneously and tend to return to prestroke levels within days.11 Although the pathophysiology of transient BP rise is still unsettled, it may reasonably be attributable to either stroke- or non-stroke–specific mechanisms, such as the damage to autonomic centers, abnormal baroceptor sensitivity, activation of neuro-vegetative and neuro-endocrine signaling, Cushing reflex due to increased intracranial pressure, stress of hospitalization, pain, and vomiting.12 Low BP levels may be also encountered, but they are much less common and generally due to concomitant cardiovascular or acute medical conditions, as cardiac arrhythmias, dehydration, and infection.13 In observational studies, both extremely high and low BP values have been associated with poor outcome, whether defined by early neurological deterioration, stroke recurrence, death, or late-dependency.14, 15 Indeed, high BP can increase the risk of edema formation and hemorrhagic transformation in ischemic stroke, and promote hematoma enlargement in cerebral hemorrhage by enhancing ongoing bleeding and rebleeding.16, 17 On the other side, the acute hypertensive response can be beneficial, as it preserves cerebral blood flow when the dysfunctional cerebral autoregulation and raised intracranial pressure make it passively dependent on perfusion pressure.18 Although the management of BP in acute stroke has been addressed in many clinical trials, there is still uncertainty about whether, when and how it should be lowered.19-21 It is likely that the range of optimal BP values and the effects of BP-lowering treatment on outcome may depend on a variety of patient-specific factors, such as stroke subtype, infarct volume and site, status of collateral circulation, preexisting history of hypertension, and associated heart failure.13 The antihypertensive drugs can exhibit themselves additional effects on cerebral blood flow, cardiac output, platelet and white blood cells functioning, sympathetic and renin-angiotensin-aldosterone systems, some of which may be advantageous, and others detrimental.20 Notably, BP after stroke is a highly dynamic variable, and trend and magnitude of BP changes over time can further influence the disease course.22-24 The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study was a randomized, double-blind, placebo-controlled clinical trial testing the effect of early dual antiplatelet treatment for the prevention of secondary stroke within the first 90 days following a transient ischemic attack or minor stroke in more than 5000 patients of Chinese descent.25 The trial showed that the combination of a loading dose of clopidogrel and aspirin within 24 hours after onset was associated with a significant reduction in secondary stroke and no difference in the rate of moderate or severe hemorrhages.25 In the current issue of The Journal of Clinical Hypertension, a post hoc analysis of the CHANCE trial found a significant interaction between mean arterial pressure (MAP) at admission and antiplatelet therapy as it relates to occurrence of stroke and combined vascular events (CVE) during the follow-up.26 Among patients with MAP <102 mm Hg, there was no significant difference in stroke recurrence between the clopidogrel-aspirin group and the aspirin arm. Conversely, the dual treatment was more effective at reducing the risk of stroke in patients with MAP 102-113 mm Hg or ≥113 mm Hg, in comparison with aspirin alone.26 The incidence of bleeding events did not differ between the treatment arms across the levels of MAP.26 Although no details about the etiology of cerebral ischemia have been provided and the exact mechanisms underlying these findings cannot be completely unraveled, speculative hypotheses may be advanced. All patients in the CHANCE trial were enrolled in China, where the prevalence of intracranial atherosclerosis is high, and an increase in MAP is generally needed to maintain cerebral perfusion when an arterial stenosis exists.26 A raised MAP may, hence, be the epiphenomenon of a status of cerebral hemodynamics deficiency that follows the derangements in cerebral blood flow induced by the atherosclerotic disease and is able to increase the risk of stroke recurrence by limiting the residual capacity of adaptation of intracranial vessels and the clearance of emboli.27, 28 In this regard, it is worth to notice that the absolute risk of stroke and CVE increased with the raise in MAP levels, mostly in the aspirin group,26 and the combined treatment with clopidogrel and aspirin has been shown to be more effective in reducing the number of microemboli than aspirin alone.29, 30 As hypertension on admission has been associated with medical history of vascular risk factors and comorbidities,26 the risk of stroke and CVE and, thus, the benefit of dual antiplatelet treatment, may be greater in patients with higher BP values. Signally, in the primary analysis of the CHANCE trial, dual antiplatelet treatment resulted more effective than aspirin monotherapy only in patients with baseline systolic BP ≥140 mm Hg.25 In summary, this subgroup analysis of the CHANCE trial provided useful insights toward the management of stroke patients by revealing how baseline MAP levels may predict the efficacy of antiplatelet therapy in preventing short-term stroke recurrence and identify high-risk patients who could get additional benefit from the combined treatment. Appropriate patient selection is of paramount importance to achieve the potential advantage of treatment after stroke and clinicians and researchers alike need to develop clues to identify subgroups that may profit from interventions that are more aggressive. Stroke management and outcome depend upon a multitude of variables related to clinical setting, patient demographics, etiology, cerebral perfusion, inflammatory response and systemic homeostasis.31-38 Taking into account the heterogeneity of these factors, their reciprocal interaction and the continuing expansion of electronic medical records, artificial intelligence algorithms are candidates to contribute in weighting therapeutic options and predicting stroke recovery by a personalized approach.39, 40 Global cooperation and fertilization across stroke and computer-science communities should be promoted to develop integrated models of care in the setting of the precision medicine in the near future. None.