VIII. Treatment of Hypertension in Association With Stroke

Prevention and Treatment

Subgroup Members: Patrice Lindsay, RN, PhD; Jean-Martin Boulanger, MD; Mukul Sharma, MD, MSc; Michael D. Hill, MD, MSc; Shelagh B. Coutts, MD; Gord Gubitz, MD
Central Review Committee: Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Alexander A. Leung, MD, MPH; Kevin C. Harris, MD, MHSc; Kerry McBrien, MD, MPH; Sonia Butalia, BSc, MD; Meranda Nakhla, MD, MSc
Chair: Doreen M. Rabi, MD, MSc
This information is based on the Hypertension Canada guidelines published in Leung, Alexander A. et al. Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults. Can J Cardiol 2017; 33(5): 557-576.

Guidelines

  1. BP management in acute ischemic stroke (onset to 72 hours)
    1. For patients with ischemic stroke not eligible for thrombolytic therapy, treatment of hypertension in the setting of acute ischemic stroke or transient ischemic attack should not be routinely undertaken (Grade D). Extreme BP increases (e.g., SBP >220 mmHg or DBP >120 mmHg) may be treated to reduce the BP by approximately 15% (Grade D), and not more than 25%, over the first 24 hours with gradual reduction thereafter (Grade D). Avoid excessive lowering of BP because this might exacerbate existing ischemia or might induce ischemia, particularly in the setting of intracranial arterial occlusion or extracranial carotid or vertebral artery occlusion (Grade D). Pharmacological agents and routes of administration should be chosen to avoid precipitous decreases in BP (Grade D).
    2. For patients with ischemic stroke eligible for thrombolytic therapy, very high BP (>185/110 mmHg) should be treated concurrently in patients receiving thrombolytic therapy for acute ischemic stroke to reduce the risk of secondary intracranial hemorrhage (Grade B).
  2. BP management after acute ischemic stroke
    1. Strong consideration should be given to the initiation of antihypertensive therapy after the acute phase of a stroke or transient ischemic attack (Grade A).
    2. After the acute phase of a stroke, BP-lowering treatment is recommended to a target of consistently <140/90 mmHg (Grade C).
    3. Treatment with an ACE inhibitor and thiazide/thiazide-like diuretic combination is preferred (Grade B).
    4. For patients with stroke, the combination of an ACE inhibitor and ARB is not recommended (Grade B).
  3. BP management in hemorrhagic stroke (onset to 72 hours)
    1. For patients with intracerebral hemorrhage in the hyperacute phase (in the first 24 hours) SBP lowering to <140 mmHg should be avoided due to an absence of benefit (relative to a target of <180 mmHg) (Grade A; new guideline) and some suggestion of harm.

Background

A. BP management in acute ischemic stroke (onset to 72 hours)

1. For patients with ischemic stroke not eligible for thrombolytic therapy, treatment of hypertension in the setting of acute ischemic stroke or transient ischemic attack should not be routinely undertaken (Grade D). Extreme BP increases (e.g., SBP >220 mmHg or DBP >120 mmHg) may be treated to reduce the BP by approximately 15% (Grade D), and not more than 25%, over the first 24 hours with gradual reduction thereafter (Grade D). Avoid excessive lowering of BP because this might exacerbate existing ischemia or might induce ischemia, particularly in the setting of intracranial arterial occlusion or extracranial carotid or vertebral artery occlusion (Grade D). Pharmacological agents and routes of administration should be chosen to avoid precipitous decreases in BP (Grade D).

Given the paucity of controlled trials, it is uncertain whether BP should be lowered (and at what thresholds) in the setting of acute stroke (22). Certainly, observational studies would suggest that all but the highest BPs should be left to settle spontaneously (23). In acute stroke patients with hypertension, multiple case reports have documented the potentially disastrous effects of sublingual vasodilator (specifically nifedipine) administration (11). In these circumstances, cerebral perfusion may be further reduced, as a consequence of rapid severe systemic hypotension, with profoundly deleterious results.

In the setting of acute stroke, 75% of patients will experience elevated BPs, potentially due to preexisting hypertension, activation of the neuroendocrine response to acute stroke, neurogenic hypertension due to the stroke itself, disruption of normal cerebral autoregulation, or development of intracranial mass. Although BP tends to fall to pre-stroke baseline values within a few days following acute stroke in the majority of patients, observational studies demonstrate that very high BP immediately following acute stroke is associated with early neurologic deterioration, stroke progression or recurrence, and mortality.

In an analysis of 17,398 acute ischemic stroke patients enrolled in the International Stroke Trial (IST), those patients with an systolic blood pressure (SBP) > 200 mm Hg had a > 50% greater risk of recurrence in the first 14 days than did those with a pressure of 130 mm Hg (1). Whether actively lowering BP in the acute phase of stroke will reduce this risk remains unclear. In the Intravenous Nimodipine West European Stroke Trial (INWEST) of 265 patients with acute ischemic stroke, lowering DBP with intravenous (IV) nimodipine > 20% was associated with increased risk of death or dependency (2). CHEP recommends generally, antihypertensive agents should not be administered in the acute phase of both ischemic stroke and ICH. In those patient with extremely high BP (e.g., > 220/110 mm Hg), pressures may be lowered approximately 15% but should not be lowered > 25% of the mean arterial pressure within the first 24 hours of stroke onset.

In the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) trial, lowering BP with candesartan (15% reduction in mean arterial pressure) was not associated with adverse outcomes, but this trial excluded patients with carotid stenosis defined by ultrasound, and the candesartan arm did not have a significantly lower BP than the placebo arm in the early phase after stroke (2,3). These and other smaller studies suggest collectively that among patients with very high BP in acute stroke, large falls in BP are associated with harm. Yet it remains unclear whether more modest reductions in BP are beneficial. In intracerebral hemorrhage (ICH), small studies, such as the pilot phase of Intensive Blood Pressure Lowering in Acute Cerebral Haemorrhage Trial (INTERACT), suggested lowering BP results in reduced enlargement of intraparenchymal hematoma) (4).

After the pilot INTERACT trial, the full Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2 (INTERACT-2) trial was conducted in Australasia and Europe, intending to provide more definitive evidence on whether BP lowering is beneficial to clinical outcomes (5). The INTERACT-2 enrolled 2839 individuals within 6 hours of spontaneous ICH. Investigators examined a strategy of lowering SBP within 1 hour of presentation to < 140 mm Hg compared with < 180 mm Hg; these targets were to be maintained for at least 7 days. The primary outcome was a composite of death and disability defined by a score of 3–6 on the modified Rankin scale 90 days after the event. The outcome rate was greater than expected in both trial arms; however, the between-group differences were less than expected. There was a suggestion of a 13% relative reduction (RR) (RR, 0.87; 95%CI, 0.75–1.01) in the primary outcome favouring the lower SBP target group but as demonstrated by the 95%CI, this finding was not conclusive.

The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial (ICH ADAPT) (6) enrolled patients within 24 hours of a spontaneous ICH if their SBP was ≥ 150 mm Hg. The SBP targets were < 150 mm Hg vs. < 180 mm Hg. The primary outcome was radiographically determined perihematoma relative cerebral blood flow (rCBF) with the main objective being to examine whether SBP lowering had a detrimental effect on rCBF. Seventy-five (75) participants were enrolled. No conclusive differences in perihematoma rCBF were demonstrated (perihematoma rCBF difference, 0.03; 95%CI, -0.018 to 0.078). The ipsilateral hemispheric rCBF was slightly less in the lower BP target group (0.04 difference), suggesting lower perfusion with a lower BP target, although the magnitude of the difference was small. The investigators interpreted their findings as suggesting no detrimental effect on perihematoma rCBF with BP reduction after ICH. Therefore, the RTF was of the view the strength of evidence did not warrant a recommendation for immediate blood pressure reduction in acute stroke.

2. For patients with ischemic stroke eligible for thrombolytic therapy, very high BP (>185/110 mmHg) should be treated concurrently in patients receiving thrombolytic therapy for acute ischemic stroke to reduce the risk of secondary intracranial hemorrhage (Grade B).

Patients with ischemic stroke, who will be receiving thrombolytic therapy, and who have elevated BP, should have their prethrombolytic BP lowered to a target of < 185/110 mm Hg. Thrombolysis is contraindicated in patients with ischemic stroke with SBP levels > 185 mm Hg and/or DBP > 110 mm Hg because of associated higher risks of ICH (8). In the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study, which identified benefit of thrombolytic therapy in AIS, in addition to subsequent thrombolytic stroke trials, patients with SBP levels > 185 mm Hg and/or DBP > 110 mm Hg were excluded; those patients who required aggressive (i.e., IV) antihypertensive treatment to reach these targets were also excluded (9). Since publication of the NINDS Study, several stroke organizations, the Canadian Stroke Network, European Stroke, and American Stroke Association guidelines recommend nonaggressive antihypertensive treatment intervention if BP exceeds this threshold prior to and concurrent with thrombolytic treatment.

B. BP management after acute ischemic stroke

1. Strong consideration should be given to the initiation of antihypertensive therapy after the acute phase of a stroke or transient ischemic attack (Grade A).

It is well established that antihypertensive therapy is associated with substantial reductions in cardiovascular events in patients who have suffered a stroke or TIA (10,11). Patients with hypertension who have had a stroke are at a high risk of recurrence, which can be reduced by antihypertensive therapy (RR, 0.72; 95%CI, 0.61 to 0.85) (11).

2. After the acute phase of a stroke, BP-lowering treatment is recommended to a target of consistently <140/90 mmHg (Grade C).

Hypertension following the acute phase of stroke is associated with increased risk of recurrent stroke and death. Following an ischemic stroke, the risk of recurrent stroke, transient ischemic attack or cardiac event ranges from 5% to 15% per year (29). Antihypertensive use lowers this risk substantially. CHEP continues to recommend lowering BP consistently to < 140/90 mm Hg following stroke. CHEP works in conjunction with the Canadian Stroke Network to provide recommendations for elevated BP in patients with acute stroke (within 4 days of stroke symptom onset).

Although antihypertensive therapy is well established in the secondary prevention of stroke, it is unclear whether lowering BP beyond 140/90 mm Hg would provide additional benefits. Benefits of aggressive BP lowering would have to be weighed against the risk of inducing cerebral hypotension and iatrogenic stroke. In a post hoc analysis of the PROGRESS trial (15), investigators determined effects of achieved follow-up BP levels on stroke risk among 6105 normotensive and hypertensive individuals with previous stroke or transient ischemic attack. Stroke incidence declined with no evidence of a J curve, with progressively lower achieved follow-up SBP throughout the range of blood pressures (112 mm Hg to 168 mm Hg). While this analysis reassures that lowering BP in a heterogeneous stroke population may not precipitate stroke in the recommended target of < 140/90 mm Hg, optimal blood pressure levels cannot be determined from this type of study analysis.

However, there are robust data from long-term cohort studies and randomized placebo controlled trials that show lowering BP is highly effective in the primary prevention of both hemorrhagic and ischemic stroke (16–20). In particular, more intensive therapy has been shown to prevent strokes better than less intensive therapy (RR, 0.80; 95%CI, 0.65 to 0.98) (21). There is Grade A and B randomized, clinical trial evidence confirming efficacy of thiazide diuretics, beta-adrenergic antagonists (β-blockers), angiotensin-converting enzyme (ACE) inhibitors and long-acting dihydropyridine calcium channel blockers (CCBs) for the prevention of stroke (see Section II of the CHEP Recommendations on Treatment and Prevention).

After the pilot INTERACT trial, the full Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial-2 (INTERACT-2) was conducted in Australasia and Europe, intending to provide more definitive evidence on whether BP lowering is beneficial to clinical outcomes (5). The INTERACT-2 enrolled 2839 individuals within 6 hours of spontaneous ICH. Investigators examined a strategy of lowering SBP within 1 hour of presentation to < 140 mm Hg compared with < 180 mm Hg; these targets were to be maintained for at least 7 days.

The Secondary Prevention of Small Subcortical Strokes (SPS3) trial (7) enrolled 3020 patients with magnetic resonance imaging-defined symptomatic lacunar infarctions (i.e., small subcortical strokes) and without surgically amenable ipsilateral carotid artery stenosis or high–risk cardio-embolic sources. Participants were enrolled 2 weeks after stroke and were randomized to < 130 mm Hg vs. 130–149 mm Hg SBP targets. After 3.7 years, there was no conclusive difference in either incidence of recurrent stroke (HR, 0.81; 95%CI, 0.64–1.03) or occurrence of adverse events (orthostatic syncope HR, 2.19; 95%CI, 0.76–6.27; all adverse events HR, 1.53; 95%CI, 0.80–2.93). The RTF noted the point estimates suggested lower recurrent stroke rates but higher adverse event rates in the < 130 mm Hg SBP target group, and concluded the strength of evidence did not warrant a target BP threshold lower than 140/90.

3. Treatment with an ACE inhibitor and thiazide/thiazide-like diuretic combination is preferred (Grade B).

The PROGRESS study demonstrated that active treatment with perindopril and indapamide after the acute phase of a non-disabling stroke or TIA lowered BP by 9/4 mm Hg and reduced the risk of recurrent stroke over 4 years (RRR, 28%; 95%CI, 17% to 38%) (10). Benefits of therapy were seen in both hypertensive and non-hypertensive patients.

4. For patients with stroke, the combination of an ACE inhibitor and ARB is not recommended (Grade B).

The ONTARGET study (30) provided an opportunity to evaluate the role of an ACE inhibitor and ARB combination in the cerebrovascular disease population because approximately 20% of the ONTARGET study population had a previous stroke. There was no benefit from an ARB and ACE inhibitor combination over ACE inhibitor alone, and combination therapy was further associated with a greater risk for hypotension and renal impairment. Thus, the CHEP has a Grade B recommendation to avoid this combination in patients with previous stroke or transient ischemic attack.

5. For patients with intracerebral hemorrhage in the hyperacute phase (in the first 24 hours) SBP lowering to <140 mmHg should be avoided due to an absence of benefit (relative to a target of <180 mmHg) (Grade A; new guideline) and some suggestion of harm.

BP is often elevated following intracerebral hemorrhage (ICH). In recent years, several trials have studied the impact of BP lowering in the context of ICH. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT)-2 enrolled 2,839 patients within 6 hours of spontaneous ICH, and compared the SBP targets of <140 mmHg vs. <180 mmHg (79). Targets were applied within the first hour of presentation and maintained for 7 days.

No statistical difference was observed between the two strategies for the primary outcome, a composite of death or stroke-related disability at 90 days (52.0% vs. 55.6% for intensive compared to standard treatment, respectively; odds ratio [OR] 0.87; 95% CI, 0.75 to 1.01). In the Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 trial, 1,000 patients presenting within 4.5 hours of spontaneous ICH were randomly assigned to SBP targets of 110 to 139 mmHg vs. 140 to 179 mmHg for the first 24 hours (80). The primary outcome was the same as in INTERACT-2. There was no difference between the 2 treatment strategies for the main outcome, and the trial was terminated early because of futility.

In addition, there was a trend towards more adverse events in the lower SBP target arm. Considered together, these 2 important trials demonstrate no measurable benefit to lowering SBP <140 mmHg in the acute period following spontaneous ICH. There is no trial evidence to delineate an appropriate SBP target, if an, above 140 mmHg. All trials to date have followed the convention in limiting SBP increases beyond 180 mmHg in their control arms.

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