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Antihypertensive therapy for secondary stroke prevention

Antihypertensive therapy for secondary stroke prevention
Literature review current through: Jan 2024.
This topic last updated: Nov 03, 2022.

INTRODUCTION — Hypertension is a major risk factor for stroke and transient ischemic attack (TIA) [1]. The risk can be reduced by persistent correction of the hypertension [2]. (See "Overview of primary prevention of cardiovascular disease".)

In addition, among patients who have had a stroke or TIA, antihypertensive therapy can reduce the rate of recurrence. (See 'Management after the acute phase of stroke' below.)

This topic will review the management of blood pressure for prevention of a recurrent stroke, including the timing of initiation (or reinstatement) of antihypertensive therapy following stroke or TIA, the choice of antihypertensive drugs, and the management of nonhypertensive patients. Long-term goal blood pressure in patients who have cerebrovascular disease is presented elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Prior history of ischemic stroke or transient ischemic attack'.)

The diagnosis of stroke subtypes and risk factor reduction for the secondary prevention of stroke other than blood pressure control are discussed separately:

(See "Clinical diagnosis of stroke subtypes".)

(See "Overview of secondary prevention of ischemic stroke".)

TREATMENT IN THE ACUTE PHASE OF STROKE — Treatment of hypertension may be an immediate concern in patients with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. However, blood pressure management in the acute phase of stroke is different from chronic therapy. Acute blood pressure management is discussed in detail elsewhere for each of the major stroke types:

(See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.)

(See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.)

(See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.)

The following sections provide a brief overview of blood pressure management in the acute phase of stroke, which necessarily transitions to decisions about long-term antihypertensive management.

Who should be treated with pharmacologic therapy? — Similar to American Heart Association (AHA) and American Stroke Association (ASA) guidelines, we recommend resumption of antihypertensive therapy for previously treated, neurologically stable patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events [3]. In addition, we recommend initiation of antihypertensive therapy for previously untreated, neurologically stable patients with any type of stroke or transient ischemic attack (TIA) who have an established blood pressure that is above goal (table 1) [4].

When to initiate (or reinstate) antihypertensive therapy — The appropriate time to initiate or reinstate antihypertensive drug therapy in hypertensive patients who have had a stroke or TIA can vary according to a number of factors, including stroke mechanism (eg, whether the stroke was ischemic or hemorrhagic), neurologic stability, and comorbid medical problems.

Patients with transient ischemic attack – In patients with a TIA, who by definition have recovered to their neurologic baseline and have no other evidence of infarction, we initiate (or reinstate) oral antihypertensive drug therapy without further delay. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".)

Patients with ischemic stroke – In patients with acute ischemic stroke, elevated blood pressures are typically tolerated (ie, "permissive hypertension") during the first 24 to 48 hours (the acute phase of an ischemic stroke) to theoretically augment cerebral blood flow and reduce expansion of the ischemic infarct core. Exceptions that require treatment are patients with extreme hypertension (>220/120 mmHg), with other acute hypertension-related end-organ failure (eg, cardiac), patients with active ischemic coronary disease, patients with aortic dissection, patients with pre-eclampsia/eclampsia, and patients who are candidates for reperfusion therapy who have persistent blood pressure elevation greater than 185/110 mmHg. (See "Initial assessment and management of acute stroke", section on 'Blood pressure in acute ischemic stroke' and "Management of acute type B aortic dissection".)

Beyond the acute period, we approach the time to start or resume antihypertensive medication as follows:

For patients with hypertension who are neurologically improving or stable and able to safely swallow oral medications or receive them through a feeding tube, we initiate (or reinstate) antihypertensive drug therapy 24 to 48 hours after ischemic stroke onset and during hospitalization.

For patients with hypertension who are neurologically unstable with fluctuating deficits or progressive deterioration, we delay starting or resuming antihypertensive drug therapy until the stroke-related deficits have stabilized or reached a nadir since blood pressure lowering may induce ischemic symptoms. This is discussed in detail separately. (See "Initial assessment and management of acute stroke", section on 'Blood pressure in acute ischemic stroke'.)

Patients with intracerebral hemorrhage – In patients with spontaneous intracerebral hemorrhage (ICH), there is often a need for intravenous antihypertensive treatment during the acute phase (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'). Intravenous antihypertensive therapy is then transitioned to oral therapy, when appropriate.

Patients with subarachnoid hemorrhage – In patients with subarachnoid hemorrhage, who are typically managed initially in the intensive care unit, antihypertensive therapy for secondary prevention is started if cerebral perfusion pressure is judged to be adequate, either by direct measurement or by an assessment of the patient's cognitive status. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.)

MANAGEMENT AFTER THE ACUTE PHASE OF STROKE

Selection of long-term antihypertensive medication — In patients with a history of stroke or transient ischemic attack (TIA), antihypertensive therapy can prevent future strokes and cardiovascular death. The choice of drug is similar in patients who have had a previous stroke or TIA as in other hypertensive patients:

Monotherapy is recommended when blood pressure is <20/10 mmHg above goal. Although the largest studies of secondary stroke prevention examined the effect of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and diuretics, there is no compelling evidence favoring one class of antihypertensive drugs over another as monotherapy for secondary prevention in such patients. ACE inhibitors, ARBs, calcium channel blockers, and diuretics are all reasonable options for initial antihypertensive monotherapy. (See "Choice of drug therapy in primary (essential) hypertension".)

There is some evidence from clinical trials that beta blockers may not reduce stroke risk compared with angiotensin inhibitors (ACE inhibitor or ARB), calcium channel blockers, and, in some trials, placebo [5-7]. Thus, unless there is a compelling indication for their use, beta blockers should not be used as monotherapy for prevention of recurrent stroke.

Combination therapy is recommended when blood pressure is ≥20/10 mmHg above goal. We use the combination of an angiotensin inhibitor plus a long-acting dihydropyridine calcium channel blocker among patients who should initiate therapy with two agents. This approach is consistent with our recommendations for other hypertensive patients who have not had a stroke or TIA. (See "Choice of drug therapy in primary (essential) hypertension".)

In a meta-analysis of eight trials and more than 35,000 patients with a prior stroke or TIA, antihypertensive drug therapy reduced the rate of stroke (8.7 versus 10.1 percent) and cardiovascular death (4.0 versus 4.7 percent) [8]. There was also a nonsignificantly lower incidence of major adverse cardiovascular events (13.6 versus 15.1 percent).

The largest studies included in this meta-analysis (the Perindopril Protection Against Recurrent Stroke Study [PROGRESS], Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS], and Post-stroke Antihypertensive Treatment Study [PATS] trials) examined ACE inhibitors, ARBs, and diuretics; therefore, many experts and the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines recommend ACE inhibitors and diuretics for patients with prior stroke or TIA [4,9-11]. In several meta-analyses, however, the effects of calcium channel blockers were not statistically different from those of angiotensin inhibitors and diuretics [12-14]. In addition, among patients who require two antihypertensive agents, a calcium channel blocker plus an ACE inhibitor (or ARB) is the ideal combination. (See "Choice of drug therapy in primary (essential) hypertension".)

Goal blood pressure

Patients with ischemic stroke or TIA and atherosclerotic disease — The majority of patients who have had an ischemic stroke or transient ischemic attack (TIA) are at high risk for a future atherosclerotic cardiovascular event. Thus, in most such patients, we use a more intensive blood pressure goal, if tolerated (table 1). Patients who become symptomatic with intensive blood pressure lowering may require a less intensive goal.

Goal blood pressure in these higher-risk patients is discussed in detail elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Prior history of ischemic stroke or transient ischemic attack'.)

Patients with ischemic stroke in the absence of atherosclerotic disease — We do not consider a stroke or TIA that was caused by a cardioembolic phenomenon (eg, atrial fibrillation) or by a paradoxical embolus as evidence of atherosclerotic cardiovascular disease.

Thus, in such patients who are not otherwise at high risk for a future atherosclerotic cardiovascular event, we use a less intensive goal blood pressure than we use for higher-risk patients (table 1). Goal blood pressure in these lower-risk patients is discussed in detail elsewhere. (See "Goal blood pressure in adults with hypertension", section on 'Goal blood pressure in lower-risk patients'.)

However, patients with cardioembolic stroke may have heart failure or other types of heart disease that would indicate lower blood pressure targets.

Patients with intracerebral hemorrhage — For prevention of recurrent intracerebral hemorrhage (ICH) in patients with spontaneous ICH, we suggest a more intensive blood pressure goal, similar to the goal in patients with ischemic stroke due to atherosclerotic disease (table 1).

In the PROGRESS trial, among the subgroup of 611 hypertensive patients with prior ICH, a modest reduction in blood pressure of 9/4 mmHg produced a 49 percent relative reduction in the risk for recurrent stroke (95% CI 18-68 percent) [15]. Post-hoc analyses found that the relationship of blood pressure lowering with reduced stroke risk was stronger for subjects with prior ICH than for those with prior ischemic stroke and that the lowest risk of recurrence was present in the patients with the lowest follow-up blood pressure levels [16]. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Blood pressure management'.)

Patients with subarachnoid hemorrhage — Hypertension is a major risk factor for subarachnoid hemorrhage. However, the optimal goal blood pressure for prevention of recurrent subarachnoid hemorrhage is unknown; for patients who are not otherwise at high risk for atherosclerotic cardiovascular events, a less intensive blood pressure goal as defined in the table is reasonable (table 1).

Rapidity by which goal is attained — Gradual blood pressure reduction (eg, approximately 10 percent per day, although there is no consensus on the definition of gradual lowering) is recommended in patients with known cerebrovascular disease or long-standing uncontrolled hypertension unless there is a hypertensive emergency.

The normal response to an acute reduction in blood pressure is to maintain tissue perfusion by autoregulatory precapillary vasodilation. Since flow is equal to pressure divided by resistance, parallel reductions in both parameters allow flow to be maintained. This response may be impaired in patients with chronic hypertension, including those who have not had a stroke.

Persistent hypertension leads to arteriolar thickening. In the cerebral and other circulations, this is in part an appropriate adaptation in that it prevents the increase in pressure from being transmitted to the capillary circulation [17].

However, arteriolar thickening can also limit the ability to maintain perfusion when the blood pressure is lowered with antihypertensive therapy since the vasodilator response is often impaired. As a result, the lower blood pressure limit at which cerebral perfusion is maintained is higher in hypertensive than in normotensive subjects (figure 1) [18]. In general, ischemic symptoms are not likely to occur unless the blood pressure is acutely reduced by more than 25 percent below the baseline level; gradual blood pressure reduction of approximately 10 percent per day is generally well tolerated.

Gradual blood pressure reduction can be aided by home blood pressure monitoring. (See "Evaluation and treatment of hypertensive emergencies in adults" and "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".)

RECOMMENDATIONS OF OTHERS — Guidelines for the prevention of recurrent stroke and transient ischemic attack (TIA) issued in 2021 by the American Stroke Association (ASA) and American Heart Association (AHA) recommend initiation of blood pressure therapy for previously untreated patients with ischemic stroke or TIA who, after the first few days (because blood pressure is typically elevated above baseline upon presentation), have an established blood pressure of ≥130 mmHg systolic or ≥80 mmHg diastolic [19]. The guidelines also recommend resumption of blood pressure therapy for previously treated patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events in those who have had an ischemic stroke or TIA and are beyond the first three days after stroke onset. The suggested goal blood pressure of <130/<80 mmHg is reasonable for secondary stroke prevention in all patients. European, Canadian, and Asian secondary stroke prevention guidelines have similar blood pressure goals as the United States guidelines [20].

For patients with intracerebral hemorrhage (ICH), 2022 guidelines from the AHA/ASA suggest a goal blood pressure of <130 mmHg systolic and <80 mmHg diastolic [21].

We generally agree with these recommendations, although our approach to goal blood pressure is more nuanced. (See "Goal blood pressure in adults with hypertension", section on 'Prior history of ischemic stroke or transient ischemic attack'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)")

Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Hypertension is a major risk factor for stroke and transient ischemic attack (TIA). The risk can be reduced by persistent correction of the hypertension. (See 'Introduction' above.)

After the acute phase of stroke, antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events. In addition, antihypertensive therapy should be initiated in previously untreated, neurologically stable patients with any type of stroke or TIA who have an established blood pressure that is above goal (table 1). (See 'Who should be treated with pharmacologic therapy?' above.)

The appropriate time to initiate or reinstate antihypertensive drug therapy in hypertensive patients who have had a stroke or TIA varies (see 'When to initiate (or reinstate) antihypertensive therapy' above):

In patients with a TIA, we initiate (or reinstate) oral antihypertensive drug therapy without further delay.

For patients with acute ischemic stroke and hypertension who are neurologically improving or stable and able to safely swallow oral medications or receive them through a feeding tube, we initiate (or reinstate) antihypertensive drug therapy 24 to 48 hours after ischemic stroke onset and during hospitalization. For patients with hypertension who are neurologically unstable with fluctuating deficits or progressive deterioration, we delay starting or resuming antihypertensive drug therapy until the stroke-related deficits have stabilized or reached a nadir since blood pressure lowering may induce ischemic symptoms.

In patients with spontaneous intracerebral hemorrhage (ICH), there is often a need for intravenous antihypertensive treatment during the acute phase. In patients with subarachnoid hemorrhage, antihypertensive therapy for secondary prevention is begun if cerebral perfusion pressure is judged to be adequate, either by direct measurement or by an assessment of the patient's cognitive status.

The choice of drug is similar in patients who have had a previous stroke or TIA as in other hypertensive patients. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers, and diuretics are all reasonable options for initial antihypertensive monotherapy. (See 'Selection of long-term antihypertensive medication' above.)

The majority of patients who have had an ischemic stroke or TIA are at high risk for a future atherosclerotic cardiovascular event. Thus, in most such patients, we use a more intensive blood pressure goal, if tolerated (table 1). Patients who become symptomatic with intensive blood pressure lowering may require a less intensive goal. (See 'Patients with ischemic stroke or TIA and atherosclerotic disease' above.)

We do not consider an ischemic stroke or TIA that was caused by a cardioembolic phenomenon (eg, atrial fibrillation) or by a paradoxical embolus as evidence of atherosclerotic cardiovascular disease. Thus, in such patients who are not otherwise at high risk for a future atherosclerotic cardiovascular event, we use a less intensive goal blood pressure than we use for higher-risk patients (table 1). (See 'Patients with ischemic stroke in the absence of atherosclerotic disease' above.)

For prevention of recurrent ICH in patients with spontaneous ICH, we suggest a more intensive blood pressure goal, similar to the goal in patients with ischemic stroke due to atherosclerotic disease (table 1). (See 'Patients with intracerebral hemorrhage' above.)

The optimal goal blood pressure for prevention of recurrent subarachnoid hemorrhage is unknown; for patients who are not otherwise at high risk for atherosclerotic cardiovascular events, a less intensive blood pressure goal as defined in the table is reasonable (table 1). (See 'Patients with subarachnoid hemorrhage' above.)

Gradual blood pressure reduction (eg, approximately 10 percent per day, although there is no consensus on the definition of gradual lowering) is recommended in patients with known cerebrovascular disease or long-standing uncontrolled hypertension unless there is a hypertensive emergency. (See 'Rapidity by which goal is attained' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Norman M Kaplan, MD, who contributed to earlier versions of this topic review.

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