Antihypertensive therapy to prevent recurrent stroke or transient ischemic attack

Author
Norman M Kaplan, MD
Section Editors
George L Bakris, MD
Scott E Kasner, MD
Deputy Editors
John P Forman, MD, MSc
John F Dashe, MD, PhD
Disclosures: Norman M Kaplan, MD Nothing to disclose. George L Bakris, MD Grant/Research/Clinical Trial
Support: Bayer, Boeringher-Ingelheim, Relypsa, Vascular Dynamics, Medtronic [diabetic neuropathy, diabetes,
hypertension (empagliflozin, patriromer)]. Consultant/Advisory Boards: Astra Zeneca, Arbor Pharma, Bayer,
Boeringher-Ingelheim, Relypsa, Vascular Dynamics, Medtronic [diabetic neuropathy, diabetes, hypertension
(empagliflozin, patriromer)]. Scott E Kasner, MD Grant/Research/Clinical Trial Support: WL Gore and Associates
[PFO, stroke (HELEX, GSO devices)]; AstraZeneca [Stroke (Ticagrelor)]. Consultant/Advisory Boards: Medtronic
[Stroke, atrial fibrillation (CoreValve, REVEAL)]; Merck [Stroke]; Pfizer [Stroke]; Novartis [Stroke]; GSK [Stroke];
AbbVie [Stroke]; Daiichi Sankyo [Stroke]; Boehringer Ingelheim [Stroke]. John P Forman, MD, MSc Nothing to
disclose. John F Dashe, MD, PhD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Oct 2015. | This topic last updated: Sep 02, 2014.
INTRODUCTION Hypertension is a major risk factor for stroke and transient ischemic attack,
with the risk increasing with every rise in systolic blood pressure (BP) [1]. The cardiovascular risk
can be minimized by persistent correction of the hypertension [2]. (See "Overview of primary
prevention of coronary heart disease and stroke", section on 'Hypertension
control' and "Hypertension: Who should be treated?", section on 'Decreased cardiovascular risk
with therapy'.)
Once the stroke has stabilized, antihypertensive therapy can reduce the rate of recurrent
stroke, independent of the baseline blood pressure. (See 'Trials of long-term antihypertensive
therapy' below.)
This topic will review the long-term role of antihypertensive therapy for prevention of a recurrent
stroke. The major randomized trials will be reviewed followed by discussions of specific issues,
such as when to lower the blood pressure, the choice of antihypertensive drugs, the blood
pressure goal in relation to the presence or absence of large artery stenosis, and the rate of blood
pressure reduction.
The approach is determined by the degree of hypertension and by the type of stroke that is
present: thromboembolic stroke; or intracerebral or subarachnoid hemorrhage. 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" and "Overview of secondary prevention of ischemic stroke".)
Acute stroke Treatment of hypertension may be an immediate concern in patients with an
acute ischemic stroke and those with a subarachnoid or intracerebral hemorrhage. Blood
pressure management in the acute phase of stroke is different from chronic therapy and is
discussed in detail elsewhere. (See "Initial assessment and management of acute stroke", section

on 'Blood pressure management' and "Spontaneous intracerebral hemorrhage: Treatment and

prognosis", section on 'Blood pressure' and "Treatment of aneurysmal subarachnoid
hemorrhage", section on 'Intracranial pressure'.)
TRIALS OF LONG-TERM ANTIHYPERTENSIVE THERAPY The efficacy of long-term
antihypertensive therapy to prevent recurrent stroke as well as other cardiovascular complications
has been evaluated in a number of randomized, placebo-controlled trials [3]. All of the major trials
included an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB). This section will review the findings in the two largest placebo-controlled trials and in metaanalyses. Trials comparing the efficacy of different antihypertensive drugs are discussed below.
(See 'Which antihypertensive drugs should be used?' below.)
PROGRESS trial The PROGRESS trial included over 6100 patients (mean age 64 years) with
an ischemic or, less often, hemorrhagic stroke or transient ischemic attack within the previous
five years (median eight months) [4]. The patients were randomly assigned to perindopril or
placebo; the diuretic indapamide was added as necessary in the perindopril group. The mean
baseline blood pressure was 147/86 mmHg; approximately one-half of patients were hypertensive
(mean 159/94 mmHg), while remaining patients had high-normal values (mean 136/79 mmHg).
The following findings were noted [4,5]:
A reduction in blood pressure of 9/4 mmHg in the perindopril group compared with placebo
decreased the rate of the primary end point of fatal or nonfatal stroke (10 versus 14 percent
with placebo, relative risk reduction 28 percent, 95% CI 17 to 38 percent). Active therapy
also reduced the risk of all cardiovascular events by 26 percent, and, although the number
of events was small, significantly reduced the rate of intracerebral hemorrhage by 50 percent
(1.2 versus 2.4 percent).
The stroke prevention benefit was related to the degree of blood pressure reduction, being
most prominent (relative risk reduction 43 percent) and statistically significant in patients
treated with combination therapy (perindopril plus indapamide) who had a 12/5 mmHg mean
reduction in blood pressure compared with placebo. In comparison, patients treated with
perindopril alone had only a 5/3 mmHg mean reduction in blood pressure and a small and
not significant benefit (relative risk reduction 5 percent). The reductions in blood pressure
were similar in the hypertensive and high-normal blood pressure groups.
The reduction in recurrent stroke with antihypertensive therapy was seen in both
hypertensive (11.1 versus 16.2 percent, relative risk reduction 32 percent) and
nonhypertensive patients (9.1 versus 11.5 percent, relative risk reduction 21 percent). Thus,
both the risk of stroke and the absolute benefit from antihypertensive therapy were greater
in the hypertensive patients. Similar findings were noted when all major vascular events
were evaluated.
A post hoc analysis from PROGRESS addressed the issue of whether the baseline blood
pressure affected the response to antihypertensive therapy, including the possibility that patients
with normal blood pressure (<120 mmHg systolic) at baseline might be harmed from such therapy
[6]. Among patients in the combination therapy arm, the relative risk reduction in stroke
was similar at all levels of baseline systolic pressure (ranging from <120 to 160 mmHg).
Although this suggests no harm from therapy in patients with low baseline pressures, there were
so few events (six) in the subgroup of 146 patients with a systolic pressure <120 mmHg at
baseline that one cannot have confidence in the results.
There was also a suggestion that the risk of recurrent stroke was lowest in patients in the lowest
quartile of attained blood pressure (median 112/72 mmHg) and progressively higher at higher

blood pressures [6]. However, the trial was not designed to evaluate different blood pressure
goals. (See 'Goal blood pressure' below.)
The value of perindopril-based therapy in the subset of patients in PROGRESS who had atrial
fibrillation is discussed separately. (See "Stroke in patients with atrial fibrillation", section on
'Control of hypertension'.)
PRoFESS trial The PRoFESS trial (Prevention Regimen for Effectively Avoiding Second
Strokes) randomly assigned 20,332 patients with noncardioembolic ischemic stroke to receive
either fixed dose telmisartan (80 mg daily) or placebo [7]. All other antihypertensive drugs, except
for angiotensin receptor blockers, were permitted as add-on therapy. Approximately threequarters of patients had a prior history of hypertension, and the average blood pressure
was 144/84 mmHg in both groups at baseline.
At an average follow-up of 2.5 years, there was no significant difference between
the telmisartan and placebo groups in the primary outcome of recurrent stroke (8.7 versus 9.2
percent, hazard ratio [HR] 0.95, 95% CI 0.86-1.04), or in secondary outcomes including major
cardiovascular events (13.5 versus 14.4 percent, HR 0.94, 95% CI 0.87-1.01). However,
significant benefit compared with placebo would not have been expected since telmisartan
therapy only reduced the blood pressure by an average 3.8/2.0 mmHg more than placebo. This
finding is similar to the lack or benefit with perindopril monotherapy in the PROGRESS trial, in
which in the mean difference in attained blood pressure was only 5/3 mmHg compared with
placebo. (See 'PROGRESS trial' above.)
In addition to the fixed telmisartan dose and the fact that most patients in the placebo group
received antihypertensive therapy, other factors that could have contributed to the small
difference in attained blood pressures in the two groups include cessation of therapy because of
side effects in some patients treated with telmisartan, and the initiation of antihypertensive therapy
in some patients in the placebo group because of the development of hypertension [7].
PATS trial The PATS trial (Post-stroke Antihypertensive Treatment Study) randomly assigned
5665 Chinese patients with a history of stroke (mostly ischemic) or TIA to treatment
with indapamide (2.5 mg daily) or placebo [8]. The average interval from stroke to randomization
was 31 months, and the average blood pressure at randomization was 154/93mmHg. At a
median follow-up of two years, active treatment reduced blood pressure by a mean of 6.8/3.3
mmHg. There were significantly fewer strokes in the active treatment compared with the placebo
group (143 versus 219, hazard ratio [HR] 0.69, 95% CI 0.540.89). In addition, indapamide
treatment reduced the rate of cardiovascular events (HR, 0.75, 95% CI 0.890.62). Limitations of
this trial include premature termination and a high drop-out rate (28 percent).
Meta-analyses The limited blood pressure reduction and lack of significant benefit in
PRoFESS is important when considering the results of meta-analyses, since PRoFESS was by
far the largest study and accounted for more than one-half of patients in the trials of secondary
stroke prevention. As illustrated by the following observations, the benefit of antihypertensive
therapy increased progressively as the proportion of patients from PRoFESS became smaller:
A meta-analysis of eight placebo-controlled trials of angiotensin inhibition included almost
30,000 patients, most of whom came from the PRoFESS trial [9]. Antihypertensive therapy
(most of the included trials in this meta-analysis compared angiotensin inhibitors with
placebo) resulted in a significant reduction in major cardiovascular events (13.1 versus 14.7
percent, risk ratio 0.92, 95% CI 0.86-0.98) and an almost significant reduction in recurrent
stroke (9.0 versus 9.6 percent, risk ratio 0.94, 95% CI 0.87-1.01).

The second meta-analysis was published in 2011 and included 40,300 patients from 16
randomized trials of antihypertensive therapy in patients with a prior stroke, approximately
one-half of whom came from PRoFESS [5]. Antihypertensive therapy was associated with
a significant reduction in recurrent stroke (relative risk 0.81, 95% CI 0.73-0.91).
APPROACH TO ANTIHYPERTENSIVE THERAPY A variety of questions must be addressed
when considering the role of antihypertensive therapy in patients who have had a stroke or
transient ischemic attack (TIA):
Which patients should be treated?
When should therapy be initiated?
Which antihypertensive drugs should be used?
What is the goal blood pressure?
Regardless of the regimen, blood pressure reduction should be gradual. (See 'Gradual blood
pressure reduction' below.)
Which patients should be treated? In accord with AHA/ASA guidelines, we recommend
resumption of antihypertensive therapy for previously treated patients with known hypertension
for both prevention of recurrent stroke and prevention of other vascular events [10]. In addition,
we recommend initiation of antihypertensive therapy for previously untreated patients with any
type of ischemic stroke or TIA who have an established blood pressure 140 mmHg systolic or
90 mmHg diastolic. (See'AHA/ASA guidelines for the Prevention of Recurrent Stroke' below.)
Unlike the 2014 AHA/ASA guidelines, we suggest (a weaker recommendation) initiation of
antihypertensive therapy for previously untreated patients with ischemic stroke or TIA of
atherothrombotic, lacunar (small vessel occlusive), or cryptogenic type, whose baseline blood
pressure is >120 mmHg systolic or >70 mmHg diastolic. This recommendation is based upon
observations in randomized trials, such as PROGRESS, that the relative risk reduction in stroke
with antihypertensive therapy was similar at all levels of baseline systolic pressure (ranging from
<120 to 160 mmHg) [6].
We do not suggest antihypertensive therapy in the following settings:
Nonhypertensive patients (ie, blood pressure <140/90 mmHg) who have had a stroke or
TIA due to a cardioembolic phenomenon (eg, atrial fibrillation) or paradoxical embolus.
Untreated patients whose baseline blood pressure <120/70 mmHg. These patients have
an increased risk of recurrent stroke if their blood pressure is further reduced compared with
patients who have higher blood pressures. (See 'Data from randomized trials' below.)
When should therapy be initiated? The timing of in-hospital initiation or resumption of
antihypertensive therapy during the acute phase of stroke is discussed in detail elsewhere.
(See "Initial assessment and management of acute stroke", section on 'Blood pressure
management'.)
For patients who have not been treated in the hospital, antihypertensive therapy should be
initiated or reinitiated as an outpatient in all appropriate patients, as noted in the preceding
section. (See 'Which patients should be treated?' above.)
Which antihypertensive drugs should be used? Our preferences for antihypertensive
therapy in patients who have had a stroke or TIA differ according to whether monotherapy or
combination antihypertensive therapy is required to achieve an adequate reduction in blood
pressure.

Monotherapy There is no compelling evidence favoring one class of antihypertensive drugs

over another as monotherapy for secondary prevention in patients who have had a stroke [11]. In
a meta-analysis of seven randomized trials of almost 30,000 patients with a prior history of stroke,
therapy with angiotensin inhibitors (ACE inhibitors or angiotensin receptor blockers) significantly,
but modestly, reduced the risk of recurrent stroke (9.0 versus 9.7 percent) and major vascular
events (14.3 versus 15.7 percent) compared with placebo [9]. In contrast, there was no significant
benefit of angiotensin inhibitors in the three trials that compared these agents with calcium
channel blockers. In addition, calcium channel blockers may be superior to angiotensin inhibitors
for the primary prevention of stroke [12]. Finally, the results of the PATS trial (see 'PATS
trial' above) suggest that diuretics are effective for secondary stroke risk reduction.
Based upon these observations, both angiotensin inhibitors (most trials have used ACE
inhibitors), calcium channel blockers, and diuretics are reasonable options for initial
antihypertensive monotherapy in patients who have had a stroke. There is some evidence from
clinical trials that beta blockers may not reduce stroke risk compared with angiotensin inhibitors,
calcium channel blockers, and, in some trials, placebo [13-15]. Thus, unless there is a compelling
indication for their use, beta blockers should not be used for prevention of recurrent stroke.
Combination therapy A separate issue is the choice of drugs when combination therapy is
necessary. We recommend the combination of an angiotensin inhibitor plus a long-acting
dihydropyridine calcium channel blocker. This recommendation contrasts with the
2014 AHA/ASA guidelines that recommend an ACE inhibitor plus a diuretic [10]. (See 'AHA/ASA
guidelines for the Prevention of Recurrent Stroke' below.)
However, the AHA/ASA guidelines did not mention the ACCOMPLISH trial of combination
antihypertensive therapy in hypertensive patients who required two drugs and were at high risk
for a cardiovascular event (defined as a history of coronary disease, stroke, peripheral arterial
disease, or diabetes or the presence of left ventricular hypertrophy or impaired renal function)
[16]. Patients in ACCOMPLISH were treated with combined therapy with benazepril plus
either amlodipine or hydrochlorothiazideand the attained blood pressures were similar in the two
groups. History of a prior stroke was present in 13 percent. The trial was terminated early at 36
months because of worse outcomes in the hydrochlorothiazide group that exceeded a
prespecified stopping rule. Benazepril plus amlodipine, compared with benazepril plus
hydrochlorothiazide, significantly reduced the incidence of the primary endpoint of cardiovascular
death or cardiovascular complications (9.6 versus 11.8 percent, hazard ratio [HR] 0.80, 95% CI
0.72-0.90) and the secondary end point of cardiovascular death or nonfatal myocardial infarction
or stroke (5.0 versus 6.3 percent, HR 0.79, 95% CI 0.67-0.92).
Based upon these observations, we recommend the combination of an angiotensin inhibitor
plus a long-acting dihydropyridine calcium channel blocker rather than a diuretic as the
combination antihypertensive regimen of choice in the treatment of patients who have had a
stroke. This recommendation assumes that the patient can tolerate and does not have a
contraindication to the use of either drug class and does not have a specific indication for the use
of another class of antihypertensive drugs. (See "Choice of drug therapy in primary (essential)
hypertension: Recommendations", section on 'Indications for specific drugs'.)
Goal blood pressure Issues related to goal blood pressure, both in general and specifically
in patients with atherosclerotic cardiovascular disease are discussed in detail elsewhere.
(See "What is goal blood pressure in the treatment of hypertension?" and "What is the goal blood
pressure in patients with atherosclerotic cardiovascular disease?", section on 'Goal blood
pressure'.)

This section will review goal blood pressure in patients who have had a stroke or transient
ischemic attack (TIA). As will be discussed in greater detail below, the recommendations depend
upon whether or not the event was due to a hemodynamically significant stenosis in a large
cervicocephalic artery (ie, internal carotid, middle cerebral, vertebral, or basilar artery).
In patients with hemodynamically significant large artery disease, we suggest cautious
blood pressure lowering as tolerated but without a specific blood pressure goal other than a
minimum reduction of 10/5 mmHg. However, in such patients whose initial blood pressure
is less than 120/70, we do not give antihypertensive therapy.
In patients without hemodynamically significant large artery stenosis, we take the
following approach:
We recommend lowering the blood pressure a minimum of 10/5 mmHg in nearly all
patients. However, in such patients whose initial blood pressure is less than 120/70, we
do not give antihypertensive therapy. (See 'Which patients should be treated?' above
and 'AHA/ASA guidelines for the Prevention of Recurrent Stroke' below.)
In patients with underlying hypertension, we recommend a goal blood pressure of less
than 140/90 mmHg compared with higher pressures and we suggest (a weaker
recommendation) lowering the systolic pressure below 130 to 135 mmHg if it can be
achieved without producing significant side effects. The evidence supporting this
approach in patients with atherosclerotic cardiovascular disease in general is
discussed in detail elsewhere. (See "What is the goal blood pressure in patients with
atherosclerotic cardiovascular disease?", section on 'Goal blood pressure'.)
For patients with recent small vessel (ie, lacunar) ischemic stroke, we suggest (a weak
recommendation) lowering the systolic blood pressure below 130 mmHg.
Data from randomized trials A number of trials, some of which have been cited above,
evaluated the relationship between blood pressure and cardiovascular outcomes in patients with
a prior stroke. The findings have addressed both the degree of blood pressure reduction from
baseline and the absolute level of blood pressure attained, with some differing results.
The main trial evaluating specific blood pressure targets in patients with ischemic stroke was
SPS3, which randomly assigned 3020 patients (mean age 63 years) with recent lacunar (ie, small
vessel) infarction to a systolic blood pressure target of either 130 to 149 mmHg or less than 130
mmHg [17]. Three-quarters of the patients were hypertensive at study entry. Treatment was open
label, using drugs from each of the major classes of antihypertensive medications prescribed by
the local clinician. At one year, the achieved average systolic blood pressures for the higher and
lower target groups were 138 and 127 mmHg, respectively, and the mean 11 mmHg difference
between the groups was sustained for the duration of the study. Patients assigned to the lower
blood pressure target group were treated with a greater number of antihypertensive medications
compared with the higher target group (mean 2.4 versus 1.8). The following outcomes were
reported [17]:
At study end, with a mean follow-up of 3.7 years, there were 277 first recurrent strokes;
the annualized rate of all recurrent stroke was nonsignificantly reduced in the lower target
compared with the higher target blood pressure group (2.25 versus 2.77 percent, hazard
ratio 0.81, 95% CI 0.64-1.03). Similarly, the rate of a composite outcome of myocardial
infarction or vascular death was nonsignificantly reduced in the lower blood pressure group.
The rate of intracerebral hemorrhage was significantly reduced in the lower target blood
pressure group, but the small number of events (n = 22) limits the strength of this finding.

There were few serious adverse events in the higher and lower target groups (annualized
rate 0.4 versus 0.3 percent), and the difference was not significant.
Thus, the SPS3 results suggest but do not establish that a systolic blood pressure target of less
than 130 mmHg is beneficial and safe for preventing recurrent stroke in patients with small vessel
ischemic stroke.
In addition to SPS3, findings from other trials also suggest that lower blood pressures are
associated with better outcomes. However, a major limitation is that none of the following trials
except for ACCORD BP was specifically designed to determine the optimal goal blood pressure.
Analyses according to the presence or absence of a large cervicocephalic artery stenosis were
not performed:
A meta-regression analysis of nine randomized trials found that each 10 mmHg reduction
in systolic pressure was associated with a 33 percent (95% CI 9 to 51 percent) reduction in
the risk of recurrent stroke, with the lowest risk occurring at an attained systolic pressure
below 120 mmHg [5].
Similar findings were noted a review from the United Kingdom Transient Ischemic Attack
trial: there was a 28 percent reduction in recurrent stroke for every 10 mmHg reduction in
systolic pressure and a 34 percent reduction for every 5 mmHg reduction in diastolic
pressure [18].
In the PROGRESS trial, the risk of recurrent stroke was lowest in patients in the lowest
quartile of attained blood pressure (median 112/72 mmHg) and progressively higher at
higher blood pressures [6]. (See 'PROGRESS trial' above.)
In a meta-analysis of 25 randomized trials of antihypertensive therapy versus placebo in
patients with a history of cardiovascular disease without hypertension, the treated patients
had significantly better cardiovascular outcomes including reductions in cardiovascular
events (relative risk 0.77, 95% CI 0.61-0.98), cardiovascular mortality (relative risk 0.83,
95% CI 0.69-0.99), and stroke (relative risk, 0.80, 95% CI 0.69-0.93) [19]. The absolute
reduction in stroke risk was 7.7 per 1000 persons.
These observations are consistent with the findings in the ACCORD BP trial of 4733 patients with
type 2 diabetes plus other cardiovascular risk factors; prior stroke was uncommon [20]. The
patients were randomly assigned to a goal systolic pressure of less than 140 or less than 120
mmHg and the mean attained systolic pressures were 134 and 119 mmHg, respectively. At a
mean follow-up of 4.7 years, there was no overall cardiovascular benefit of lowering the systolic
pressure below 120 mmHg but, on subset analysis, there was a small but significant reduction in
the annual rate of stroke (0.32 versus 0.53 percent, hazard ratio 0.59). More aggressive therapy
was also associated with significantly higher rate of serious adverse effects attributable to
antihypertensive drugs (3.3 versus 1.3 percent).
In contrast to these observations, harm rather than benefit from an attained systolic pressure
below 120 mmHg was noted an analysis from the PRoFESS trial cited above (by far the largest
trial) in which the average reduction in blood pressure with telmisartan therapy was only 3.8/2.0
mmHg more than with placebo [21]. (See'PRoFESS trial' above.)
At a mean follow-up of 2.5 years, patients with a post-baseline mean systolic pressure of 130 to
139 mmHg had the lowest rate of recurrent stroke and the lowest rate of a composite outcome of
stroke, myocardial infarction, or vascular death. Patients with a mean systolic pressure of 120 to
129 mmHg had slightly but nonsignificantly higher rates of recurrent stroke, while the risk of
recurrent stroke was significantly increased in patients with mean systolic blood pressures of less
than 120 mmHg systolic (adjusted hazard ratio 1.29, 95% CI 1.07-1.56), 140 to 149 mmHg

systolic (adjusted hazard ratio 1.23), and 150 mmHg systolic (adjusted hazard ratio 2.08). The
same groups had a similar increase in risk for the composite end point of stroke, myocardial
infarction, or vascular death.
As discussed in the following sections, the goal blood pressure depends upon whether or not the
patient has hemodynamically significant large artery stenosis, which some have defined on
imaging studies as 80 percent stenosis and/or poor collateral flow (if it can be detected).
(See "Evaluation of carotid artery stenosis".)
Patients with hemodynamically significant large artery stenosis Identifying
hemodynamically or clinically significant stenosis in a large cervicocephalic artery (internal
carotid, middle cerebral, vertebral, or basilar artery) is important clinically since these patients
have an increased long-term risk of recurrent stroke and may develop ischemic symptoms after
blood pressure lowering. This was illustrated in a study of 102 patients who had a history of
ischemic stroke of transient ischemic attack (TIA) and a large artery stenosis of 50 percent or
more [22]. Hemodynamically significant was defined clinically as the occurrence of symptoms
related to the stenosis during a change of position from supine to prone, following effort, or after
the introduction or increase in dose of an antihypertensive drug. The rate of recurrent stroke or
TIA in the territory of the stenotic artery at two years was 61 percent in patients with a
hemodynamically significant stenosis compared with 32 percent in patients without a significant
stenosis.
There is no consensus regarding the criteria for defining hemodynamically significant stenosis. In
addition to the clinical criteria used in the preceding study, some have used criteria based upon
imaging studies. As an example, we have used the following criteria: 80 percent
stenosis and/or poor collateral flow (if collateral flow can be detected). Others have used
parameters such as cerebral blood volume and oxygen extraction [23].
Another problem is that, even in patients at increased risk, there is currently no reliable method
of determining which patients can safely tolerate intensive blood pressure lowering.
In summary, in patients thought to have a hemodynamically significant stenosis of a large
cervicocerebral artery based upon one or more of the above criteria, we suggest cautious blood
pressure lowering as tolerated but without a specific blood pressure goal other than a minimum
reduction of 10/5 mmHg below the previous baseline.
The patient should be carefully monitored for hypotensive or neurologic symptoms caused by
either failure of autoregulation of cerebral blood flow or by hemodynamic compromise due to large
vessel stenosis. If the patient develops recurrent neurologic symptoms referable to a stenotic
artery when the blood pressure is lowered below a particular threshold, we recommend
management to maintain blood pressure above that threshold. (See 'Gradual blood pressure
reduction' below.)
If a hemodynamically significant stenosis of an extracranial carotid artery is corrected by
endarterectomy or stenting, we attempt to gradually achieve the blood pressure goals described
in the following section on patients without hemodynamically significant large artery stenosis in
order to reduce the risks of recurrent stroke and other cardiovascular events.
Patients without hemodynamically significant large artery stenosis In patients who have
had a stroke or transient ischemic attack that did not result from a hemodynamically significant
large cervicocephalic artery stenosis as defined in the preceding paragraph, our
recommendations for goal blood pressure are similar to those in other patients with atherosclerotic
cardiovascular disease:

We recommend lowering the blood pressure a minimum of 10/5 mmHg in all patients.
However, in such patients whose initial blood pressure is less than 120/70, we do not give
antihypertensive therapy.
In patients with underlying hypertension, we recommend a goal blood pressure of less
than 140/90 mmHg compared with higher pressures and we suggest (a weaker
recommendation) lowering the systolic pressure below 130 to 135 mmHg if it can be
achieved without producing significant side effects. The evidence supporting this approach
in patients with atherosclerotic cardiovascular disease in general is discussed in detail
elsewhere. (See "What is the goal blood pressure in patients with atherosclerotic
cardiovascular disease?", section on 'Goal blood pressure'.)
For patients with recent small vessel (ie, lacunar) ischemic stroke, we suggest (a weak
recommendation) lowering the systolic blood pressure below 130 mmHg. (See 'Data from
randomized trials' above.)
Gradual blood pressure reduction The normal response to an acute reduction in BP is to
maintain tissue perfusion by autoregulatory precapillary vasodilation. Since flow is equal to
pressure divided by resistance, parallel reductions in both parameters allows 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 [24].
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) [25]. In general, ischemic
symptoms are not likely to occur unless the BP is acutely reduced by more than 25 percent below
the baseline level.
Based upon these concerns, gradual BP reduction (ie, no more than a 5 mmHg reduction in
systolic pressure at a time) is recommended in patients with known cerebrovascular disease or
long-standing uncontrolled hypertension unless there is a hypertensive emergency.
(See "Evaluation and treatment of hypertensive emergencies in adults".)
AHA/ASA GUIDELINES FOR THE PREVENTION OF RECURRENT STROKE Guidelines for
the prevention of recurrent stroke and transient ischemic attack issued in 2014 by the American
Heart Association and American Stroke Association (AHA/ASA) recommend initiation of blood
pressure therapy for previously untreated patients with ischemic stroke or TIA who, after the first
several days, have an established blood pressure 140 mmHg systolic or 90 mmHg diastolic
[10]. 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 several
days after stroke onset.
We generally agree with these recommendations.
The AHA/ASA made the following additional comments about long-term antihypertensive therapy
to prevent recurrent stroke [10]:
The target blood pressure level and degree of reduction are uncertain, and treatment
should be individualized, but it is reasonable to achieve a systolic pressure <140 mmHg and

a diastolic pressure <90 mmHg. For patients with a recent lacunar stroke, it might be
reasonable to target a systolic BP of <130 mmHg. (See 'Goal blood pressure' above.)
Lifestyle modifications have been associated with blood pressure reductions and are a
reasonable part of the antihypertensive regimen. Important modifications include weight
loss, salt restriction, a diet rich in fruits, vegetables, and low-fat dairy products, regular
aerobic physical activity, and limited alcohol consumption. (See "Overview of hypertension
in adults", section on 'Nonpharmacologic therapy'.)
The optimal antihypertensive drug regimen is uncertain but the available data indicate that
diuretics or the combination of diuretics and an ACE inhibitor are useful. The choice of
specific drugs should be individualized with respect to patient characteristics such as
extracranial cerebrovascular occlusive disease, renal impairment, cardiac disease, and
diabetes.
We disagree with the recommendation for combined therapy with diuretics and an angiotensin
inhibitor. Our reasons for disagreeing with the AHS/ASA guidelines and our preference for
combination antihypertensive therapy are discussed in detail above. (See 'Combination
therapy' above.)
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials,
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Basics topics (see "Patient information: Stroke (The Basics)" and "Patient information:
Medicines after an ischemic stroke (The Basics)")
Beyond the Basics topics (see "Patient information: Stroke symptoms and diagnosis
(Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Treatment of hypertension may be an immediate concern in patients with an acute
ischemic stroke and those with a subarachnoid or intracerebral hemorrhage. Blood pressure
management in the acute phase of stroke is different from chronic therapy and is discussed
in detail elsewhere. (See "Initial assessment and management of acute stroke", section on
'Blood pressure management' and "Spontaneous intracerebral hemorrhage: Treatment and
prognosis", section on 'Blood pressure' and"Treatment of aneurysmal subarachnoid
hemorrhage", section on 'Intracranial pressure'.)
Once the stroke has stabilized, antihypertensive therapy can reduce the rate of recurrent
stroke, independent of the baseline blood pressure. (See 'Trials of long-term
antihypertensive therapy' above.)
The target blood pressure level and degree of reduction are uncertain, and treatment
should be individualized. Benefit has been associated with an average blood pressure

reduction of approximately 10 mmHg systolic and 5 mmHg diastolic. (See 'PROGRESS

trial' above.)
Lifestyle modifications that have been associated with blood pressure reductions should
be included as part of the antihypertensive regimen. Important modifications include weight
loss, salt restriction, a diet rich in fruits, vegetables, and low-fat dairy products, regular
aerobic physical activity, and limited alcohol consumption. (See 'AHA/ASA guidelines for the
Prevention of Recurrent Stroke' above.)
For previously treated patients with known hypertension who are beyond the first few days
after stroke onset, we recommend resumption of antihypertensive therapy for both
prevention of recurrent stroke and prevention of other vascular events. For patients
previously untreated with antihypertensive therapy who are beyond the first few days after
stroke onset, we make the following recommendations (see 'Which patients should be
treated?' above):
For patients with ischemic stroke or TIA of any type who have an established blood
pressure 140 mmHg systolic or 90 mmHg diastolic, we recommend initiation of
antihypertensive therapy (Grade 1A).
For patients with ischemic stroke or TIA of atherothrombotic, lacunar (small vessel
occlusive), or cryptogenic type, and an established blood pressure >120 mmHg
systolic or >70 mmHg diastolic, we suggest initiation of antihypertensive therapy
(Grade 2C).
We do not suggest antihypertensive therapy in the following settings:
-Nonhypertensive patients (ie, blood pressure <140/90 mmHg) who have had a
stroke or TIA due to a cardioembolic phenomenon (eg, atrial fibrillation).
-Patients whose baseline blood pressure is <120/70 mmHg. These patients have
an increased risk of recurrent stroke if their blood pressure is further reduced
compared with patients who have higher blood pressures. (See 'Data from
randomized trials' above.)
The timing of in-hospital initiation or reinitiation of antihypertensive therapy during the acute
phase of stroke is discussed in detail elsewhere. For patients who have not been treated in
the hospital, antihypertensive therapy should be initiated or reinitiated as an outpatient in all
appropriate patients. (See "Initial assessment and management of acute stroke", section on
'Blood pressure management' and 'When should therapy be initiated?' above.)
Our preferences for antihypertensive therapy in patients who have had a stroke or TIA
differ according to whether monotherapy or combination antihypertensive therapy is
required to achieve an adequate reduction in blood pressure (see 'Which antihypertensive
drugs should be used?' above):
There is no compelling evidence favoring one class of antihypertensive drugs over
another as monotherapy for secondary prevention in patients who have had a stroke.
Both angiotensin inhibitors (most trials have used ACE inhibitors), calcium channel
blockers, and diuretics are reasonable options for initial antihypertensive monotherapy
in such patients. Unless there is a compelling indication for their use, beta blockers
should not be used for prevention of recurrent stroke. (See 'Monotherapy' above.)
We disagree with the 2014 AHA/ASA guidelines that recommend an ACE inhibitor
plus a diuretic for patients who have had a stroke or TIA and requirecombination
antihypertensive therapy. Based upon observations from the ACCOMPLISH trial, we
recommend the combination of an angiotensin inhibitor plus a long-acting
dihydropyridine calcium channel blocker rather than a diuretic as the combination
antihypertensive regimen of choice in the treatment of patients who have had a stroke.

This recommendation assumes that the patient can tolerate and does not have a
contraindication to the use of either drug class and does not have a specific indication
for the use of another class of antihypertensive drugs. (See 'Combination
therapy' above.)
Our recommendations for goal blood pressure in patients who have had a stroke or TIA
depend upon whether or not the event was due to a hemodynamically significant stenosis
in a large cervicocephalic artery (ie, internal carotid, middle cerebral, vertebral, or basilar
artery) (see 'Goal blood pressure' above):
In patients with hemodynamically significant large artery disease, we suggest
cautious blood pressure lowering as tolerated but without a specific blood pressure
goal other than a minimum reduction of 10/5 mmHg. However, in such patients whose
initial blood pressure is less than 120/70, we do not give antihypertensive therapy.
(See 'Patients with hemodynamically significant large artery stenosis' above.)
In patients without hemodynamically significant large artery stenosis, we take the
following approach (see 'Patients without hemodynamically significant large artery
stenosis' above):
-We recommend lowering the blood pressure a minimum of 10/5 mmHg in nearly
all patients. However, in such patients whose initial blood pressure is less
than 120/70, we do not give antihypertensive therapy.
-In patients with underlying hypertension, we recommend a goal blood pressure
of less than 140/90 mmHg compared with higher pressures and we suggest (a
weaker recommendation) lowering the systolic pressure below 130 to 135 mmHg
if it can be achieved without producing significant side effects. The evidence
supporting this approach in patients with atherosclerotic cardiovascular disease
in general is discussed in detail elsewhere.
-For patients with recent small vessel (ie, lacunar) ischemic stroke, we suggest
(a weak recommendation) lowering the systolic blood pressure below 130
mmHg.
In patients with hemodynamically significant large artery disease who are given
antihypertensive therapy, the patient should be carefully monitored for hypotensive or
neurologic symptoms caused by either failure of autoregulation of cerebral blood flow or by
hemodynamic compromise due to large vessel stenosis. If the patient develops recurrent
neurologic symptoms referable to a stenotic artery when the blood pressure is lowered
below a particular threshold, we recommend management to maintain blood pressure above
that threshold. (See 'Patients with hemodynamically significant large artery stenosis' above.)
If a hemodynamically significant stenosis of an extracranial carotid artery is corrected by
endarterectomy or stenting, we attempt to gradually achieve the blood pressure goals
described in the following section on patients without hemodynamically significant large
artery stenosis in order to reduce the risks of recurrent stroke and other cardiovascular
events. (See 'Patients with hemodynamically significant large artery stenosis' above.)
Regardless of the regimen, blood pressure reduction should be gradual. (See 'Gradual
blood pressure reduction' above.)
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