Antihypertensive Drugs for Secondary Prevention After Ischemic Stroke or

Transient Ischemic Attack

Abstract and Introduction

Abstract
Background and Purpose: Approximately 30% of ischemic strokes occur after a
previous stroke or transient ischemic attack. Arterial hypertension is one of the best
established risk factors for first and recurrent stroke, both ischemic and hemorrhagic.
Guidelines for the secondary prevention of ischemic stroke support the use of blood
pressure (BP)–lowering drugs in most patients. However, the evidence for these
recommendations comes from meta-analyses that included both ischemic and
hemorrhagic stroke patients, whereas these 2 conditions differ quantitatively in several
aspects. With this systematic review and meta-analysis, we aimed at summarizing the
current evidence on BP-lowering drugs for secondary prevention in patients with
ischemic stroke or transient ischemic attack.
Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of
Controlled Trials up to January 31, 2020. We included randomized controlled trials
comparing any specific BP-lowering drug, as monotherapy or combination, with either a
control or another BP-lowering drug.
Results: Eight studies that enrolled 33 774 patients with ischemic stroke or transient
ischemic attack were included in the meta-analysis. Mean follow-up was 25 months
(range, 3–48). Moderate-quality evidence indicated that a subsequent stroke occurred
in 7.9% (ischemic in 7.4% or hemorrhagic in 0.6%) of patients taking any type of BP-
lowering drug compared with 9.7% of patients taking placebo (odds ratio, 0.79 [95% CI,
0.66–0.94]; absolute risk difference, −1.9% [95% CI, −3.1% to −0.5%]). Moderate-
quality evidence indicated that mortality occurred similarly in patients taking any type of
BP-lowering treatment compared with placebo, with an absolute risk of 7.3% and 7.9%,
respectively (odds ratio, 1.01 [95% CI, 0.92–1.10]; absolute risk difference, 0.1% [95%
CI, −0.6% to 0.7%]).
Conclusions: The use of BP-lowering drugs in patients with ischemic stroke or transient
ischemic attack is associated with a 1.9% risk reduction of stroke but does not affect the
all-cause mortality risk.
Introduction
Stroke is the second most common cause of death worldwide, and it is expected to
remain one of the leading causes of death and adult disability for the foreseeable future.
Annually, 15 million people have a stroke, of which one-third will die and one-third will
be permanently disabled.[1–3] Although primary prevention is most important in reduction
of the burden of stroke, effective secondary prevention is also essential. About 85% of
strokes are ischemic; the remaining are hemorrhagic. Approximately 30% of ischemic
strokes occur in individuals with a previous stroke or transient ischemic attack (TIA),
which are also at higher risk for subsequent myocardial infarction and death from
vascular causes; recurrent ischemic strokes are more severe than first strokes.
Arterial hypertension is one of the best established risk factors for first and recurrent
stroke, both ischemic and hemorrhagic.[2,6] Evidences from meta-analyses of
randomized controlled trials (RCTs), most of which were conducted across all stroke
types, support the use of blood pressure (BP)–lowering drugs for reducing the risk of
recurrent stroke.[7–11] However, given the heterogeneous causes and hemodynamic
consequences of ischemic and hemorrhagic strokes, the management of BP in adults
with stroke is complex, and additional high-quality evidence concerning antihypertensive
use for secondary prevention by index stroke type is needed. [6,12]
With this systematic review and meta-analysis, we aimed at summarizing the current
evidence on BP-lowering drugs for secondary prevention in patients qualifying with
ischemic stroke or TIA and at estimating the relative efficacy and safety of various drug
classes.

Methods

The data that support the findings of this study are available from the corresponding
author upon reasonable request.

Protocol and Registration

The systematic review protocol was developed using guidance from the Preferred
Reporting Items for Systematic Review and Meta-Analysis Protocols statement. [13] We
addressed all 17 items within the Preferred Reporting Items for Systematic Review and
Meta-Analysis Protocols checklist and registered the review in PROSPERO
(International Prospective Register of Systematic Reviews; CRD42018100148). [14] The
manuscript was written accordingly to the Preferred Reporting Items for Systematic
Review and Meta-Analysis statement.[15]

Search Strategy and Selection Criteria

We conducted a systematic review and meta-analysis. We searched MEDLINE,
EMBASE, and the Cochrane Central Register of Controlled Trials electronic databases
from inception date to January 31, 2020, with no language restrictions. Search terms
included extensive controlled vocabulary (MeSH [Medical Subject Headings] and
Emtree) and keywords, including the names of antihypertensive drugs along with
differing terms for stroke and cerebrovascular disease in various combinations
(Materials in the Data Supplement). Reference lists of relevant RCTs or review were
also handsearched. Details on the search strategies can be found on the PROSPERO
protocol.[14] We did not formally search for additional unpublished or ongoing studies
because from a preliminary check on https://www.clinicaltrials.gov/ and the International
Clinical Trials Registry Platform (http://apps.who.int/trialsearch/), we did not identify
additional studies relevant for the review question.

Eligibility Criteria and Study Selection

We included RCTs comparing any BP-lowering drug, as monotherapy or combination
therapy, with either a control (placebo or no therapy) or another active BP-lowering
drug, as monotherapy or combination therapy, at any dose for secondary prevention in
adults (≥18 years old) of both sexes with a diagnosis of ischemic stroke or TIA in which
hemorrhage had been ruled out. We included all settings of care (eg, acute or nursing
homes, hospitals or ambulatory, primary or secondary, inpatients or outpatients), and
both acute or delayed treatments. RCTs comparing the effect of different doses of the
same drug were excluded, except those that included another eligible comparator. We
excluded also non-English language study reports and RCTs designed to test a BP
reduction strategy using several BP-lowering drugs of different classes rather than the
efficacy of a specific BP-lowering drug.
Two authors independently selected the studies, extracted relevant information from the
included studies (see the protocol registered in PROSPERO for details), [14] and
assessed the study risk of bias. Any discrepancy was resolved by consensus and
arbitration by the third author. We contacted study authors to retrieve outcome data not
available in the full text.

Outcomes
Primary outcomes were all-cause mortality and the proportion of patients who
developed a stroke following BP-lowering drug use, irrespective of its nature (ischemic
or hemorrhagic) and severity. Secondary outcomes included the proportion of patients
who developed an ischemic stroke; an ischemic stroke or TIA irrespective of severity; a
hemorrhagic stroke, defined as an acute extravasation of blood into and around the
brain parenchyma (subdural hematoma and epidural hematoma were excluded); a
cardiovascular event defined as any sudden death, fatal or nonfatal acute coronary
syndrome, stroke, intracranial hemorrhage, or pulmonary embolism; a fatal
cardiovascular event defined as any death due to any vascular cause, including
unexplained sudden death; and serious adverse events of hypotension, syncope,
injurious falls, electrolyte abnormalities, bradycardia, or acute renal failure. We recorded
the outcomes at the longest available follow-up for all analyses.

Study Risk of Bias, Assessment, and Certainty of Evidence

We evaluated the risk of bias for each included study using the criteria of The Cochrane
Collaboration.[16] The following domains of bias were considered: selection (random
sequence generation, allocation concealment), performance (blinding of participants
and personnel), detection (blinding of outcome assessment), attrition (incomplete
outcome data), and selective outcome reporting. We explicitly judged the risk of bias in
each criterion as low, high, or unclear. We evaluated incomplete outcome data as
having a low risk of bias when the numbers and reasons for dropouts were balanced (ie,
in the absence of a significant difference) between arms. Our assessment of
methodological quality included published trial protocols when available. Finally, for
each study, we explicitly judged also the overall risk of bias as follows: we considered
allocation concealment, blinding of participants and personnel, blinding of outcome
assessment, and incomplete outcome data to classify each study as having low risk of
bias when we judged all of the selected criteria as having low risk of bias; high risk of
bias when we judged at least 1 criterion among those selected as having high risk of
bias; and unclear risk of bias in the remaining cases. This appraisal was conducted by 2
reviewers independently, with conflicts resolved by the third reviewer. We examined the
overall certainty of the evidence for primary and secondary outcomes using the GRADE
(Grading of Recommendations, Assessment, Development and Evaluations) framework
methodology.[17] We used the GRADEpro software for assessing the certainty of
evidence.[18]

Statistical Analysis
We estimated treatment effects from each study using the odds ratio (OR) with 95%
CIs. For our study, we had planned to perform a network meta-analysis. [14] However,
due to the limited number of studies and scarce available data, the network meta-
analysis was not feasible. For all outcomes with at least 2 studies, we performed
standard pairwise meta-analyses with a random-effects model. We determined the
presence of statistical heterogeneity by visual inspection of the forest plots and
calculation of the I2 statistic.[19] We performed subgroup analyses considering the
following potential sources of heterogeneity (effect modifiers): inclusion limited to
hypertensive patients (normotensive and hypertensive patients versus hypertensive
patients only) or noncardioembolic ischemic strokes (all ischemic strokes versus
noncardioembolic ischemic strokes only) and time from the index ischemic event to
randomization (acute patients treated within the first week versus stabilized patients
treated after the first week). We performed sensitivity analyses for each primary and
secondary outcome, including only trials that were classified as having a low risk of
bias. All analyses were conducted with STATA, version 16.0 (StataCorp, College
Station, TX).
We presented the results from meta-analyses as summary OR and relative 95% CIs.
We also reported absolute risk difference (ARD) estimates, calculated using as baseline
the proportion of patients with an event in the control arm of the included studies and
applying the OR estimated in the meta-analysis to compute the absolute difference
between the intervention and control arms. Relative (ORs) and absolute estimates
(ARDs) and the certainty of the evidence were reported in Table 2.

Results

From a total of 4709 citations identified by the search, 62 articles were retrieved in full
text. Overall, 22 articles referring to 15 RCTs evaluated BP-lowering treatments for
secondary prevention in patients with previous ischemic stroke or TIA and were
included in our review 
Seven RCTs included also hemorrhagic or undetermined strokes but did not report or
provide separated outcomes for ischemic strokes only; consequently, they were
excluded from the meta-analysis.[20–26] The characteristics of these 7 studies are
summarized in Table I in the Data Supplement.
Finally, 8 studies reported data suitable for our purpose and were included in the meta-
analysis.[8,27–40] The characteristics of these 8 studies are summarized in Table 1.
The 8 RCTs included in the meta-analysis enrolled 33 774 patients with ischemic stroke
or TIA; the mean follow-up was 25 months (range, 3–48). Among the 8 studies, 2
evaluated the use of BP-lowering drugs in acute stroke patients within 48 hours from
stroke onset, with a follow-up between 3 and 6 months, [38–40] while the remaining 6
enrolled stabilized patients with a follow-up between 1 and 4 years. PATS,
[8]
 PROGRESS,[33,34] and SCAST[39] studies included also hemorrhagic and undetermined
stroke cases that were excluded from the meta-analysis. The studies were published
between 1970 and 2015, males ranged between 57% and 72% (weighted mean, 66%),
and mean age from 60 to 71 years (weighted mean, 65 years). Most studies included
both hypertensive and normotensive patients and excluded patients with cardioembolic
strokes (we included in this group also the PRoFESS study [Prevention Regimen for
Effectively Avoiding Second Strokes], reporting 1.8% cardioembolic strokes [35]). Different
treatments were evaluated across studies included in the meta-analysis: 3 studies were
on angiotensin II receptor blockers, 1 on angiotensin-converting enzyme inhibitor with or
without a diuretic, 1 on diuretic, 1 on β-blocker, 1 on calcium channel blocker, and 1 on
a combination of 4 drugs.
Overall, only 4 trials were judged at low risk of bias
Risk of bias of the included studies.
PATS indicates Post-Stroke Antihypertensive Treatment Study; PRoFESS, Prevention
Regimen for Effectively Avoiding Second Strokes; PROGRESS, Perindopril Protection
Against Recurrent Stroke Study; SCAST, Scandinavian Candesartan Acute Stroke Trial;
TIA, transient ischemic attack; and VENTURE, Valsartan Efficacy on Modest Blood
Pressure Reduction in Acute Ischemic Stroke.
Not all RCTs contributed information to all outcomes. The study estimates and the
pooled estimates of any BP-lowering treatment versus placebo/no treatment for each
primary outcome are shown in Figure 3. The corresponding estimates for each
secondary outcome are shown in Figures I through III in the Data Supplement. Table
2 presents the relative and absolute estimates, and the certainty of evidence (GRADE
assessment), for each primary and secondary outcomes.

Forest plots of meta-analysis estimates of any blood pressure–lowering drug against

placebo/no treatment for primary outcomes..
A, All-cause mortality; (B) and all strokes. θ indicates treatment effect; PATS, Post-
Stroke Antihypertensive Treatment Study; PRoFESS, Prevention Regimen for
Effectively Avoiding Second Strokes; PROGRESS, Perindopril Protection Against
Recurrent Stroke Study; REML, restricted maximum likelihood; TIA, transient ischemic
attack; and VENTURE, Valsartan Efficacy on Modest Blood Pressure Reduction in
Acute Ischemic Stroke.
Six RCTs, including 27 803 patients, evaluated all-cause mortality as outcome.
Moderate-quality evidence due to study risk of bias indicated that mortality occurred
similarly in patients taking any type of BP-lowering treatment compared with placebo,
with an absolute risk of 7.3% and 7.9%, respectively (OR, 1.01 [95% CI, 0.92–1.10];
I2=0%; ARD, 0.1% [95% CI, −0.6% to 0.7%]).
Six RCTs, including 31 785 patients, evaluated all stroke as outcome. Moderate-quality
evidence due to between-study heterogeneity indicated that a stroke (ischemic or
hemorrhagic) occurred in 7.9% of patients taking any type of BP-lowering drug
compared with 9.7% of patients taking placebo (OR, 0.79 [95% CI, 0.66–0.94]; I 2=61%;
ARD, −1.9% [95% CI, −3.1% to −0.5%]).
Two RCTs, including 5507 patients, evaluated our secondary outcome ischemic stroke
or TIA. High-quality evidence indicated that ischemic stroke or TIA occurred in 10.6% of
patients on BP-lowering treatment compared with 13.2% of those on placebo (OR, 0.78
[95% CI, 0.66–0.91]; I2=0%; ARD, −2.6% [95% CI, −4.1% to −1.0%]).
The protective effect of BP-lowering treatment, although not statistically significant, can
be also postulated for the following secondary efficacy outcomes: ischemic stroke,
hemorrhagic stroke, cardiovascular event, and cardiovascular death.
Two RCTs, including 25 303 patients, evaluated the occurrence of serious adverse
events. High-quality evidence indicated that these events occurred in 2.9% of patients
taking any type of antihypertensive treatment compared with 2.3% of patients taking
placebo (OR, 1.25 [95% CI, 1.07–1.46]; I2=0%; ARD, 0.6% [95% CI, 0.1%–1.0%]).
Subgroup analysis including studies that compared angiotensin II receptor blockers with
placebo did not show any significant effect of these drugs on our primary and secondary
outcomes, except for increased occurrence of serious adverse events (data not
published).
Results of the subgroup analyses in stabilized and noncardioembolic strokes were
similar to those of the overall analysis, while the subgroup analyses in hypertensive
patients and the sensitivity analysis including only RCTs at low risk of bias were not
statistically significant also for the all stroke primary outcome (Table II in the Data
Supplement).

Discussion

In our systematic review, we found 8 RCTs that enrolled ≈33 500 patients with ischemic
stroke or TIA in developed countries, including Asia. Compared with other community-
based studies on ischemic stroke,[41] here, the mean age is slightly lower (65 years) and
the male/female ratio a little bit higher (1.94), but, overall, the general characteristics of
this population seem adequate for our purposes.
In this meta-analysis, which is the first that focused on patients qualifying with ischemic
stroke or TIA, the use of BP-lowering treatments was associated with a 1.9% risk
reduction of stroke. Our results are in accordance with previous meta-analyses, based
on RCTs that included patients with TIA or stroke, both ischemic and hemorrhagic, [7–
11]
 and confirm the current guidelines and expert recommendations for the secondary
prevention after ischemic stroke or TIA.[5,12,42,43] In particular, the absolute risk reduction
is higher for new ischemic stroke or TIA (−2.6%) rather than for new hemorrhagic stroke
(−0.3%). However, BP-lowering agents seem to have less protective effects for
recurrent ischemic stroke, as shown by the absolute risk reduction of −1%.
On the contrary, BP-lowering treatments increase the risk of serious adverse events by
0.6% and do not show any effect on the all-cause mortality risk. Mortality was not
altered by BP-lowering treatments also in 2 other meta-analyses that considered this
outcome in a similar combined sample size (15 527 and 35 110 patients, respectively).
[7,11]
 However, if we consider cardiovascular deaths only, our results point to a possible
protective effect of BP-lowering treatment, although not statistically significant (OR, 0.89
[95% CI, 0.77–1.01]), which is indeed confirmed in 2 other larger meta-analysis that
included also hemorrhagic strokes (risk ratio, 0.85 [95% CI, 0.75–0.96] [10] and 0.85 [95%
CI, 0.76–0.95][11]). These results suggest that BP-lowering treatments may reduce the
risk of cardiovascular death also in patients with ischemic stroke or TIA but could
slightly increase the risk of noncardiovascular death.
These results were the first obtained in patients with ischemic cerebrovascular disease
only, while previous meta-analysis, even in subgroup analysis, included also patients
with hemorrhagic stroke in variable percentage (probably between 5% and 15% of the
combined sample size).[7–11] Although ischemic and hemorrhagic strokes share some
features qualitatively, especially when considering elevated BP as a risk factor, they
differ quantitatively in several aspects. For example, while there is a lot of evidence
supporting the use of BP-lowering treatments for secondary prevention in patients with
TIA or stabilized ischemic stroke, there are still many concerns about the treatment of
elevated BP in patients with acute ischemic stroke, due to impairment of cerebral
autoregulation: while elevated BP is associated with an increased rate of hemorrhagic
transformation, the ischemic tissue is also vulnerable to acute BP reduction, potentially
leading to infarct growth.[44,45] On the contrary, in patients with acute intracerebral
hemorrhage, the acute lowering of elevated systolic BP is recommended in most cases;
[46]
 only recently, following the results of a single, large RCT, some concerns were raised
also for intensive BP lowering in patients with acute cerebral hemorrhage.
[12]
 Furthermore, given the same BP-lowering agent and considering the risk reduction of
major vascular events, patients with hemorrhagic stroke seem to have an increased
benefit compared with patients with ischemic stroke. [34] Finally, the protective effect of
intensive BP treatment on recurrent stroke seems higher in patients with previous
hemorrhagic stroke rather than in those with ischemic stroke, although this difference is
not statistically significant.[47]
Our meta-analysis has also some limitations, mainly due to the lack of data, and several
questions remain unanswered. First, most of the RCTs included in this meta-analysis
enrolled patients with stabilized, noncardioembolic ischemic stroke, and our results
cannot be broadened to acute patients and all ischemic strokes (irrespective of
cardioembolic source). Second, 2 of the included RCTs (VENTURE [Valsartan Efficacy
on Modest Blood Pressure Reduction in Acute Ischemic Stroke] and SCAST) have short
follow-up (3–6 months) and are probably more suitably designed to evaluate the effect
of BP reduction on early vascular events. Third, our results support BP reduction
irrespective of the initial BP level; unfortunately, we do not have data in normotensive
patients only. Fourth, we decided to exclude RCTs designed to test a BP reduction
strategy rather a specific antihypertensive drug; therefore, we do not have data either
on the degree of BP reduction or on the target BP. Fifth, with this study, we aimed also
at providing a ranking of the various drug classes via network meta-analysis, but this
was not feasible due to the limited number of studies and scarce available data. In our
meta-analysis, most of the evidence came from 2 RCTs (PATS and PROGRESS) that
used a diuretic alone or in association with an angiotensin-converting enzyme inhibitor,
which are recommended also in the current guidelines. [5,12] Unfortunately, only 1 small
RCT included in this meta-analysis tested a calcium channel blocker, [28] while there are
evidences that these drugs are superior for the prevention of stroke. [48] Additional RCTs
are need to answer these questions.

Conclusions

The results of our study support the use of BP-lowering treatments in secondary
prevention after ischemic stroke or TIA, in particular when stabilized and without
cardioembolic origin. BP-lowering treatments may reduce the risk of cardiovascular
death but do not affect the all-cause mortality risk.
However, scanty data were available to provide robust results based on subgroup and
sensitivity analyses, as by specific drug classes. Thus, additional RCTs are warranted.