Is fixed-combination antihypertensive therapy needed in post-stroke patients?






John CHALMERS,AC, FAA, FRACP
Hisatomi ARIMA,MD, PhD
The George Institute for Global
Health, University of Sydney
and the Royal Prince Alfred
Hospital, Sydney
AUSTRALIA

Is fixed-combination antihypertensive therapy needed in post-stroke patients?


by J. Chalmers and H. Arima, Australia



Combination antihypertensive therapy is now recommended for the vast majority of patients who need blood pressure–lowering therapy. Patients with previous stroke form a particularly important group for whom combination therapy has been shown to be both beneficial and superior. The best evidence for this comes from the PROGRESS trial (Perindopril pROtection aGainst REcurrent Stroke Study), which clearly demonstrated that a regimen based on the angiotensin-converting enzyme inhibitor perindopril, with additional use of the diuretic indapamide, as required, reduced the incidence of recurrent stroke by around one quarter. In the PROGRESS trial, combination therapy with perindopril and indapamide produced an even larger reduction in the risk of stroke (relative risk reduction, 43%), which is consistent with the larger blood pressure reduction obtained with combination therapy compared with single drug therapy (12.3/5.0 mm Hg vs 4.9/2.8 mm Hg). Similar trends toward greater reductions associated with combination therapy were also observed for all other outcomes including major vascular events, coronary heart events, heart failure, disability, dependency, cognitive decline, and death. Therefore, the combination of perindopril and indapamide can be recommended for the prevention of recurrent stroke and associated cardiovascular events in all patients with cerebrovascular disease.

Medicographia. 2013;35:426-432 (see French abstract on page 432)



Combination antihypertensive therapy is now recommended for the vast majority of patients who need blood pressure–lowering therapy, including those with hypertension (defined as systolic blood pressure ≥140 mm Hg), and also patients with high cardiovascular risk, whether hypertensive or not.1-5 Furthermore, in the past 10 years, these recommendations have broadened to cover the use of combination therapy to initiate drug treatment for patients with more severe hypertension (systolic blood pressure ≥160 mm Hg) or patients at high cardiovascular risk.1-4 In addition, many guidelines now recommend that fixed-dose (or “single pill”) combinations may be used, as they may facilitate adherence and improve blood pressure control.1-5

Patients with previous stroke form a particularly important group for whom combination therapy has been shown to be both beneficial and superior. The best evidence for this comes from the PROGRESS trial (Perindopril pROtection aGainst REcurrent Stroke Study), which clearly demonstrated that a regimen based on the angiotensin-converting enzyme inhibitor perindopril, with additional use of the di- uretic indapamide, as required, reduced the incidence of recurrent stroke, major vascular events, coronary heart events, and heart failure by around one quarter.6,7 Even more important, the main analysis and all subsequent analyses have confirmed that the greatest reductions in stroke and all other major cardiovascular events were obtained in the subgroup treated with both perindopril and indapamide.6-9

Since then, a number of other studies have reported the effects of blood pressure–lowering after stroke, using a variety of other regimens.10,11 Some of these studies compared active treatment with placebo,11 while others compared two active treatments.10 None of these studies involved combination therapy either in the trial as a whole, or in a specific subset of patients. In this article, we examine the results of PROGRESS and of the more recent trials and present analyses based both on PROGRESS and on a meta-regression of numerous studies. The particular focus of this article will be on the evidence regarding the use of combination blood pressure–lowering therapy in patients with cerebrovascular disease and on the possible benefits observed with the combinations that have been tested.

The PROGRESS trial – results and implications

Background
Stroke kills over 5 million people every year, so that it now constitutes the second largest cause of death across the world.12 Many more people have a stroke and survive it—well over 15 million annually—but around one-third of survivors are disabled. Recurrent stroke is also common in survivors and prevention of recurrence is a major challenge. While aspirin therapy has been shown to be effective for reducing recurrence after ischemic stroke, prior to PROGRESS no strategies were available to prevent stroke recurrence after a hemorrhagic stroke.13

The PROGRESS trial was launched as an investigator-initiated study to test the hypothesis that routine blood pressure lowering in patients who had suffered a stroke or a transient ischemic attack, would be both safe and effective in reducing the incidence of recurrent stroke. A number of small trials had been conducted before PROGRESS with mixed results, and there was continuing uncertainty regarding the wisdom and safety of lowering blood pressure in patients who had survived a stroke.14

As there was good evidence from observational studies that the association between blood pressure and both primary and secondary stroke was positive and continuous, well into the normal range of blood pressure,15,16 all patients with previous stroke or transient ischemic attack could be enrolled in PROGRESS, whether they were hypertensive or normotensive.6,14 Furthermore, PROGRESS was deliberately planned to include patients from China and Japan, where stroke is particularly common.

Brief description of the PROGRESS trial
Patients were eligible for PROGRESS if they had a stroke or a transient ischemic attack in the past five years. They also had to have no definite indication or contraindication to treatment with an angiotensin converting-enzyme inhibitor. There were no blood pressure entry criteria and both hypertensive and normotensive individuals were eligible. Potentially eligible individuals entered a 4-week run-in period during which they received open-label perindopril, 2 mg daily for 2 weeks followed by 4 mg daily for another 2 weeks. Participants who tolerated this treatment were randomly assigned on a double blind basis to either continuing active therapy or matching placebo. Active therapy consisted of a flexible regimen whereby all participants received perindopril 4 mg daily, with addition of the diuretic indapamide 2.5 mg daily (2 mg in Japan), in patients without definite indication or contraindication to treatment with a diuretic. The purpose of allowing combination therapy was to maximize the magnitude of blood pressure reduction achieved; and physicians were asked, prior to randomization, to determine whether the individual participants should be randomized to single therapy with perindopril (or matching placebo) or to combination therapy with both perindopril and indapamide (or double placebo). After the first few months, patients were seen every six months, and blood pressure was measured with a mercury sphygmomanometer.

The primary study outcome was stroke (fatal or nonfatal), and secondary outcomes included stroke subtypes, major vascular events (nonfatal stroke, nonfatal myocardial infarction, or death due to any vascular cause), disability, dementia, and cognitive decline. Prespecified subgroup analyses included comparison of treatment effects among participants randomized to combination therapy or to single therapy.

Patient enrolment, follow-up, and baseline characteristics
A total of 7121 patients entered the 4-week run-in phase and 1016 were found ineligible or withdrew during that time, so that 6105 were randomized. Of those randomized, 3051 were assigned active treatment, with 1770 stratified to the combination of perindopril 4 mg and indapamide 2.5 mg and 1281 stratified to perindopril alone. A total of 3054 patients were assigned placebo treatment, with 1774 on double placebo and 1280 on single placebo. The mean duration of follow-up was 3.9 years. Only 3 patients were lost to follow-up and had unknown vital status at the end of the study, 2 on active treatment and 1 on placebo.

The baseline characteristics of all randomized participants are summarized in Table I (page 428). There was a good balance between those on active treatment and those on placebo. There was also a good balance between those stratified to combination therapy or to single therapy, though as expected, those on combination therapy or double placebo, were younger, had higher baseline blood pressures, and were more likely to be hypertensive or to have coronary disease (Table I).


Table I
Table I. Baseline
characteristics
of PROGRESS
participants.

Abbreviations: CHD,
coronary heart disease;
DBP, diastolic blood
pressure; PROGRESS,
Perindopril pROtection
aGainst REcurrent
Stroke Study; SD,standard
deviation; SBP,
systolic blood pressure;
TIA, transient ischemic
attack.
Adapted and expanded
from reference 6
:
PROGRESS Collaborative
Group. Lancet.
2001;358:1033-1041.
© 2001, Elsevier.



Figure 1
Figure 1. PROGRESS trial: Cumulative incidence of stroke among 3051 participants assigned active treatment and 3054 participants
assigned placebo (A) and among 1770 participants assigned combination therapy and 1774 assigned double placebo (B).

Abbreviation: PROGRESS, Perindopril pROtection aGainst REcurrent Stroke Study.
After reference 6: PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041. © 2001, Elsevier.



Effects on blood pressure
Overall, across the whole 4 years of follow up, blood pressure was reduced by an average of 9.0/4.0 mm Hg among those randomized to active treatment compared with those assigned placebo.6 The reduction was considerably greater among those treated with combination therapy (12.3/5.0 mm Hg), and was actually twice that observed in participants treated with single therapy (4.9/2.8 mm Hg).6

Effects on stroke
Active treatment reduced the risk of stroke by 28% overall (P<0.0001).6 The Kaplan-Meier curves diverged early and continued to separate during follow-up (Figure 1). Among participants treated with combination therapy, perindopril plus indapamide, the greater reduction in blood pressure was matched by a greater 43% reduction in stroke risk, compared with those receiving single therapy with perindopril alone (Figure 2, panel A).6 The reductions in stroke subtypes, particularly hemorrhagic stroke and ischemic stroke, were also markedly accentuated in patients on combination therapy, not only compared with those on single therapy,6 but also compared with the overall reduction for those on any active treatment, whether single or dual (Figure 3, page 430). Thus, combination therapy achieved a 76% reduction in hemorrhagic stroke, a 36% reduction in ischemic stroke (Figure 3), and a 46% reduction in fatal or disabling stroke.6

A subsidiary analysis of PROGRESS data examined the effects of randomized blood pressure–lowering treatment on the risk of stroke by strata of baseline blood pressure. Combination therapy with perindopril and indapamide provided consistently greater benefits, which were significant across a range of subgroups defined by baseline systolic and diastolic blood pressures ranging from ≥160/100 mm Hg to <120/80 mm Hg (Figure 2, panel B).17,18

Effects on major vascular events
Out of the 6105 randomized patients, 1062 participants experienced a major vascular event, fatal or nonfatal, 458 in the active treatment group and 604 in the placebo group, a reduction of 26% with active treatment (Figure 3).6 The reduction in major vascular events was much greater in participants receiving the combination of perindopril plus indapamide (40%; P<0.001).

Figure 2
Figure 2. (A) Effects
of combination and
single drug therapy
on stroke and major
vascular events and
(B) effects of combination
therapy on
stroke by baseline
blood pressure in
the PROGRESS trial.

Solid boxes represent
estimates of hazard ratio
of outcomes; the areas of
the boxes are proportional
to the inverse variance
of the estimates; vertical
lines represent 95% CI;
diamonds represent estimates
and 95% CI for
overall effects.
Abbreviations:
CI, confidence interval;
PROGRESS, Perindopril
pROtection aGainst
REcurrent Stroke Study.
Panel A: modified from
reference 6
: PROGRESS
Collaborative Group.
Lancet. 2001;358:1033-
1041. © 2001, Elsevier.
Panel B: after reference
18
: Arima and Chalmers.
J Clin Hypertens
(Greenwich). 2011;13:
693-702. © 2011, Wiley
Periodicals, Inc.



Figure 3
Figure 3. Effects of blood
pressure lowering on serious
clinical outcomes in the
PROGRESS trial.

Solid boxes represent estimates of
relative risk of outcomes (hazard
ratio for stroke, major coronary
events, heart failure, major vascular
events, vascular death and total
death, and odds ratio for disability,
dependency, dementia and cognitive
decline). Other conventions
as for Figure 2.
Abbreviations: CI, confidence
interval; PROGRESS, Perindopril
pROtection aGainst REcurrent
Stroke Study.
Based on data from reference 6:
PROGRESS Collaborative Group.
Lancet. 2001;358:1033-1041;
reference 7: PROGRESS Collaborative
Group. Eur Heart J. 2003;24:
475-484; reference 8: PROGRESS
Collaborative Group. Stroke.
2003;34:2333-2338; reference 9:
PROGRESS Collaborative Group.
Arch Intern Med. 2003;163:1069-
1075; and reference 18: Arima H
and Chalmers J. J Clin Hypertens
(Greenwich). 2011;13:693-702.



Effects on other outcomes
Active treatment resulted in significant reductions in many secondary outcomes including major coronary events, heart failure, disability and dependency, and cognitive decline (Figure 3, left panel).6-9 Once again, these effects were substantially magnified in the group receiving combination treatment (Figure 3, right panel), where, for example, the reduction in the risk of dementia reached 23% (P<0.05) in those who receiving perindopril and indapamide (Figure 3).9

Association between the risk of stroke and achieved blood pressure in clinical trials

The PROGRESS trial
An observational analysis of PROGRESS revealed that the lowest risk of recurrent stroke was observed in the one quarter of patients who achieved the lowest follow-up blood pressure levels (with a median of 112/72 mm Hg), with no excess of serious complications.17 Similar relationships were observed for both ischemic and hemorrhagic stroke (Figure 4),17 both in patients with and without chronic kidney disease.19 These observational data are supported by the evidence shown in Figure 2 (panel B), demonstrating the efficacy of combination therapy across subgroups, defined by baseline systolic and diastolic blood pressures down to <120/80 mm Hg.17,18

Randomized trials after PROGRESS
Several randomized trials completed after PROGRESS have reported the effects of blood pressure lowering on recurrent stroke, though none has looked specifically at the effects of combination therapy.10,11,20-23 A meta-regression of these and a few small earlier trials is shown in Figure 5, and this suggests that each 10-mm Hg reduction in systolic blood pressure is associated with a 33% reduction in the risk of recurrent stroke.18 This is consistent with analyses from other observational studies reporting that every 10-mm Hg reduction in systolic blood pressure was associated with a 28% lower risk of recurrent stroke.16


Figure 4
Figure 4. Annual rates of ischemic
stroke and intracerebral hemorrhage
according to achieved follow-up
systolic blood pressure levels in the
PROGRESS trial.

Annual incidence rates and P values were controlled
for age, sex, smoking, diabetes, study
treatment, and combination therapy. Solid boxes
represent estimates of annual incidence rates of
stroke. The centers of the boxes are placed at
the estimates of annual incidence rates and at
median values of systolic blood pressure; the
areas of the boxes are proportional to the number
of events. Vertical lines represent 95% confidence
intervals. P trend=0.0005 for ischemic stroke,
<0.0001 for intracerebral hemorrhage. PROGRESS, Perindopril pROtection aGainst REcurrent Stroke Study. After reference 17: Arima et al. J Hypertens.
2006;24:1201-1208. © 2006, Lippincott
Williams & Wilkins.



Figure 5
Figure 5. Meta-regression analysis of 9 randomized
controlled trials of blood pressure lowering to investigate
association of reduction in systolic blood
pressure with risk reduction for recurrent stroke.

A total of 9 randomized controlled trials for secondary prevention
of stroke published after 1990 with information on reduction in
systolic blood pressure were included. The area of each circle
is proportional to the inverse variance of the log of relative risk.
The fitted line represents summary meta-regressions for recurrent
stroke.
Abbreviations: CI, confidence interval; Dutch TIA, Dutch Transient
Ischemic Attack trial; FEVER, Felodipine EVEnt Reduction;
HOPE, Heart Outcomes Prevention Evaluation; MOSES, MOrbidity
and mortality after Stroke, Eprosartan compared with
nitrendipine for Secondary prevention; PATS, Post-stroke antihypertensive
treatment study; PRoFESS, Prevention Regimen for
efFEctively avoiding Second Strokes; PROGRESS, Perindopril
pROtection aGainst REcurrent Stroke Study; SCOPE, Study on
COgnition and Prognosis in the Elderly; TEST, Timolol, Encainide,
Sotalol Trial.
After reference 18: Arima and Chalmers. J Clin Hypertens
(Greenwich). 2011;13:693-702. © 2011, Wiley Periodicals, Inc.


Implications and conclusions

The totality of the studies and analyses reported here make it clear that reduction in the risk of recurrent stroke in patients with cerebrovascular disease is closely tied to the magnitude of reduction in blood pressure, as well as to the level of blood pressure achieved, at least to below 130/80 mm Hg when this is well tolerated in the individual patient. It is also abundantly clear from the PROGRESS trial, which conducted a rigorous comparison of the effect of combination therapy with the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide, that combination therapy is essential in order to achieve sufficient reduction in blood pressure for this to translate into effective reduction in the risk of stroke. The specificity of this message is absolutely in line with the results of numerous national and international studies on the need for combination therapy for effective reduction in the burden of cardiovascular disease, as reflected in all major guidelines.1-5,24

It is also abundantly clear that the combination of perindopril and indapamide is the one specific combination that has been rigorously tested and found to be truly effective for the prevention of recurrent stroke. The absolute risk reductions observed with the combination of perindopril and indapamide suggest that 5 years’ treatment with this combination would avoid one major vascular event, fatal or nonfatal, for every 11 patients treated. Therefore, this combination can be recommended for the prevention of recurrent stroke and associated cardiovascular events in all patients with cerebrovascular disease.


References
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7. PROGRESS Collaborative Group. Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease. Eur Heart J. 2003;24:475-484.
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9. PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163:1069-1075.
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Keywords: combination therapy; hypertension; indapamide; perindopril; PROGRESS; stroke