PROGRESS

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PROGRESS Collaborative Group. "Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack". Lancet. 2001. 358(9287):1033–1041.
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Clinical Question

In patients with a history of CVA (including ischemic or hemorrhage stroke, TIA or amaurosis fugax) does the use of perindopril +/- indapamide lead to decreased risk of future stroke?

Bottom Line

Among patients with a history CVA (including ischemic or hemorrhage stroke, TIA or amaurosis fugax), patient treated with anti-hypertensive therapy with perindopril (and the addition of indapamide at the discretion of the treating clinician) had decreased risk of recurrent strokes.

Major Points

Hypertension is one of the well recognized major modifiable risk factors with regards to prevention of stroke. [1] The optimal management of BP in the context of secondary prevention is less clear. A meta-analysis conducted prior to the PROGRESS trial suggested that blood pressure reductions of 6-8 mm Hg systolic and 3-4 mm Hg diastolic decreased the risk of recurrent strokes by a fifth. [2] However, the confidence intervals were very wide in this particular meta-analysis.

The PROGRESS trial provides RCT evidence suggesting that the reduction of blood pressure is beneficial for secondary prevention of stroke in both hypertensive and normotensive patients. Treatment with combination therapy with indapamide and perindopril decreased blood pressure and recurrence of stroke. This trial is often misquoted in stating that perindopril therapy leads to decreases in stroke recurrence when there was a non-significant decrease with perindopril therapy alone. The authors have repeatedly re-enforced that the trial's result shows BP reduction is beneficial and less focus should be paid to the particular agent being used.

Guidelines

AHA/ASA Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack 2014:

  • Initiation of BP therapy is indicated for previously untreated patients with ischemic stroke or TIA who, after the first several days, have an established BP ≥140 mmHg systolic or ≥90 mmHg diastolic (Class I;Level of Evidence B).
  • Initiation of therapy for patients with BP <140 mmHg systolic and <90 mmHg diastolic is of uncertain benefit (Class IIb; Level of Evidence C). (Revised recommendation)
  • Resumption of BP therapy is indicated 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 (Class I; Level of Evidence A). (Revised recommendation)
  • Goals for target BP level or reduction from pretreatment baseline are uncertain and should be individualized, but it is reasonable to achieve a systolic pressure <140 mmHg and a diastolic pressure <90 mmHg (Class IIa; Level of Evidence B). For patients with a recent lacunar stroke, it might be reasonable to target an SBP of <130 mmHg (Class IIb; Level of Evidence B). (Revised recommendation)
  • Several lifestyle modifications have been associated with BP reductions and are a reasonable part of a comprehensive antihypertensive therapy (Class IIa; Level of Evidence C). These modifications include salt restriction; weight loss; the consumption of a diet rich in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity; and limited alcohol consumption.
  • The optimal drug regimen to achieve the recommended level of reductions is uncertain because direct comparisons between regimens are limited. The available data indicate that diuretics or the combination of diuretics and an angiotensin-converting enzyme inhibitor is useful (Class I; Level of Evidence A).
  • The choice of specific drugs and targets should be individualized on the basis of pharmacological properties, mechanism of action, and consideration of specific patient characteristics for which specific agents are probably indicated (eg, extracranial cerebrovascular occlusive disease, renal impairment, cardiac disease, and DM) (Class IIa; Level of Evidence B).

Design

  • Multicenter, double-blind, randomized controlled trial
  • N=6105
    • Placebo (n=3054)
      • Single placebo (n=1280)
      • double placebo (n=1774)
    • Anti-hypertensive treatment (n=3051)
      • perindopril only (n=1281)
      • combination of perindopril and indapamide (n=1770)
  • Setting:172 collaborating centers from ten countries in Asia, Australasia, and Europe
  • Enrollment: 1995-2001
  • Mean follow-up: 3.9 years
  • Analysis: Intention-to-treat
  • Primary outcome: Repeat stroke

Population

Inclusion Criteria

  • A history of stroke (intracerebral haemorrhage or ischaemia) or transient ischaemic attack within the previous 5 years.
  • There were no blood pressure entry criteria (recommended those with uncontrolled hypertension get antihypertensive agents other than ACE inhibitors before entry to the trial).
  • Clinically stable for at least 2 weeks after most recent vascular event

Exclusion Criteria

  • Other indication for treatment with ACE-I (E.g. heart failure)
  • Contraindications for ACE-I
  • Patient found to be intolerant of perindopril during the open label run-in phase (2MG perindopril daily for 2 weeks, followed by 4MG perindopril daily for 2 weeks)

Baseline Characteristics

Given for group given hypertensive therapy (N=3051), groups are similar

  • Mean age (SD): 64 (10)
  • Number of women (%): 923 (30%)
  • Number of Asian patients (%): 1176 (39%)
  • Type of CVA:
    • Ischemic: 2157 (71%)
    • Hemorrhagic: 332 (11%)
    • Unknown: 134 (4%)
    • TIA or amaurosis fugax: 22%
  • Median time from qualifying event in months (IQR): 8 (2-21)
  • Current smoker: 606 (20%)
  • Diabetic: 394 (13%)
  • CAD: 493 (16%)
  • Mean SBP in mmHg (SD): 147 (19)
  • Mean DBP in mmHg (SD): 86 (11)
  • Hypertensive based on BP at first visit: 1464 (48%)
  • Patient being treatment with an anti-hypertensive agent: 1510 (50%)

Interventions

  • Perindopril 4MG PO daily. Addition of indapamide 2.5 MG PO daily (with the exception of Japan where it was 2.0 MG PO daily) at the discretion of the clinician if there was no contraindication for a diuretic.

Outcomes

  • Active group had blood pressure reduced by an overall average of 9.0/4.0 mm Hg (SE 0.3/0.2) compared to placebo
  • Combination therapy (12.3/5.0 mm Hg [0.5/0.3]) was twice as great as those among participants treated with single-drug therapy (4.9/2.8 mm Hg [0.6/0.3]).

Primary Outcomes

Active treatment vs. placebo

  • Recurrent Stroke Rates: 307 (10%) vs. 420 (14%), RR reduction 28% [95% CI 17-38%]; p<0.0001

Secondary Outcomes

Active treatment vs. placebo

  • Fatal or disabling stroke with disability: 123 (4.0%) vs 181 (5.9%), RR reduction 33% [95% CI 15-46%]
  • Major vascular events (including non-fatal stroke, non-fatal myocardial infarction, or death due to any vascular cause): 458 (15%) vs. 604 (20%), RR reduction 26% [95% CI 16-34%]
    • Vascular death: 181 (5.9%) vs. 198 (6.4%), RR reduction 9% [95% CI -12-25%]
    • Non-fatal MI: 60 (2.0) vs. 96 (3.1%), RR reduction 38% [95% CI 14-55%], [NB: This is corrected from 14-15% in erratum in Lancet 2001 Nov 3;358(9292):1556.]
    • Non-fatal strokes: 275 (9.0%) vs. 380 (12.4%), RR reduction 29% [95% CI 17-39%]
  • Total and cause-specific deaths
    • Stroke: 42 (1.4%) vs. 50 (1.6%), RR reduction 16% [95% CI -27-44%]
    • Coronary: 58 (1.9%) vs. 62 (2.0%), RR reduction 7% [95% CI -34-39%]
    • Other Vascular: 81 (2.6%) vs. 86 (2.8%), RR reduction 6% [95% CI -28-30%]
    • Cancer: 64 (2.1%) vs 65 (2.1%), RR reduction 2% [95% CI -39-30%]
    • Other non-vascular: 61 (2.0%) vs 56 (1.8%), RR reduction 4% [95% CI -12 to 18%]
  • Hospital admissions: 1252 [41%] vs 1349 [44%], relative risk reduction 9% [95% CI 1-15]

Subgroup Analysis

  • There was a small differences between blood pressure reductions seen among those classified as hypertensive (9.5/3.9 mm Hg [0.6/0.3]) and those classified as non-hypertensive at the first visit (8.8/4.2 mm Hg [0.5/0.3]).

Combination and single drug effects

  • Stroke in combination vs. placebo: 150 (8.5%) vs. 255 (14.4%), RR reduction 43% [95% CI 30-54%]
  • Stroke in perindopril only vs. placebo: 157 (12.3%) vs. 165/1280 (12.9%), RR reduction 5% [95% CI -19-23%]
  • Major vascular event in combination vs. placebo: 231 (13.1%) vs. 367/1774 (20.7%), RR reduction 40% [95% CI 29-49%]
  • Major vascular event in perindopril only vs. placebo: 227/1281 (17.7%) vs. 237/1280 (18.5%), RR reduction 4% [95% CI 15-20%]

Drug effects in hypertensive patients

  • Stroke in active treatment vs. placebo: 163 (11.1%) vs. 235 (16.2%), RR reduction 32% [95% CI 17-44%]
  • Major vascular event in active treatment vs. placebo: 240 (16.4%) vs. 331 (22.8%), RR reduction 29% [95% CI 16-40%]

Drug effects in normotensive patients

  • Stroke in active treatment vs. placebo: 144 (9.1%) vs. 185 (11.5%), RR reduction 27% [95% CI 8-42%]
  • Major vascular event in active treatment vs. placebo: 218 (13.7%) vs. 273 (17.0%), RR reduction 24% [95% CI 9-37%]

Adverse Events

Comparisons are active treatment vs. placebo

  • Cough: 66 (2·2%), placebo 12 (0·4%) vs. 69 (0.4%) [NB: This is corrected from 47 (2.2%) vs. 69 (0.4%) in the original publication in erratum in Lancet 2002 Jun 15;359(9323):2120.]
  • Hypotension: 64 (2.1%) vs. 29 (0.9%)
  • Angioedema: 3 (0.10%) vs. O

Criticisms

  • The blood pressure cut off delineating hypertension at intake was 160/90 mmHg
  • 14% of patients (1016/7121) withdrew prior to randomization in open-label period due to side effects or other reason affecting the applicability of this study.
  • The study population was predominantly male (70%)
  • There was no indapamide alone arm in this trial, which make the results difficult to interpret, especially when the PATS trial previously shown indapamide reduces recurrent stroke risk by 29% when used as secondary prevention with only a 5/2 mm Hg BP reduction. [3]
  • Patients with large vessel stenosis were not identified or excluded from this trial. Evidence from carotid stenosis trials suggest that the results of PROGRESS and PATS should not be generalized to those with large vessel stenosis as the correlation between hypertension and stroke risk is different and over aggressive treatments may lead to watershed injury, especially in those with bilateral carotid disease.[4] [5]

Funding

  • Funded by grants from Servier, the Health Research Council of New Zealand, and the National Health and Medical Research Council of Australia.

Further Reading

  1. UK-TIA Study Group. The United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin Trial: final results. J Neurol Neurosurg Psychiatry. 1991; 54: 1044–1054.
  2. Rodgers A, Neal B, MacMahon S. The effects of blood pressure lowering in cerebrovascular disease. Neurol Rev Int 1997; 2: 12–15.
  3. PATS Collaborative Group. Post-stroke antihypertensive treatment study: a preliminary result. Chin Med J. 1995; 108: 710–717.
  4. European Carotid Surgery Trialists’ Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998; 351: 1379–1387.
  5. Barnett HJM, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, et al, for the North American Symptomatic Carotid Endarterectomy Trial Collaborators. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998; 339: 1415–1425.