Clinical Question

Does a perindopril-based blood-pressure-lowering regimen (with optional indapamide) reduce recurrent stroke and major vascular events in patients with previous stroke or TIA, regardless of baseline blood pressure?

Inclusion Criteria

• History of stroke (focal neurological deficit lasting >24 h due to intracerebral haemorrhage or ischaemia) or TIA (focal neurological or monocular deficit <24 h from arterioembolic/thrombotic disease) within the previous 5 years
• No definite indication for an ACE inhibitor (e.g., heart failure) in the responsible physician's opinion
• No definite contraindication to an ACE inhibitor (e.g., previous intolerance)
• Clinically stable for at least 2 weeks after the most recent vascular event (recommended)
• Successful completion of and adherence to a 4-week open-label perindopril run-in (2 mg daily × 2 weeks then 4 mg daily × 2 weeks)
• No blood pressure entry threshold (both hypertensive and non-hypertensive patients eligible)

Exclusion Criteria

• Definite indication for an ACE inhibitor (e.g., heart failure)
• Definite contraindication to an ACE inhibitor (e.g., prior intolerance)
• Uncontrolled hypertension not managed with non-ACE-inhibitor agents before entry
• Withdrawal during the 4-week active run-in for intolerance (dizziness/hypotension 3.4%, cough 2.7%, other suspected intolerance 2.3%, participant decision 2.0%)
• One case of non-fatal angio-oedema during run-in was documented and excluded

Baseline Characteristics

Arms

Outcomes

Criticisms

• Assignment to combination vs single-drug therapy was NOT randomised — the choice was made by the treating physician before randomisation, so heterogeneity between combination and monotherapy effects could reflect patient selection despite modest baseline differences and lack of adjustment sensitivity.
• Perindopril-alone (5/3 mm Hg BP fall) group produced no discernible stroke reduction; the interpretation that benefit is 'purely a BP effect' is inferred, not directly randomised.
• Open-label 4-week perindopril run-in with exclusion of 14% of registered patients for intolerance limits generalisability to less selected populations (survivor/tolerance bias).
• No blood pressure entry threshold means findings extend to non-hypertensives, but non-hypertensives had a lower absolute event rate and thus smaller absolute benefit.
• Mean age 64 (SD 10); relatively few patients over 75; limited data for very elderly or high-frailty populations.
• 39% Asian recruitment (large China/Japan cohorts) — informative but analyses show consistency between Asian and non-Asian participants.
• Effect on major coronary events (26% RRR) may be over-estimated; confidence interval wide (6-42) and larger than predicted from BP change alone.
• Study drug was single-fixed-dose perindopril; results may not generalise to other ACE inhibitors or to different doses/regimens.
• No formal individual-patient BP target; the 'active' arm's benefit reflects mean BP reduction rather than a treat-to-target strategy.
• Funded in part by Servier (manufacturer of perindopril/indapamide), though authors state independence in design, conduct, and analysis.

Funding

Grants from Servier (manufacturer of perindopril and indapamide), the Health Research Council of New Zealand, and the National Health and Medical Research Council of Australia. The study was designed, conducted, analysed, and interpreted by the investigators independently of all sponsors.