PEP‐CHF.

Methods	Study design: RCT Centres: 53 centres (Bulgaria (3), Czech Republic (5), Hungary (10), Ireland (1), Poland (26), Russia (1), Slovakia (2), and the UK (5)) Start of enrolment: 2000 End of enrolment: 2003 Mean follow‐up: mean follow‐up 26.2 months (range, excluding deaths 12.0‐54.2) Run‐in period: "A 24‐h open label run in phase, during which patients will receive a single 2‐mg dose of perindopril"
Participants	Inclusion criteria: "Patients had to be aged ≥70 years and treated with diuretics for a clinical diagnosis of CHF due to LV diastolic dysfunction as defined below and to have had a cardiovascular hospitalization within the previous 6 months. Patients had to be able to walk without the aid of another person in order to exclude very frail patients who might not respond to any treatment.""Patients had to be aged 70 years and treated with diuretics for a clinical diagnosis of CHF due to LV diastolic dysfunction as defined below and to have had a cardiovascular hospitalization within the previous 6 months. Patients had to be able to walk without the aid of another person in order to exclude very frail patients who might not respond to any treatment." "As there are no widely agreed criteria for the diagnosis of diastolic heart failure, at least three out of nine clinical and at least two out of four additional echocardiographic criteria were required. Clinical criteria were: exertional breathlessness; orthopnoea or paroxysmal nocturnal dyspnoea; ankle swelling; improved breathlessness with diuretic therapy; increased jugular venous pressure; prior episode of clinical pulmonary oedema; prior MI; cardiothoracic ratio > 0.55; and previous radiological pulmonary oedema. Echocardiographic criteria were: an LV wall motion index of 1.4–1.6 inclusive, roughly equivalent to an LVEF fraction between 40 and 50%, since abnormal diastolic dysfunction is often associated with some impairment of systolic function; a left atrial diameter > 25 mm/m2 body surface area or > 40 mm because chronic elevation of LV filling pressure should lead to atrial dilatation; an interventricular septum or posterior LV wall ≥ 12 mm in thickness suggesting hypertrophy, a common cause of impaired diastolic function or, finally, evidence of impaired LV filling by at least one of the criteria recommended by the European Society of Cardiology Study Group on Diastolic Heart Failure. These included an E/A ratio < 0.5 or deceleration time of > 280 ms from the mitral inflow pattern or an isovolumic relaxation time of > 105 ms. These criteria effectively exclude patients with atrial fibrillation (AF) and therefore, in a protocol modification early in the course of the study, this arrhythmia was counted as equivalent to evidence of impaired LV filling by Doppler." Exclusion criteria: "Patients with a wall motion index of < 1.4, roughly equivalent to an LVEF of 40%, were excluded." "Important exclusion criteria were haemodynamically significant valve disease, stroke within the previous month, sitting systolic arterial pressure < 100 mmHg, serum creatinine > 200 mmol/L or potassium > 5.4mmol/L, history of ACE‐inhibitor intolerance or use of an ACE‐inhibitor or angiotensin receptor blocker within the previous week, potassium‐sparing diuretics (other than low‐dose spironolactone), or potassium supplements." Randomised (N): 850 (424 intervention, 426 control) Withdrawn (N): due to serious adverse events 13 (9 intervention, 4 control) Lost to follow‐up (N): 4 (4 intervention, 0 control) Analysed (N): 846 (420 intervention, 426 control) Age (years, median, IQR): intervention: 75, 72–79; control:75, 72‐79 Sex (% men): intervention: 46; control: 43 Ethnicity (%): not reported Systolic blood pressure (mmHg, median, IQR): intervention: 138, 128–150; control: 140, 129–150 Heart rate (beats/min, median, IQR): intervention: 74, 66 to 81; control: 73, 66 to 82 BMI (median, IQR): intervention: 27.5, 25.1 to 30.0; control: 27.6, 25.3 to 30.7 Serum creatinine (mg/dL, median, IQR, converted from umol/L using http://www.endmemo.com/medical/unitconvert/Creatinine.php): intervention: 1.07, 0.92‐1.24; control: 1.10, 0.95‐1.26 B‐type natriuretic peptide (pg/mL): not reported NT pro B‐type natriuretic peptide (pg/mL): intervention: 335, 160–1014 (for subgroup n =191); control: 453, 206–1045 (for subgroup n = 184) LVEF (%, median, IQR): intervention: 65, 56– 66; control: 64, 56– 66 NYHA class I/II (%): intervention: 77; control: 74 NYHA class III/IV (%): intervention: 23; control: 26 Hypertension (%): intervention: 79; control: 79 Diabetes (%): intervention: 21; control: 20 Atrial fibrillation (%): intervention: 19; control: 22 Hospitalisation for heart failure: not reported Coronary heart disease (%): intervention: 27; control: 26 Stroke not reported Diuretic (%); intervention: loop: 47, thiazide 54, low dose spironolactone 9; control: loop: 44, thiazide 55, low dose spironolactone 11 Digoxin (%): intervention: 11; control: 13 Beta‐blocker (%): intervention: 55; control: 54 ACEI: study drug ARB not reported MRA (%): intervention: 9; control: 11
Interventions	Intervention: perindopril. "Patients were reviewed weekly for the first 5 weeks to ensure that treatment was tolerated and to check serum potassium and creatinine. The dose of perindopril was increased to 4 mg once daily at the second follow‐up visit if no clinical contraindication, such as hypotension or worsening renal function existed. Study medication was reduced or discontinued if serum creatinine rose to > 250 mmol/L or by > 50 mmol/L from baseline or potassium rose to > 5.5mmol/L. Patients were reviewed at 8, 12, and every 12 weeks thereafter until 1 year follow‐up, then according to the investigator’s judgment until the end of the study." Comparator: placebo Concomitant medication: not reported
Outcomes	Planned: "The primary end‐point of this study will be the time to first occurrence of the combined end‐point of total mortality and unplanned heart failure related hospitalisation." "Secondary 1. Death all causes 2. Death or worsening symptoms and/or signs of CHF requiring hospitalisation or an increase in diuretic treatment for CHF of >40 mg/day of frusemide compared to baseline or equivalent. This will be a time to first event analysis. 3. Cardiovascular mortality. 4. Number of days alive and out of hospital. 5. Number of days alive and not in hospital for cardiovascular reasons including CHF 6. QoL questionnaire change from baseline to 1 year. 7. CHF symptom score change from baseline to 1 year. 8. NYHA heart failure score change from baseline to 1 year." (Cleland 1999) Reported: primary outcome, all‐cause mortality, cardiovascular mortality, HF hospitalisation, days in hospital for cardiovascular reasons, days in hospital for any reason, NYHA class, 6‐min walk distance, plasma concentrations of NTproBNP, cardiovascular death or unplanned HF related hospitalisation, stroke, acute coronary syndrome, blood pressure, serum potassium and creatinine Planned but not reported: QoL
Notes	Protocol (Cleland 1999) mentions subgroup analyses by age and sex but not found in published papers. Emailed investigators. No response.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"patients were randomly assigned from a computer‐generated list in blocks of four within treatment centres"
Allocation concealment (selection bias)	Low risk	"through a centrally administered process, concealed from the study investigators."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The study medication was provided in externally indistinguishable tablets."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Potential classifying events were independently classified by MT and JGFC, blind to treatment allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	4/850 lost to follow up
Selective reporting (reporting bias)	Low risk	Primary outcomes reported, but not all secondary outcomes reported as planned (eg QoL)
Other bias	Low risk	"Servier funded the trial and provided site monitors for source data verification. The sponsor had access to the database and participated in the analysis under the supervision of an independent statistician (NF). The Steering Committee wrote the manuscript. Servier representatives commented on it prior to submission."