I‐PRESERVE.

Methods	Study design: parallel RCT Centres: 293 centres in 25 countries (Argentina, Australia, Belgium, Brazil, Canada, Czech Republic, Denmark, France, Germany, Greece, Hungary, Ireland, Italy, Mexico, The Netherlands, Norway, Poland, Portugal, Russia, South Africa, Spain, Sweden, Switzerland, UK, USA) Start of enrolment: June 2002 End of enrolment: April 2005 Mean follow‐up: mean follow‐up time was 49.5 months, and the trial included 16,798 patient‐years of follow‐up Run‐in period: "Eligible patients were treated with single‐blind placebo for 1 to 2 weeks before randomization"
Participants	Inclusion criteria: "All patients were at least 60 years of age and had heart failure symptoms and a left ventricular ejection fraction of at least 45%. In addition, we required patients to have been hospitalized for heart failure during the previous 6 months and have current New York Heart Association (NYHA) class II, III, or IV symptoms with corroborative evidence; if they had not been hospitalized, they were required to have ongoing class III or IV symptoms with corroborative evidence. Such evidence could include findings of pulmonary congestion on radiography, left ventricular hypertrophy or left atrial enlargement on echocardiography, or left ventricular hypertrophy or left bundle‐branch block on electrocardiography. Treatment with an angiotensin‐converting–enzyme (ACE) inhibitor was permitted only when such therapy was considered essential for an indication other than uncomplicated hypertension." Exclusion criteria: "Exclusion criteria included previous intolerance to an angiotensin‐receptor blocker; an alternative probable cause of the patient’s symptoms (e.g. significant pulmonary disease); any previous left ventricular ejection fraction below 40%; a history of acute coronary syndrome, coronary revascularization, or stroke within the previous 3 months; substantial valvular abnormalities; hypertrophic or restrictive cardiomyopathy; pericardial disease; cor pulmonale or other cause of isolated right heart failure; a systolic blood pressure of less than 100 mm Hg or more than 160 mm Hg or a diastolic blood pressure of more than 95 mm Hg despite antihypertensive therapy; other systemic disease limiting life expectancy to less than 3 years; substantial laboratory abnormalities (such as a hemoglobin level of less than 11 g per deciliter, a creatinine level of more than 2.5 mg per deciliter [221 µmol per liter], or liver‐function abnormalities); or characteristics that might interfere with compliance with the study protocol" Randomised (N): 4128 (2067 intervention, 2061 control) Withdrawn (N): for reasons other than death 1368 (702 intervention, 684 control) Lost to follow‐up (N): 73 (29 intervention, 44 control) Analysed (N): 4128 (2067 intervention, 2061 control) Age (years, mean, SD): intervention: 72, 7; control: 72, 7 Sex (% men): intervention: 41; control: 39 Ethnicity (%): intervention: white 94, control: white 93 Systolic blood pressure (mmHg, mean, SD): intervention: 137, 15; control: 136, 15 Heart rate (beats/min, mean, SD): intervention: 72, 11; control: 71, 10 BMI (mean, SD): intervention: 29.7, 5.2; control: 29.6, 5.3 Serum creatinine (mg/dL, mean, SD): intervention: 1.0, 0.32; control: 1.0, 0.34 B‐type natriuretic peptide (pg/mL): not reported NT pro B‐type natriuretic peptide (pg/mL, median, IQR): intervention: 360, 139–987; control: 320, 131–946 LVEF (%, mean, SD): intervention: 59, 9; control: 60, 9 NYHA class I (%): 0 NYHA class II (%): intervention: 21; control: 22 NYHA class III (%): intervention: 77; control: 76 NYHA class IV (%): intervention: 3; control: 3 Hypertension (%): intervention: 89; control: 88 Diabetes (%): intervention: 28; control: 27 Atrial fibrillation (%): intervention: 29; control: 29 Hospitalisation for heart failure in the last six months (%): intervention: 44; control: 44 Myocardial infarction (%): intervention: 24; control: 23 Stroke or TIA (%): intervention: 10; control: 10 Diuretic (%): intervention: loop: 52, thiazide: 38, spironolactone 15; control: loop: 52, thiazide: 38, spironolactone 15 Digoxin (%): intervention: 14; control: 13 Beta‐blocker (%): intervention: 59; control: 58 ACEI (%): intervention: 26; control: 25 ARB (%): study drug MRA (%): intervention: 15; control: 15
Interventions	Intervention: irbesartan. "Patients were started on 75 mg of irbesartan or placebo once daily. The dose was doubled to 150 mg after 1 to 2 weeks and was doubled again to 300 mg after an additional 1 to 2 weeks, according to a forced‐titration protocol as tolerated." "At the end of the titration phase, 84% of the patients in the irbesartan group and 88% of those in the placebo group had reached the 300‐mg dose (mean doses, 275 mg and 284 mg, respectively)." Comparator: "matching placebo" Concomitant medication: "During the study, the proportion of patients receiving an ACE inhibitor rose from 25% in the two groups at baseline to 39% in the irbesartan group and 40% in the placebo group, the use of spironolactone rose from 15% in the two groups at baseline to 28% in the irbesartan group and 29% in the placebo group, and the use of beta‐blockers rose from 59% in the irbesartan group and 58% in the placebo group to 73% in the two groups."
Outcomes	Planned: "The primary end point is defined as time from randomization to the first occurrence of the composite outcome of death (all cause) or cardiovascular hospitalization. [...] The endpoint additionally includes myocardial infarction or stroke occurring during any hospitalization at any point during the study. Secondary endpoints include the effect of irbesartan as compared with placebo in reducing the risk of: cardiovascular death, all‐cause mortality, combined vascular endpoint: cardiovascular death, nonfatal myocardial infarction (MI) or nonfatal stroke; or combined HF endpoint: HF mortality or hospitalizations; [...] quality of life as measured by the Minnesota Living with Heart Failure questionnaire, change in New York Heart Associatioin (NYHA) functional class, change in global assessment of symptoms, N‐terminal B‐type natriuretic peptide levels in blood." (Carson 2005) Reported: all planned outcomes reported
Notes	Emailed trialists to enquire about differing data in different publications and to ask for subgroup data. No response.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"using an automated, central randomization system"
Allocation concealment (selection bias)	Low risk	"The randomization schedule was implemented with the use of an interactive voice‐response system."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"All investigators and committee members who were involved in the conduct of the study (except for members of the data and safety monitoring board) were unaware of study‐group assignments." "double‐blind" (Carson 2005) "matching placebo"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	"blinded review of event rates in 2004" but blinding of event adjudication not specified overall
Incomplete outcome data (attrition bias) All outcomes	Low risk	"At the end of the study, vital‐status data were not available for 29 patients (1%) in the irbesartan group and 44 patients (2%) in the placebo group. If contact could not be made at end of study, data for these patients were censored from the analysis at the date they were last known to be alive." "Data from all patients who underwent randomization were analyzed according to the intention‐to‐treat principle."
Selective reporting (reporting bias)	Low risk	all planned outcomes reported (comparison between published protocol (Carson 2005) and main results paper (Massie 2008)
Other bias	Low risk	"Dr. Massie reports receiving grant support from Bristol‐Myers Squibb, Sanofi‐Aventis, and Merck, consulting fees from Bristol‐ Myers Squibb, Sanofi‐Aventis, Merck, Duke Clinical Research Institute, Momentum Research, Novartis, GlaxoSmithKline, Scios–Johnson & Johnson, Corthera, and Niles Therapeutics, and lecture fees from Merck; Dr. Carson, receiving consulting fees from Bristol‐Myers Squibb, Sanofi‐Aventis, and Merck and lecture fees from AstraZeneca and Novartis; Dr. McMurray, receiving support from Bristol‐Myers Squibb (to Glasgow University) for his work on this trial; Dr. Komajda, receiving consulting fees from Bristol‐Myers Squibb and Servier and lecture fees from Servier, Sanofi‐Aventis, and AstraZeneca; Dr. McKelvie, receiving consulting fees from Bristol‐Myers Squibb and Sanofi‐Aventis and lecture fees from Bristol‐Myers Squibb, Sanofi‐Aventis, Pfizer, Merck, and AstraZeneca; Dr. Zile, receiving consulting fees from Bristol‐Myers Squibb and Sanofi‐Aventis; Ms. Anderson, being employed by the Statistical Data Analysis Center at the University of Wisconsin–Madison, which conducted statistical analysis for this trial, supported by Bristol‐Myers Squibb and Sanofi‐Aventis; Drs. Donovan and Ptaszynska, being employees of and having an equity interest in Bristol‐Myers Squibb; and Dr. Staiger, being an employee of and having an equity interest in Sanofi‐Aventis." study sponsors: Bristol‐Myers Squibb and Sanofi‐Aventis. "The sponsors or a contract research organization collected the trial data, which were then analyzed at the Statistical Data Analysis Center at the University of Wisconsin, Madison, independently of the sponsors."