AREA IN‐CHF.

Methods	Study design: RCT. Centres: 46 cardiology centres in Italy. Start of enrolment: September 2002. End of enrolment: July 2005. Follow‐up: 12 months. Run‐in period: not reported.
Participants	Inclusion criteria: aged 18 to 80 years, established evidence of NYHA class II HF, stable, optimised therapy according to European Society of Cardiology criteria, and an LV ejection fraction (EF) ≤ 45%, as measured locally up to 6 months before enrolment. Exclusion criteria: creatinine 2.5 mg/dL; K 5.0 mEq/L; valvular heart disease amenable to surgical treatment; congenital heart disease; unstable angina or acute myocardial infarction or coronary revascularisation procedure within 3 months before enrolment; intravenous therapy with inotropic drugs within 3 months before enrolment; treatment with lithium salts, Kþ‐sparing diuretics, TNF‐a antagonists, or MRA during the last 3 months; history of resuscitated ventricular arrhythmias (unless this occurred within 24 h of a previous acute myocardial infarction or in subjects with an implantable cardioverter defibrillator); other clinical or general conditions contraindicating participation in a clinical trial. Randomised (N): 467 total (225 LVEF > 40%) (231 (116) intervention, 236 (109) control) Withdrawn (N): for reasons other than death 18 (14 intervention,4 control) Lost to follow‐up: not reported Analysed: not reported Age (years, mean, SD): intervention: 62.3, 9.5; control: 62.7, 9.5 Sex (% men): intervention: 81.8; control: 85.2 Ethnicity: not reported Systolic blood pressure (mmHg, mean, SD): intervention: 127.9, 16.2; control: 128.0, 17.2 Heart rate (beats/min, mean, SD): intervention: 68.0, 11.8; control: 65.7, 10.7 BMI (mean, SD): intervention: 26.7, 3.5; control: 26.9, 3.6 Serum creatinine (mg/dL, mean, SD): intervention: 1.1, 0.3; control: 1.1, 0.2 B‐type natriuretic peptide: not reported NT pro B‐type natriuretic peptide: not reported LVEF (%, mean, SD): intervention: 39.9, 8.6; control: 39.7, 8.6 NYHA class: not reported Hypertension (%): intervention: 48.5; control: 42.4 Diabetes (%): intervention: 20.9; control: 19.9 Chronic atrial fibrillation (%): intervention: 7.4; control: 8.5 Hospitalisation for heart failure (%): intervention: 44.6; control: 49.2 Coronary heart disease: not reported Stroke (%): intervention: 1.7; control: 3 Diuretic (%); intervention: 67.8; control: 72 Digoxin: not reported Beta‐blocker (%): intervention: 81.3; control: 77.5 ACEI (%): intervention: 84.9; control: 74.6 ARB (%): intervention: 12.1; control: 24.2 MRA (%): study drug
Interventions	Intervention: canrenone. "The dose of 25 mg/o.d. of canrenone at randomization was increased to 50 mg/o.d. after the first month, if serum Kþ was 5 mEq/L, and in the absence of deterioration in renal function. During follow‐up, if serum Kþ increased up to 5 mEq/L and/or creatinine increased up to 2.5 mg/dL, the dosage of canrenone was reduced to 25 mg/o.d. Subjects requiring down‐titration of study medications were asked to return to the outpatient clinic within 2 weeks for a supplemental visit to evaluate the effectiveness of this change in therapy. If serum Kþ remained .5.5 mEq/L, or if creatinine was 3 mg/dL or had increased by over 1 mg/dL, the study medication was discontinued and the patient managed with conventional treatment only." Comparator: placebo Concomitant medication: "Aspirin, diuretics, digoxin, nitrates, antiarrhythmic agents, oral anticoagulants, and any other therapy were allowed when indicated by the local investigators."
Outcomes	Planned: unclear Reported: "The pre‐specified primary endpoint was the change in echocardiographic LV end‐diastolic volume (LVEDV) over 12 months, measured centrally at the Echocardiographic Reading Centre. Secondary endpoints included changes in EF, estimated diastolic filling pressure, NYHA class, BNP, cardiac mortality, hospitalization for cardiac causes, and the combination of cardiac mortality and hospitalization for cardiac causes"
Notes	Subgroup of participants of interest; response with outcome data for subgroup of participants LVEF > 40% received from trialists; baseline characteristics above are for all trial participants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	not reported
Allocation concealment (selection bias)	Unclear risk	not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	double blind, placebo‐controlled
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	echocardiography data were "read at the end of the study by one experienced independent observer who was blinded to all clinical data and treatment allocation" not reported for other outcomes
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	ITT for all outcomes
Selective reporting (reporting bias)	Unclear risk	unable to assess as protocol and NCT record published/registered after enrolment completed
Other bias	Low risk	"The ANMCO Research Center coordinated the study, managed the data, and undertook analyses, under the supervision of the steering committee, who designed the AREA IN‐CHF study. The funding source (Therabel GiEnne Pharma SpA) had no role in the trial design, conduct, data collection, analyses and data interpretation."