J‐DHF.

Methods	Study design: parallel RCT Centres: "multicenter" but no further details Start of enrolment: May 2004 End of enrolment: March 2009 Mean follow‐up: 3.2 years Run‐in period: no
Participants	Inclusion criteria: "All patients were at least 20 years of age, and had an LVEF of > 40% when diagnosed as having heart failure. Clinical diagnosis of heart failure was based on a slight modification of the Framingham criteria as previously described within the 12 months before study entry. There were no changes in baseline therapy and symptoms of heart failure within a month before study entry in any patients." Exclusion criteria: Current symptomatic hypotension, • Hypertension that has not been controlled to the satisfaction of the investigator by drugs other than β‐blocker • Hemodynamically significant (in the investigators opinion) LV outflow tract obstruction (from either aortic stenosis or ventricular hypertrophy) or mitral valve stenosis • Important aortic or mitral regurgitation in the investigator’s opinion • Heart rate < 50 beats/min • Second‐ or third‐degree heart block without permanent pacemaker in situ • Acute coronary syndrome • Arrhythmogenic right ventricular cardiomyopathy • Primary pulmonary hypertension or pulmonary hypertension not from LV dysfunction • Serious cerebrovascular disease • Acute myocardial infarction within the last 3 months • Patients who require intravenous inotropes • Cerebrovascular accident within the last 6 months • Percutaneous coronary intervention or open heart surgery within the last 3 months • On the waiting list for percutaneous coronary intervention or open heart surgery • Serum creatinine > 3.0 mg/dL or creatinine clearance ≤ 30 mL/min • Known bilateral renal artery stenosis • Serum potassium > 5.5 mEq/L • Serious liver disease • Prescription of β‐blocker within the last month or a history of a life‐threatening adverse event induced by β‐blocker • Any change in cardiovascular drug therapy within a month before randomization • History of chronic obstructive pulmonary disease or restrictive lung disease • Diabetes mellitus that has not been controlled to the satisfaction of the investigator • History of any life‐threatening noncardiac disease (eg, cancer) within 5 years • Other diseases likely to cause death or serious disability within 1 year • Patients unable to walk without personal aid • Arteriosclerosis obliterans with Fontaine Grade II or more. • Severe anemia (hemoglobin ≤ 6.0 g/dL) • Uncontrolled thyroid dysfunction Randomised (N): 245 (120 intervention, 125 control) Withdrawn (N): for reasons other than death (6 intervention, 0 control) Lost to follow‐up (N): (5 intervention, 3 control) Analysed (N): (120 intervention, 125 control) Age (years, mean, SD): intervention: 73, 10; control: 71, 11 Sex (% men): intervention: 57.5; control: 58.4 Ethnicity (%): not reported Systolic blood pressure (mmHg, mean, SD): intervention: 134, 21; control: 133, 21 Heart rate (beats/min, mean, SD): intervention: 72, 11; control: 74, 13 BMI (mean, SD): intervention: 24.2, 4.4; control: 24.1, 4.1 Serum creatinine (mg/dL, mean, SD): intervention: 0.98, 0.37; control: 1.01, 0.45 B‐type natriuretic peptide (pg/mL, mean, SD): intervention: 219.2, 294.9; control: 234.9, 281.6 NT pro B‐type natriuretic peptide (pg/mL): not reported LVEF (%, mean, SD): intervention: 62, 10; control: 63, 11 NYHA class I (%): intervention: 18.3; control: 18.4 NYHA class II (%): intervention: 69.2; control: 75.2 NYHA class III (%): intervention: 10.8; control: 4.8 NYHA class IV (%): intervention: 1.7; control: 1.6 Hypertension (%): intervention: 80.0; control: 80.8 Diabetes (%): intervention: 27.5; control: 33.6 Atrial fibrillation (%): intervention: 50.8; control: 45.6 Hospitalisation for heart failure (%): intervention: 60.0; control: 60.0 Ischaemic heart disease (%): intervention: 28.3; control: 24.0 Stroke (%): intervention: 11.7; control: 12.8 Diuretic (%); intervention: 63.3; control: 56.8 Digoxin (%): intervention: 19.2; control: 21.6 Beta‐blocker (%): study drug ACEI (%): intervention: 24.2; control: 22.4 ARB (%): intervention: 50.8; control: 56.0 MRA (%): intervention: 20.8; control: 25.6
Interventions	Intervention: carvedilol. "In the carvedilol arm, carvedilol was up‐titrated from 1.25 mg twice daily to the target dose of 10 mg twice daily within 8 weeks based on tolerability. Patients were maintained at the target dose or the maximum tolerated dose for the remainder of the study." Comparator: usual care Concomitant medication: "In both arms, patients were treated with standard cardiovascular therapy excluding beta‐blockers."
Outcomes	Planned: "The primary outcome is a composite of cardiovascular death and unplanned admission to hospital for congestive heart failure. The secondary outcomes are listed as follows: all‐cause mortality; worsening of the symptoms (defined by either a decrease by 1 Mets in the SAS questionnaire score or an increase by 1 class in the New York Heart Association functional class for at least 3 months compared with the baseline); an increase in brain natriuretic peptide by 30% of the value at the randomization in patients with brain natriuretic peptide 200 pg/mL at the randomization; unplanned admission to hospital for congestive heart failure; or a need for modification of the treatment for heart failure (changes in oral medicine for at least 1 month or addition of intravenous inotropes for at least 4 hours)." (Hori 2005) Reported: as planned
Notes	Emailed investigators on 13 November 2017 to ask about data on cardiovascular mortality and all‐cause mortality as different numbers are provided in Table 2 of Yamamoto 2013 (primary reference). No response.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"patients were randomized to the arm " but no details
Allocation concealment (selection bias)	Unclear risk	no information
Blinding of participants and personnel (performance bias) All outcomes	High risk	"open"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Deaths and hospitalizations were adjudicated by a blinded independent Endpoint Committee, using prespecified criteria." "Outcomes were assessed by the Endpoint Committee (see Appendix) where all the committee members were blinded to the allocated group."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"The primary outcome was a composite of cardiovascular death and unplanned hospitalization for heart failure using a time‐to‐first‐event ana‐ lysis and the intention‐to‐treat principle." unspecified for secondary outcomes lost to follow‐up low/similar in both groups (4.2% intervention, 2.4% control)
Selective reporting (reporting bias)	Low risk	outcomes reported as planned in published protocol (Hori 2005)
Other bias	Low risk	authors CoI: "none declared" funding: "The Ministry of Health, Labor andWelfare, Japan; the Japan Heart Foundation."