Komajda 2017.

Study characteristics
Methods	Study design: RCT Unit of randomisation: No information Total duration of study: 25 June 2013 to 7 July 2015 Run‐in period: 2 weeks Intervention time: 8 months Follow‐up: 8 months Setting: 86 centres in 19 countries
Participants	Type of heart failure: CHF N = 179 participants (ivabradine: 95; placebo: 84) Mean age: Ivabradine: 72 ± 6 years Placebo: 73 ± 6 years Gender: Ivabradine: 36 (37.9%) male, 59 (62.1%) female Placebo: 27 (32.1%) male, 57 (67.9%) female Severity of condition: LVEF ≥ 45% Inclusion criteria: NYHA class II/III Sinus rhythm HR ≥ 70 bpm NT‐pro‐BNP ≥ 220 pg/mL BNP ≥ 80 pg/mL LVEF ≥ 45% Age ≥ 50 years Exclusion criteria: Severe valvular disease Primary hypertrophic or restrictive cardiomyopathy Systemic illness Infiltrative heart disease Permanent atrial fibrillation Recent (< 3 months) atrial fibrillation‐related hospitalisation Pacemaker carriage Severe or uncontrolled hypertension Withdrawals: No information
Interventions	Intervention: Ivabradine max. 5 mg twice a day After 2 weeks, if resting HR > 60 bpm: ivabradine max. 7.5 mg twice a day If HR was 50 to 60 bpm, the dose was maintained at 5 mg twice a day If HR was < 50 bpm: reduction of ivabradine to 2.5 mg twice a day At any time during the study the drug dose could be adjusted up or down by 2.5 mg bpm if there were signs or symptoms related to bradycardia Comparison: Placebo Concomitant medications: SC Excluded medications: Non‐dihydropyridine calcium channel blockers Class I antiarrhythmics Strong inhibitors of cytochrome P450 3A4
Outcomes	Outcomes and time points measured in the study: [Day 0 and months 2, 4, 8] Primary endpoints: Echo‐Doppler ratio Distance on the 6‐minute walking test Plasma NT‐pro‐BNP concentration Secondary endpoints: HR Total mitral flow duration Indexed left ventricular end‐diastolic volume Stroke volume LA volume Index ECG Indexed left ventricular mass Ratio of arterial elastance/ventricular end‐systolic elastance NYHA class Quality of life (KCCQ) Occurrence of emergent adverse events Conclusion: "In patients with HFpEF, HR reduction with ivabradine did not improve outcomes. These findings do not support the use of ivabradine in HFpEF"
Notes	Funding for trial: "The EDIFY trial was sponsored by Les Laboratories Servier (Surenes, France). The sponsor was responsible for study management, data collection and data analysis" Notable conflicts of interest of authors: No information Contact to authors/unpublished data: We contacted M Komajda via email on 22 November 2018 to ask for way of randomisation and missing data. We did not receive an answer.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The randomization was balanced (1:1) and stratified on centres." No information provided about method of generating the random sequence.
Allocation concealment (selection bias)	Unclear risk	Insufficient information to base judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Randomized, double‐blind, placebo‐controlled trial." "Study investigators and participants were masked to treatment for the duration of the trial."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to base judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to base judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to base judgement
Other bias	Unclear risk	Insufficient information to base judgement