Tsutsui 2016.

Study characteristics
Methods	Study design: RCT Unit of randomisation: No information Total duration of study: 15 months (December 2013 to February 2015) Run‐in period: 2 weeks Intervention time: 6 weeks Follow‐up: 2 weeks Setting: 73 institutions in Japan
Participants	Type of heart failure: CHF, LV‐dysfunction N = 126 (ivabradine and BB: 84; placebo: 42) Mean age: 59 ± 13.1 years Gender: 108 (85.7%) male, 18 (14.3%) female Severity of condition: HFrEF ≤ 35% Inclusion criteria: Age ≥ 20 years Resting HR ≥ 75 bpm in sinus rhythm Stable symptomatic CHF of NYHA functional class ≥ II LVEF ≤ 35% Under optimal, stable treatment according to the Japanese Guideline for Treatment of CHF (Matsuzaki 2010) Exclusion criteria: Congenital heart disease MI within 2 months Persistent atrial fibrillation or atrial flutter Sick sinus syndrome Sinoatrial node block or second‐ or third‐degree atrioventricular block Atrioventricular pacing operative for ≥ 40% of the day or with backup pacing rate ≥ 60 bpm Severe or uncontrolled hypertension or symptomatic hypotension Moderate or severe hepatic disease Severe renal disease Anaemia Withdrawals: 4 withdrawals Additionally 3 participants (1 in the 2.5 mg group and 2 in the 5 mg group) were excluded for violation of the major inclusion criteria
Interventions	Intervention: Starting dose of ivabradine 2.5 mg twice a day (2.5 mg group); 5 mg twice a day group. The dose was increased up to 7.5 mg twice a day. The final mean doses at 6 weeks were similar between the 2.5 mg and 5 mg groups (6.5 ± 1.8 mg twice a day vs 7.1 ± 1.1 mg twice a day, P = 0.416) Comparison: Placebo Concomitant medications: SC ACE inhibitor Angiotensin‐receptor blocker BB Mineralocorticoid receptor antagonist Diuretics Digitalis Excluded medications: Non‐dihydropyridine calcium‐channel blockers Class I antiarrhythmics Moderate or strong inhibitors of cytochrome P450 3A4
Outcomes	Outcomes and time points measured in the study: [0, 6 weeks] Primary endpoint: Reduction in resting HR from baseline at the 6‐week treatment Secondary endpoint: Change in NYHA functional class LVEF Concentrations of plasma B‐type natriuretic peptide (BNP) NT‐pro‐BNP Conclusion: "Ivabradine starting at 2.5 or 5 mg BID effectively reduced resting HR in Japanese HF patients. Ivabradine at the starting dose of 2.5 mg BID could be safer than 5 mg BID."
Notes	Funding for trial: "This trial was designed and performed by the sponsor (Ono Pharmaceutical)." Notable conflicts of interest of authors: "The data were collected and analyzed and the first draft manuscript was written by the sponsor. It was fully reviewed and revised by the authors." Contact to authors/unpublished data: We contacted H Tsuitsui via email on 22 November 2018 to ask for way of randomisation and missing data. H Tsuitsui answered on 26 November 2018, providing information about method of randomisation and that there were no additional data.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"We used a computer‐based dynamic allocation method by baseline resting heart rate and the dose of beta‐blocker to balance the baseline." (H Tsuitsui via email on 22 November 2018)
Allocation concealment (selection bias)	Unclear risk	Insufficient information to base judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The pts and investigators were masked to the treatment allocation."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to base judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% missing data. Outcomes reported for 122 of 126 participants (96.8%).
Selective reporting (reporting bias)	Low risk	All outcomes stated in the methods section were adequately reported or explained in the results.
Other bias	Unclear risk	"This trial was designed and performed by the sponsor (Ono Pharmaceutical). The data were collected and analyzed and the first draft manuscript was written by the sponsor. It was fully reviewed and revised by the authors."