Tsutsui 2019.

Study characteristics
Methods	Study design: RCT Unit of randomisation: No information Total duration of study: 35 months (October 2016 to August 2019) Run‐in period: 2 weeks Intervention time: 52 weeks Follow‐up: 52‐week follow‐up of the last enrolled patient. Setting: 146 institutions in Japan
Participants	Type of heart failure: CHF, LV‐dysfunction N = 254 (ivabradine 127; PC: 127) Mean age: 60.6 ± 13.5 years Gender: 209 (82.4%) male, 45 (17.6) female Severity of condition: HFrEF ≤ 35% Inclusion criteria: Age ≥ 20 years Optimised and unchanged medications and dosages for CHF ≥ 4 weeks NYHA functional class II, III, or IV ≥ 4 weeks, and stable clinical condition ≥ 4 weeks LVEF 35% within the previous 12 weeks Resting heart rate ≥ 75 beats/min in sinus rhythm A history of hospital admission for worsening heart failure within the previous 52 weeks Exclusion criteria: Myocardial infarction or coronary revascularisation within the previous 8 weeks Severe primary valvular disease or scheduled surgery for valvular heart disease Stroke or transient cerebral ischaemia within the previous 4 weeks Active myocarditis Congenital heart diseases Heart transplantation candidates Cardiac resynchronisation therapy within the previous 24 weeks Pacemaker with atrial or ventricular pacing (except for biventricular pacing) > 40% of the day, or with stimulation threshold at the atrial or ventricular level ≥ 60 bpm Persistent atrial fibrillation or flutter Sick sinus syndrome, sinoatrial block, second‐ and third‐degree atrioventricular block Symptomatic or sustained (≥ 30 s) ventricular tachycardia unless a cardioverter/defibrillator is implanted Cardioverter/defibrillator shock within the previous 24 weeks Family history or congenital long QT syndrome or treated with selected QT‐prolonging drugs Severe or uncontrolled hypertension (SBP > 180 mmHg or DBP > 110 mmHg) Hypotension (sitting SPB < 85 mmHg or symptomatic hypotension) Moderate or severe liver disease, severe renal disease, or anaemia Withdrawals: 11 withdrawals 2 lost to follow‐up
Interventions	Intervention: Ivabradine Starting dose of ivabradine 2.5 mg twice a day. The dose was adjusted at each visit up to 7.5 mg twice a day. Comparison: Placebo Concomitant medications: BB (carvedilol, bisoprolol) Excluded medications: BB (other than carvedilol, bisoprolol) Non‐dihydropyridine calcium‐channel blockers Class I antiarrhythmics moderate and strong cytochrome P450 3A4 inhibitors Cytochrome P340 3A4 inducers unapproved drugs
Outcomes	Outcomes and time points measured in the study: Primary endpoints: composite of cardiovascular death hospital admission for worsening HF Secondary endpoints all‐cause cardiovascular, or HF death hospital admission for all causes cardiovascular causes or worsening HF, and a composite of cardiovascular death, hospital admission for worsening HF, or hospital admission for non‐fatal myocardial infarction Changes in resting HR Changes in NYHA functional class LVEDV index LVESV index LVEF BNP and NT‐pro‐BNP Conclusion: "In conclusion, ivabradine had efficacy and safety in Japanese patients with HFrEF, consistent with the SHIFT study."
Notes	Funding for trial: The trial was performed by the sponsor, Ono Pharmaceutical Co, Ltd Notable conflicts of interests: "H.T. received remuneration from Otsuka, Takeda, Mitsubishi Tanabe, Daiichi Sankyo, Boehringer Ingelheim Japan, Bayer, and Pfizer; research funding from Boehringer Ingelheim Japan and Mitsubishi Tanabe; and scholarship funds from MSD, Daiichi Sankyo, Sankyo, Mitsubishi Tanabe, Otsuka, Bayer, and Boehringer Ingelheim; scholarship funds from Daiichi Sankyo, Mitsubishi Tanabe, Otsuka, Bayer, Boehringer Ingelheim, Takeda, Mochida, and Ono Pharma Co.; and is affiliated with an endowed department sponsored by Medtronic Japan. M.Y. received remuneration and scholarship funds from Ono Pharmaceutical Co. Ltd. K.Y. received remuneration from Otsuka Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., and Mitsubishi Tanabe Pharma Co. Ltd; and scholarship funds from St. Jude Medical Japan Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Johnson & Johnson, Biotronik Japan Inc., Japan Lifeline Co. Ltd., Teijin Pharma Ltd., Mitsubishi Tanabe Pharma Co. Ltd., Fukuda Denshi, Takeda Pharmaceutical Co. Ltd., Nihon Kohden Co. Ltd. Novartis, Pfizer Inc, and Boston Scientific Co. Ltd. Y. Sakata received remuneration from Otsuka Pharmaceutical and Daiichi Sankyo, and scholarship funds from Ono Pharmaceutical. T.T. and Y. Kawasaki are employees of Ono Pharmaceutical. The remaining authors have nothing to disclose." Contact to authors/unpublished data: No information
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A minimization method for dynamic allocation was used with adjustment for study site, baseline resting HR (≥85 and <85 beats/min), and β‐blocker dose before study treatment (0, >0–<50, and ≥50% of the target dose of carvedilol 20 mg/day and bisoprolol 5 mg/day) to balance baseline covariates."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to base judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were masked to treatment allocation, and study medications (ivabradine or placebo) were the same size and colour.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"An endpoint adjudication committee, independent from the sponsor and ivestigators, evaluated all clinical events according to prespecified definitions in a blinded manner"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% missing data. Outcomes reported for 253 of 254 participants (99.6%).
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 Co., Ltd. The data were collected and analyzed, and the first draft manuscript was written by the sponsor."