Swedberg 2010.

Study characteristics
Methods	Study design: RCT Unit of randomisation: No information Total duration of study: 42 months (3 October 2006 to 31 March 2010) Run‐in period: 14 days Intervention time: 1 year Follow‐up: 18 to 28 months Setting: 677 centres in 37 countries
Participants	Type of heart failure: CHF, LV‐dysfunction N = 6505 (ivabradine and BB: 3241; placebo: 3264) Mean age: 60.4 ± 11.4 years Gender: 4970 (76.4%) male, 1535 (23.6%) female Severity of condition: LVEF ≤ 35% Inclusion criteria: Symptomatic HF LVEF of ≤ 35% Sinus rhythm with heart rate ≥ 70 bpm Had been admitted to hospital for HF within the previous year Were on stable background treatment including a BB if tolerated Exclusion criteria: Recent (< 2 months) MI Ventricular or atrioventricular pacing operative for 40% or more of the day Atrial fibrillation or flutter Symptomatic hypotension Patients have not been on optimum and stable background treatment for at least 4 weeks Non‐dihydropyridine calcium‐channel blockers Class I antiarrhythmics Strong inhibitors of cytochrome P450 3A4 Withdrawals: 131 participants (Nnew = 6505)
Interventions	Intervention: 5 to 7.5 mg twice a day The mean dosage was 6.4 (SD 1.6) mg twice a day at 28 days (end of titration) and 6.5 (SD 1.6) mg twice a day at 1 year Comparison: Placebo Concomitant medications: Renin‐angiotensin‐aldosterone system antagonists 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, 1 year] HR Primary endpoint: the composite of cardiovascular death or hospital admission for worsening HF Secondary endpoints: the composite of cardiovascular death or hospital admission for worsening HF in participants receiving at least 50% of the target daily dose of a BB (as defined by the European Society of Cardiology guidelines) at randomisation. (For metoprolol tartrate, for which a dose is not identified in the guidelines, the study authors defined the target dose as 150 mg daily.) all‐cause death cardiovascular death hospital admission for worsening HF all‐cause admission to hospital cardiovascular admission death from HF the composite of cardiovascular death, hospital admission for worsening HF, or hospital admission for non‐fatal MI KCCQ Conclusion: "Our results support the importance of heart‐rate reduction with ivabradine for improvement of clinical outcomes in HF and confirm the important role of HR in the pathophysiology of this disorder"
Notes	Funding for trial: "Funding Servier, France" "The sponsor was responsible for data management and final data analyses. All analyses were verified by the independent statistical centre at Robertson Centre for Biostatistics, University of Glasgow, UK. The executive committee was responsible for the design of the study, the interpretation of the results, the development and writing of the report, and the decision to submit for publication and, after study conclusion and unmasking, had full access to all data. Members of the medical and scientific departments of the sponsor supported the work of the executive committee, but did not make any scientific or research decisions independent of this committee" Notable conflicts of interest of authors: "KS, MK, MB, JSB, IF, and LT have received fees, research grants, or both from Servier. ADB and GL are employees of Servier. KS has received also research grants from Amgen and AstraZeneca, and honoraria from Amgen, Novartis, and AstraZeneca. MK has received consultancy fees from Nile Therapeutics and Bristol‐Myers Squibb, and payment for service on speakers’ bureau from Sanofi‐Aventis, Menarini, Bristol‐Myers Squibb, Merck, and AstraZeneca. IF has received fees from Medtronic, Biotronik, Solvay, Vifor Pharma, IKKF, and GlaxoSmithKline. MB has received fees AstraZeneca, Boehringer Ingelheim, Sanofi‐Aventis, and Pfizer. JSB has received consulting fees from Celladon, Gilead, Sanofi‐Aventis, ARMGO, Novartis, Novacardia (Merck), BioMarin, Roche, Pfizer, Rigel, BioTronik, Salix, XOMA, Lux, Cardiopep, Bristol‐Myers Squibb, and Cardioxyl. LT has received consultancy fees from Medtronic and Menarini, and payment service for speakers’ bureau from Abbot, AstraZeneca, and Pfizer" Contact to authors/unpublished data: We contacted K Swedberg via email on 22 November 2018 to ask for NYHA class and missing data. We did not receive an answer.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly allocated to treatment groups by computer‐generated assignment."
Allocation concealment (selection bias)	Low risk	"The allocation sequence was generated at the sponsor level through validated in‐house application software; access was restricted to people responsible for study therapeutic units production until database lock."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Double‐blind trial"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No blinding. However, the measured outcomes are objective outcomes (mortality, length of stay, etc.) and thus not likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less than 20% missing data. Outcomes reported for 6505 of 6558 participants (99.2%).
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	"Members of the medical and scientific departments of the sponsor supported the work of the executive committee, but did not make any scientific or research decisions independent of this committee."