SENIORS.

Methods	Study design: RCT Centres: multi‐centre, international (Czech Republic, Hungary, Italy, Ukraine, UK, France, Germany, Romania, Spain, Switzerland, The Netherlands) Start of enrolment: September 2000 End of enrolment: December 2002 Mean follow‐up: 21 months Run‐in period: no
Participants	Inclusion criteria: "To be eligible, patients had to be age ≥ 70 years, provide written informed consent, and have a clinical history of chronic HF with at least 1 of the following features: documented hospital admission within the previous 12 months with a discharge diagnosis of congestive HF or documented LVEF ≤ 35% within the previous 6 months. " Exclusion criteria: "The main exclusion criteria were new drug therapy for heart failure in the 6 weeks prior to randomization, any change in cardiovascular drug therapy in the 2 weeks prior to randomization, heart failure due primarily to uncorrected valvular heart disease, contraindication or previous intolerance to beta‐blockers (e.g. heart rate < 60 beats/min or systolic blood pressure < 90 mmHg), current use of beta‐blockers, significant hepatic or renal dysfunction, cerebrovascular accidents within the previous 3 months, and being on a waiting list for percutaneous coronary intervention or cardiac surgery or other major medical conditions that may have reduced survival during the period of the study." Randomised (N): 2128 (1067 intervention, 1061 control); subgroup of interest: 643 (nebivolol N = 320, placebo N = 323) Withdrawn not reported Lost to follow‐up (N): 37 (16 intervention, 21 control) Analysed (N): 2128 (1067 intervention, 1061 control) Age (years, mean, SD): intervention: 76.1, 4.8; control: 76.1, 4.6 Sex (% men): intervention: 61.6; control: 64.7 Ethnicity (%): not reported Systolic blood pressure (mmHg, mean, SD): intervention: 138.6, 20.1; control: 139.5, 21.1 Heart rate (beats/min, mean, SD): intervention: 79.2, 13.6; control: 78.9, 13.7 BMI: not reported Serum creatinine (mg/dL, mean, SD)*: intervention: 1.2, 0.4; control: 1.2, 0.4 B‐type natriuretic peptide (pg/mL): not reported NT pro B‐type natriuretic peptide (pg/mL): not reported LVEF (%, mean, SD): intervention: 36, 13; control: 36, 12 NYHA class I (%): intervention: 3.0; control: 2.7 NYHA class II (%): intervention: 56.5; control: 56.3 NYHA class III (%): intervention: 38.7; control: 38.7 NYHA class IV (%): intervention: 1.8; control: 2.3 Hypertension (%): intervention: 61.1; control: 62.3 Diabetes (%): intervention: 26.9; control: 25.3 Atrial fibrillation (%): intervention: 33.8; control: 35.5 Hospitalisation for heart failure: not reported Coronary heart disease (%): intervention: 68.9; control: 67.6 Stroke (%): intervention: 0.1; control: 0 Diuretic (%); intervention: 85.8; control: 85.5 Digoxin (%): not reported Beta‐blocker (%): study drug ACEI (%): intervention: 81.7; control: 82.6 ARB (%): intervention: 6.2; control: 7.1 MRA (%): intervention: 28.8; control: 26.4
Interventions	Intervention: nebivolol "Nebivolol or placebo tablets were provided in identical packaging and tablet appearance. The initial dose was 1.25 mg once daily, and, if tolerated, this was increased to 2.5 and 5 mg, respectively, every 1–2 weeks, reaching a target of 10 mg once daily over a maximum of 16 weeks." Comparator: placebo Concomitant medication: exclusion criteria: current use of beta blockers
Outcomes	Planned: planned in protocol (Shibata 2002): primary: all cause mortality and cardiovascular hospital admissions (time to first event). Secondary: all cause mortality, composite of all cause mortality or all cause hospital admissions, cardiovascular hospital admissions, cardiovascular mortality, functional capacity by NYHA class, functional capacity by 6 min walk test Reported: reported: compliance to treatment, haemodynamics, death or cardiovascular hospital admission, all cause mortality, cardiovascular hospital admissions, total mortality, cardiovascular mortality, all cause hospitalisation
Notes	subgroup of interest, partial outcome data reported baseline data for all participants, outcome data for subgroup only (nebivolol N = 320, placebo N = 323) emailed trialists to ask for details on HF hospitalisation for LVEF > 40%, withdrawal due to AE, hyperkalaemia. No response.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization to nebivolol or placebo on a 1:1 basis was carried out by telephone call to a central office (Clinical Data Care, Lund, Sweden)."
Allocation concealment (selection bias)	Low risk	"Patients were allocated a treatment number which corresponded to the appropriate study treatment packs."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐blind"; no details
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT used
Selective reporting (reporting bias)	Low risk	primary outcomes reported as planned
Other bias	Low risk	"Dr. van Veldhuisen has received lecture fees from Menarini and was a member of the steering committee of the SENIORS trial. Dr. Cohen‐Solal has received lecture and consultancy fees from Menarini, and was a member of the steering committee for the SENIORS trial and received lecture fees. Dr. Böhm has received speaker fees from Menarini. Dr. Anker has received speaking honoraria from Menarini Ricerche SpA, Roche, Merck, and Tanabe. Dr. Babalis’s department has received a grant from Menarini. Dr. Coats has received honoraria from Menarini. Dr. Poole‐Wilson has received honoraria from Menarini for speaking about the SENIORS trial. Dr. Flather has received research grant funding to his institution from Menarini and speaker fees from Menarini for lectures at scientific meetings and symposia. The original SENIORS trial was supported by Menarini Ricerche SpA, Italy. Funding for additional statistical analyses for the present study to the Clinical Trials and Evaluation Unit in London were obtained. All members of the Steering Committee of the SENIORS trial have received honoraria for speaking on aspects of heart failure and beta‐blockers at meetings funded by companies in the pharmaceutical industry." "SENIORS is sponsored by Menarini Ricerche SpA."