ELANDD.

Methods	Study design: multicenter, double‐blind, placebo controlled, randomised, parallel group trial Centres: 12 in 8 European countries Start of enrolment: not reported End of enrolment: not reported Follow‐up: 6 months Run‐in period: not reported
Participants	Inclusion criteria: "To be included into the study, patients had to fulfil the following criteria: willing and able to sign the informed consent form and comply with the requirements of the study, aged ≥ 40 years, have a documented history of HF and persistent symptoms during effort [New York Heart association (NYHA) class II–III ], an LVEF ≥ 45%, and LV end‐diastolic internal diameter < 3.2 cm/m2 or LV end‐diastolic volume index < 102 mL/m2 by echocardiography, radionuclide ventriculography, or nuclear magnetic imaging, or any abnormality of LV diastolic function documented by echocardiography, according to the guidelines of the European Study Group on Diastolic Heart Failure. This last inclusion criterion was revised in April 2007 following the online publication of the new consensus statement on the diagnosis of HFPEF by the European Society of Cardiology. Accordingly, an E/E ratio > 15 at tissue Doppler echocardiography was required as an inclusion criterion. Patients with an E/E‘ ratio between 8 and 15 could be included when additional abnormalities of diastolic function were found. These included an E/A ratio < 0.5 and/or a deceleration half‐time > 280 ms in patients older than 50 years, and/or a duration of reverse pulmonary vein atrial systole flow–mitral valve atrial wave flow > 30 ms, and/or a left atrial volume index > 40 mL/m2 , and/or an increased LV mass index" Exclusion criteria: "Major exclusion • Patients unable to perform 6‐mi walking test • Planned invasive cardiac procedures or cardiac surgery during the time of the study • Recent (< 3 months) acute coronary syndrome or stroke • Exercise‐induced myocardial ischaemia as main cause of exercise limitation as shown by symptoms (angina) or by previous exams (exercise test, stress echocardiography or myocardial scintigraphy) • Concomitant diseases (COPD, peripheral vasculopathy, orthopaedic disease) as main cause of exercise limitation • Major contraindications to beta‐blocker therapy (sinus bradycardia, \50/min; atrio‐ventricular block, bronchial asthma sensitive to beta‐agonists administration) • Ongoing treatment with beta‐blockers, diltiazem or verapamil • Systolic blood pressure \100 mm Hg • Pregnancy, breast feeding or childbearing potential during the study • History of alcohol or other illicit drug abuse • Expected poor compliance to drug therapy • Participation in any other clinical trial with an investigational product or scheduled to receive any such product during the study or in the 4 weeks following the study • Suffering from any other medical condition that may exclude the patient for safety reasons or interfere with the objective of the study." Randomised (N): 116 (57 intervention, 59 control) Withdrawn (N): for reasons other than death 22 (14 intervention (9 lack of tolerance, 1 protocol violation, 3 consent withdrawal, 1 other), 8 control (consent withdrawal 1, protocol violation 5, 2 other)) Lost to follow‐up (N): 1 (1 intervention, 0 control) Analysed (N): 93 (42 intervention, 51 control) Age (years, mean, SD): intervention: 66.5, 9.8; control: 65.3, 11.3 Sex (% men): intervention: 35; control: 36 Ethnicity (%): not reported Systolic blood pressure (mmHg, mean, SD): intervention: 128, 17 (Table 3 of Conraads), 134, 21 (Table 2); control: 129, 23 (Table 3) 133, 18 (Table 2) Heart rate (beats/min, mean, SD): intervention: 76, 15 (Table 3) 73, 14 (Table 2); control: 78, 13 (Table 3), 73, 11 (Table 2) BMI (mean, SD): intervention: 30.3, 4.5; control: 30.2, 4.9 Serum creatinine (mg/dL, mean, SD): intervention: 88.5, 33.1; control: 85.8, 25.1 B‐type natriuretic peptide (pg/mL): not reported NT pro B‐type natriuretic peptide (pg/mL, median, range): intervention: 147 (9‐3577); control: 126 (15‐2055) LVEF (%, mean, SD): intervention: 61.9, 7.8; control: 63.2, 9.2 NYHA class I (%): 0 NYHA class II (%): intervention: 77; control: 78 NYHA class III (%): intervention: 21; control: 22 NYHA class IV (%): 0 Hypertension (%): intervention: 86; control: 86.4 Diabetes (%): intervention: 21; control: 20 Atrial fibrillation (%): not reported Hospitalisation for heart failure: not reported Coronary heart disease (%): intervention: 17; control: 20 Stroke (%): not reported Diuretic (%); intervention: 49; control: 54 Digoxin (%): not reported Beta‐blocker (%): study drug ACEI (%): intervention: 75; control: 80 ARB (%): not reported MRA (%): not reported
Interventions	Intervention: nebivolol. "Nebivolol was started at 2.5 mg/day and gradually up‐titrated to 10 mg/day over a period of 5 weeks. Down‐titration to lower doses was allowed if the higher dose was not tolerated. Treatment at maintenance doses was continued for an additional 21 weeks (6 months of treatment in total)." Comparator: placebo Concomitant medication: "Ongoing treatment with other drugs was maintained throughout the study."
Outcomes	Planned: " The primary endpoint of the study is the change from baseline in the distance walked during the 6‐min walking test (6MWT) after 6 months of treatment with nebivolol versus placebo. Additional secondary endpoints are the changes from baseline after 6 months, with nebivolol versus placebo, in the following measurements: • Symptoms, assessed using a five‐level scale (extremely worsened, moderately worsened, unchanged, moderately improved, extremely improved); • New York Heart Association (NYHA) functional class; • Minnesota living with heart failure questionnaire [21]; • Maximal exercise duration, peak oxygen consumption, [VO2] and slope of the minute ventilation [VE] to carbon dioxide [VCO2] relation, at cardiopulmonary exercise testing. • Changes in parameters related to LV diastolic function, including peak E velocity at the Doppler recording of transmitral inflow tracing, peak E0 velocity of the mitral valve annulus measured at the level of the septal and lateral wall, respectively, by tissue Doppler recording, and the E/E' ratio. Lastly, the effects of treatment on major outcomes (death, hospitalization and unexpected visit to the outpatient clinic or heart failure unit) as well as adverse events are assessed." Reported: as planned
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated 1:1 randomization"
Allocation concealment (selection bias)	Unclear risk	not reported
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"double‐blinded"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	reasons provided for withdrawal
Selective reporting (reporting bias)	Low risk	reported as planned
Other bias	Low risk	The trial is funded by a grant from Menarini. "We thank Joachim Klinger Director of Data Management and Statistics, Harrison Clinical Research Deutschland, and Lieven Huysse, who worked at Menarini at the time of the study, for management and statistical support."