PARAMOUNT.

Study characteristics
Methods	Study design: RCT Centres: 65 centres and 13 countries Start of enrolment: 2 November 2009 End of enrolment: 31 March 2011 Follow‐up: 36 weeks Run‐in period: "2‐week, single‐blind, placebo run‐in period" "continued background treatment" "ACE inhibitors and ARBs were required to be discontinued 24 h before randomisation"
Participants	Inclusion criteria: "Men and women aged 40 years or older with a left ventricular ejection fraction (LVEF) of 45% or higher and a documented history of heart failure with associated signs or symptoms (dyspnoea on exertion, orthopnoea, paroxysmal dyspnoea, and peripheral oedema) were eligible. Patients were required to have NT‐proBNP greater than 400 pg/mL at screening, be on diuretic therapy, and have a systolic blood pressure less than 140 mm Hg, or 160 mm Hg or less if on three or more blood pressure drugs at randomisation, have an estimated glomerular filtration rate (eGFR) of at least 30 mL/min per 1·73 m2 at screening (calculated by the Modification of Diet in Renal Disease formula), and a potassium concentration of no more than 5·2 mmol/L." Exclusion criteria: "Patients were excluded if they had previous LVEF less than 45% at any time, isolated right heart failure due to pulmonary disease, dyspnoea due to non‐cardiac causes such as pulmonary disease, anaemia, or severe obesity, primary valvular or myocardial diseases, or coronary artery or cerebrovascular disease needing revascularisation within 3 months of screening or likely to need revascularisation during the trial. " Randomised (N): 308 (intervention: 149; control: 152) Withdrawn (N): for reasons other than death: 44 (intervention: 20 participants = 13 adverse events, 6 withdrawal of consent, 1 protocol violation; control: 24 participants = 16 adverse events, 8 withdrawal of consent Lost to follow‐up (N): 16 (intervention: 8 participants = 1 death, 4 lost to follow up, 3 adminstrative reasons; control: 8 participants = 1 lost to follow up, 2 death, 5 adminstrative reasons Analysed (N): depending on outcome (adverse events: ITT, others PP) Age (years, mean, SD): intervention: 70.9 ± 9.4; control: 71.2 ± 8.9 Sex (% men): intervention: 43; control: 44 Ethnicity (%): not reported Systolic blood pressure (mmHG, median, IQR): intervention: 136 (130‐145); control: 136 (126‐145) Heart rate (beats/minutes, SD): intervention: 69 ± 12; control: 70 ± 14 BMI (mean, SD): intervention: 30.1 ± 5.5; control: 29.8 ± 6.1 Serum creatinine not reported B‐type natriuretic peptide not reported NT pro B‐type natriuretic peptide (pg/mL, median (IQR)): intervention: 828 (460 ‐ 1341); control: 939 (582 ‐ 1490) LVEF (%, mean, SD): intervention: 58±7.3; control: 58 ± 8.1 NYHA class I (%): intervention: 1; control: 1 NYHA class II (%): intervention: 81; control: 78 NYHA class III (%): intervention: 19; control: 21 NYHA class IV (%): 0 Hypertension (%): intervention: 95; control: 92 Diabetes (%): intervention: 41; control: 35 Atrial fibrillation (%): intervention: 40; control: 43 Hospitalisation for heart failure (%): intervention: 40; control: 45 Coronary heart disease (myocardial infarction, %): intervention: 21; control: 20 Stroke (%): not reported Diuretic (%): 100 Digoxin (%): not reported Beta‐blocker (%): intervention: 79; control: 80 ACEI (%): intervention: 56; control: 53 ARB (%): intervention: 38; control: 41 MRA (%): intervention: 19; control: 23
Interventions	Intervention: LCZ696 (Sacubritril/ Valsartan), 50 mg twice daily, titated to final dose of 200 mg twice daily over 2 to 4 weeks Comparator: valsartan 40 mg twice daily, titrated to their final doses of 160 mg twice daily over 2 to 4 weeks Concomitant medication: "at the discretion of the treating physicians"
Outcomes	Planned (from first entry on clinicaltrials.gov): primary outcome measures: change in log‐scale in NT‐proBNP. Secondary outcome measures: change in log‐scale in BNP, MR‐proBNP, cGMP; change in echocardiography parameters; class indicators of signs and symptoms of heart failure at each visit; change in the overall summary score and individual domain score of the Kansas City Cardiomyopathy questionnaire; change in clinical composite score (NYHA and global patient assessment score) Reported: "The primary study endpoint was change from baseline in NT‐proBNP assessed at 12 weeks. Secondary endpoints included changes in echocardiographic measures (left ventricular volumes and ejection fraction, left atrial volume, measures of diastolic function) and change in blood pressure, as well as change in New York Heart Association (NYHA) class, clinical composite assessment, and quality of life (Kansas City cardiomyopathy questionnaire; KCCQ).
Notes	Funding: Novartis. "PARAMOUNT was designed jointly by the academic steering committee and the sponsor, which funded the trial. The sponsor was responsible for study management, data collection, and data analysis; all analyses were replicated by an independent statistician at the Brigham and Women's Hospital. The report was drafted by the first author and revised by all authors who have read and agree to the report as written and the decision to submit for publication. The first author had full access to and takes full responsibility for the integrity of the data." Trialists' conflict of interest: SDS, MZ, BP, AV, AS, MP, and JJVM have received research support and have consulted for Novartis. VS, TB, JG and ML are employees of Novartis. EK‐K and MT declare that they have no conflicts of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"computer‐generated random sequence with a block size of four, stratified by previous use of ACE inhibitor or ARB and region."
Allocation concealment (selection bias)	Low risk	"assignment used a central inter‐active voice response system with randomisation codes generated by the sponsor. The system assigned a randomisation number to each patient, which linked the patient to a treatment gorup and specified a unique drug number for study drug to be dispensed. Placebo and active treatment were identical in appearance."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"study investigators and participants were masked to treatment for the duration of the trial"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Unclear ‐ sponsor was responsible for study management, data collection, and data analysis ‐ all analyses were replicated by an independent statistician at the Brigham and Women’s Hospital
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT used
Selective reporting (reporting bias)	Low risk	Appears all primary and secondary outcomes mentioned
Other bias	Low risk	No concerns