Real-world Effectiveness and Safety of Savagen (Sacubitril/Valsartan) in Malaysian HFrEF Patients

Background: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), reduces cardiovascular mortality and heart failure hospitalisation in HFrEF and has favourable effects on NT-proBNP and cardiac remodelling. Savagen is a locally available generic formulation registered on the basis of bioequivalence. Bioequivalence supports registration but does not describe clinical response, persistence, tolerability or patient-reported outcomes in Malaysian patients under usual care. Because diet influences symptom control, fluid balance, renal function and potassium, dietary diversity is assessed as an exploratory, hypothesis-generating measure; it will not be used to infer a causal effect of Savagen on diet.

Design: Multicentre, prospective, single-arm cohort at a minimum of two Malaysian hospitals offering an HFMTAC (initial sites: Hospital Shah Alam and Hospital Sultan Idris Shah, Serdang), with a total duration of 24 months from Q3 2026. Savagen is prescribed within its approved indication; initiation, dose selection, titration, continuation and discontinuation remain under the treating physician's judgement, and no study-specific dosing regimen is imposed. Background guideline-directed therapy (beta-blockers, loop diuretics, MRAs, SGLT2 inhibitors) is permitted; concomitant ACE inhibitors, aliskiren and nesiritide are not.

Procedures: Visit 1 (Month 0): written informed consent, eligibility confirmation, demographics, medical and heart failure history, NYHA class, concomitant medications, vital signs, clinical status, KCCQ, Dietary Diversity Score (DDS) questionnaire, NT-proBNP, serum creatinine, eGFR and serum potassium, transthoracic echocardiography if not already done within the specified timeframe, and Savagen initiation details. Visit 2 (Month 6): vital signs, clinical status, Savagen dose and titration history, concomitant medications, KCCQ, DDS, NT-proBNP, serum creatinine, eGFR, serum potassium, AEs/SAEs, hospitalisations, and adherence. Visit 3 (Month 12): all Month 6 procedures plus final echocardiography (LVEF), cardiovascular death and study completion status. Safety monitoring after initiation or titration (blood pressure, renal function, potassium, volume status) follows routine institutional practice. Participants may be withdrawn for safety concerns (e.g., symptomatic hypotension or systolic BP <90 mmHg with symptoms, rapidly worsening dyspnoea, fluid overload, severe hyperkalaemia, clinically significant worsening renal function, suspected angioedema, pregnancy); withdrawn participants receive a final safety follow-up within 14 to 30 days where possible and are not replaced.

Sample size: Assuming a 40% reduction in NT-proBNP, SD 0.9 (log-transformed within-patient change), two-sided alpha 0.05 and 80% power, the minimum sample is 60; allowing 20% loss to follow-up, target enrolment is approximately 80.

Analysis: Paired t-test or Wilcoxon signed-rank test for change in NT-proBNP (primary) and in LVEF, KCCQ, serum creatinine, eGFR, serum potassium and DDS; linear mixed-effects models for NT-proBNP, KCCQ and DDS trajectories; Kaplan-Meier analysis for the composite of cardiovascular death or first HF hospitalisation, with Cox regression if event numbers allow; correlation and covariate-adjusted regression to explore associations between DDS and clinical outcomes (hypothesis-generating); multivariable regression for baseline predictors of improvement or adverse outcomes. Missing data are described; complete-case analysis is used where missingness is small, with sensitivity analyses where appropriate.

Safety and ethics: AEs and SAEs are recorded from enrolment until completion or withdrawal, including onset, severity, seriousness, outcome, action taken and relationship to Savagen; SAEs are reported to the ethics committee and regulatory authorities per Malaysian Good Pharmacovigilance Practices. An independent monitoring committee periodically reviews cumulative safety data. The study is registered with NMRR, requires MREC approval, and follows the Declaration of Helsinki and ICH-GCP; all participants give written informed consent. Blood samples are used only for the specified tests and are not retained.