Efficacy and Safety of Ivabradine Once-Daily Prolonged-Release versus Twice-Daily Immediate-Release Formulation in Patie
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ORIGINAL RESEARCH
Efficacy and Safety of Ivabradine Once-Daily Prolonged-Release versus Twice-Daily ImmediateRelease Formulation in Patients with Stable Chronic Heart Failure with Systolic Dysfunction: A Randomized, Double-Blind, Phase 3 Non-Inferiority (PROFICIENT) Study Ajit Mullasari . The PROFICIENT investigators Received: September 2, 2020 Ó The Author(s) 2020
ABSTRACT Introduction: Dosing frequency is an important factor influencing medication compliance in patients with heart failure (HF), which in turn is imperative in achieving the desired therapeutic outcome. Here we assessed the efficacy and safety of ivabradine prolonged-release (PR) once-daily (test) vs. ivabradine immediate-release (IR) twicedaily (reference) formulations in patients with stable chronic HF with systolic dysfunction. Methods: Patients with sinus rhythm and heart rate (HR) C 50 bpm, left ventricular ejection fraction B 40% (HF with reduced ejection fraction), on guideline-based standard care, receiving a stable dose of ivabradine IR 5/7.5 mg twice daily for C 1 month were enrolled in this randomized, double-blind, phase 3 non-inferiority study. Patients were randomly assigned 1:1 to ivabradine PR (10 mg/15 mg) based on the ivabradine IR dosage or continued ivabradine IR (5 mg/7.5 mg). The primary endpoint was change in resting ECG HR from baseline to the Digital Features To view digital features for this article go to https://doi.org/10.6084/m9.figshare.12932993. List of author present in PROFICIENT investigators are available in acknowledgment section. A. Mullasari (&) Madras Medical Mission, Mogappair, Chennai, Tamil Nadu 300037, India e-mail: [email protected]
end of 3 months, assessed by 12-lead ECG. Safety assessments and 24-h Holter HR monitoring (in a subgroup of patients) were also performed. Non-inferiority was concluded if the upper limit of the 95% CI of the difference between the test and reference was less than the margin of 6.5 bpm in the per-protocol set. Results: A total of 169 out of 180 randomized patients (93.9%) completed the study (PR = 84; IR = 85). The least-square mean (standard error [SE]) for change in HR from baseline to 3 months was 0.76 (1.188; 95% CI -1.59:3.11) in ivabradine PR vs. ivabradine IR, which was within the prespecified margin of 6.5 bpm, confirming the noninferiority of ivabradine PR. The change from baseline to 3 months was comparable between the treatment groups for 24-h Holter ECG monitoring (p = 0.3701), mean HR awake (p = 0.3423), and mean HR asleep (p = 0.1501). Thirty-nine treatment-emergent adverse events (TEAEs) were reported; the majority in both groups were of mild or moderate severity and were subsequently resolved. Seven serious adverse events were reported (ivabradine PR = 2; ivabradine IR = 5), of which one was fatal (ivabradine IR group). The bradycardia events reported were comparable between groups. Conclusion: Ivabradine PR was found to be non-inferior to ivabradine IR in the management of patients with stable CHF, with a comparable safety profile. Once-daily ivabradi
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