Authors
Swedberg K, Komajda M, Böhm M, et al
Title
Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study
References
J Am Coll Cardiol. 2012 May 29;59(22):1938-45.
Background
An elevated resting heart rate is a known risk factor for death and hospitalization in HF patients. Ivabradine inhibits the SA node If current without effect on contractility and conduction.
Purpose
To determine if ivabradine, when added to guideline-based treatment including β-blocker therapy, positively affects clinical outcomes in patients with symptomatic systolic heart failure
Design
  • event-driven, multinational, randomised, double-blinded, placebo controlled, parallel-group trial
  • 6558* stable symptomatic chronic HF patients, ≥18 years in sinus rhythm with resting HR ≥70 bpm, a HF hospitalization within the past year and LVEF ≤35%
  • treated with guideline based therapy including β-blocker and RAAS antagonists
*46 patients removed from trial due to invalid data/misconduct, therefore results based on 6505 patients (3241 ivabradine, 3264 placebo)
Exclusion Criteria
  • MI <2 months ago, atrial flutter/fibrillation, ventricular or AV pacing requirements for ≥40% of the day, symptomatic hypotension
  • use of non-DHP-CCB, class I antiarrhythmics and strong P450 CYP3A4 inhibitors at randomization and during the study
Follow-Up
Median 22.9 months (range from 18-28 months)
Treatment Regimen
  • Placebo vs. ivabradine 5 mg PO twice daily x 14 days, then if resting HR:
    • > 60 bpm, increase ivabradine 7.5 mg PO twice daily
    • 50-60 bpm, continue ivabradine 5 mg PO twice daily
    • <50 bpm or symptomatic bradycardia, decrease ivabradine 2.5 mg PO twice
  • starting at day 28, follow-up visit every 4 months visit until conclusion of study assessing if study drug dose to be maintained or adjusted as above; study treatment was stopped if on ivabradine 2.5 mg twice daily and symptomatic bradycardic or resting HR <50 bpm
Results

Primary Endpoints

Composite of CV death or hospitalization for worsening HF: 24% (ivabradine) vs. 29% (placebo); HR 0.82 (0.75-0.9), p<0.0001 (effect primarily driven by worsening HF requiring hospitalization).

Secondary Endpoints

Ivabradine
n=3241		Placebo
n=3264		Hazard Ratiop
All cause death
16%17%0.90 (0.80-1.02)0.092
CV death
14%15%0.91 (0.80-1.03)0.128
HF death
3%5%0.74 (0.58-0.94)0.014
All cause hospitalization
38%42%0.89 (0.82-0.96)0.003
Worsening HF hospitalization
16%21%0.74 (0.66-0.83)<0.0001
Any CV Hospitalization
30%34%0.85 (0.78-0.92)0.0002

  • NYHA class improvement: 28% (ivabradine) vs. 24% (placebo), p=0.001
  • Requiring withdrawl of treatment: Symptomatic bradycardia, 1% (ivabradine) vs. <1% (placebo), p=0.002. Asymptomatic bradycardia, 1% (ivabradine) vs. <1% (placebo), p<0.0001
Summary
When added to guideline-based therapy in symptomatic HF (LVEF ≤35%), ivabradine significantly reduces HF death and hospitalizations due to worsening HF but does not reduce CV death as compared to placebo.