From the Guidelines
Ivabradine should be considered for patients with symptomatic heart failure, left ventricular ejection fraction ≤35%, and heart rates ≥70 beats per minute who are already on optimal medical therapy, as evidenced by the SHIFT trial 1. The BEAUTIFUL and SHIFT trials are key clinical studies evaluating ivabradine in cardiovascular disease.
- The BEAUTIFUL trial examined ivabradine in patients with coronary artery disease and left ventricular dysfunction (ejection fraction <40%), showing that while ivabradine did not reduce the primary composite endpoint of cardiovascular death or heart failure hospitalization in the overall population, it did reduce coronary events in a subgroup with heart rates ≥70 beats per minute 2.
- The SHIFT trial focused specifically on patients with symptomatic heart failure, left ventricular ejection fraction ≤35%, and heart rates ≥70 beats per minute who were already on optimal medical therapy, demonstrating that ivabradine significantly reduced the risk of heart failure hospitalization and cardiovascular death 1. Based on these trials, ivabradine is typically prescribed at a starting dose of 5 mg twice daily, which can be adjusted to 2.5-7.5 mg twice daily depending on heart rate response, with a target heart rate of 50-60 beats per minute, as recommended by the 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure 3. Ivabradine works by selectively inhibiting the If current in the sinoatrial node, reducing heart rate without affecting blood pressure or myocardial contractility, making it particularly valuable for heart failure patients who cannot tolerate maximum beta-blocker doses, as noted in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 4. Key considerations for the use of ivabradine include:
- It should be used in addition to optimal medical therapy, including beta-blockers at maximum tolerated doses 3.
- It is contraindicated in patients with atrial fibrillation, as it may increase the incidence of this arrhythmia 5.
- It may be beneficial for patients with left ventricular dysfunction and heart failure, but should be used with caution in this population, as noted in the expert consensus document on personalized treatment of angina 5.
From the FDA Drug Label
The Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT) was a randomized, double-blind trial comparing ivabradine and placebo in 6,558 adult patients with stable New York Heart Association (NYHA) class II to IV heart failure, left ventricular ejection fraction ≤ 35%, and resting heart rate ≥ 70 bpm
SHIFT demonstrated that ivabradine reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis (hazard ratio: 0.82, 95% confidence interval 0.90, p < 0. 0001)
The SHIFT trial for ivabradine was a study that demonstrated the drug's effectiveness in reducing the risk of hospitalization for worsening heart failure or cardiovascular death in patients with heart failure.
- The trial included 6,558 adult patients with stable NYHA class II to IV heart failure.
- The primary endpoint was a composite of the first occurrence of either hospitalization for worsening heart failure or cardiovascular death.
- The results showed a hazard ratio of 0.82 (95% CI: 0.75, 0.90, p < 0.0001) in favor of ivabradine. There is no information about the BEAUTIFUL trial in the provided text, however, it is known that the BEAUTIFUL trial was another study that investigated the effects of ivabradine in patients with coronary artery disease and left ventricular dysfunction 6.
From the Research
Beautiful and Shift Trials for Ivabradine
The BEAUTIFUL and SHIFT trials are two significant studies that investigated the effects of ivabradine in patients with heart failure.
- The BEAUTIFUL trial 7 was a randomized controlled trial that evaluated the effect of ivabradine on outcomes in patients with left-ventricular systolic dysfunction.
- The SHIFT trial 8, 9, 10, 7, 11 was a large, randomized, double-blind, placebo-controlled, multicenter trial that assessed the effect of reducing heart rate with ivabradine on outcomes in adults with symptomatic chronic heart failure and left ventricular systolic dysfunction.
Key Findings
The key findings from these trials include:
- A significant reduction in the relative risk of the primary composite endpoint (i.e., the composite of cardiovascular death or hospital admission for worsening heart failure) in the ivabradine treatment group compared to the placebo group 8.
- A reduction in heart failure hospitalization and deaths in patients with stable heart failure with reduced ejection fraction and a heart rate of at least 70 beats per minute at rest on maximally tolerated beta-blocker therapy 9.
- An association between ivabradine and reduced cardiac remodeling, reduced heart rate variability, improvement in exercise tolerance, improved heart failure class of New York Heart Association, and better quality of life 9.
- A significant relative risk reduction for the composite of cardiovascular mortality or heart failure hospitalization, driven by heart failure hospitalizations, in patients with left-ventricular systolic dysfunction and heart rate ≥ 70 b.p.m. 7.
Trial Results
The results of the BEAUTIFUL and SHIFT trials demonstrate the benefits of ivabradine in patients with heart failure, including:
- A 13% relative risk reduction for the composite of cardiovascular mortality or heart failure hospitalization 7.
- A 19% relative risk reduction for heart failure hospitalizations 7.
- A 15% relative risk reduction for the composite of cardiovascular mortality, heart failure hospitalizations, or myocardial infarction hospitalization 7.
- A 10% relative risk reduction for cardiovascular mortality and non-fatal myocardial infarction 7.
- A 23% relative risk reduction for myocardial infarction hospitalization 7.