What are the BEAUTIFUL (MorBidity-mortality EvAlUation of the IF inhibitor ivabradine in patients with coronary disease and left ventriculAr dysfunction) and SHIFT (Systolic Heart failure treatment with the IF inhibitor ivabradine Trial) trials for ivabradine (ivabradine)?

From the Guidelines

Ivabradine is recommended for heart failure patients with reduced ejection fraction who remain symptomatic despite optimal medical therapy, have a resting heart rate of at least 70 beats per minute, and are in sinus rhythm, based on the results of the SHIFT trial. The BEAUTIFUL trial evaluated ivabradine in patients with stable coronary artery disease and left ventricular dysfunction, showing no significant reduction in the primary composite endpoint of cardiovascular death, myocardial infarction, or heart failure hospitalization 1. However, the SHIFT trial demonstrated that ivabradine significantly reduced the risk of heart failure hospitalization and cardiovascular death compared to placebo in patients with symptomatic heart failure, left ventricular ejection fraction of 35% or less, and heart rates of 70 beats per minute or higher 1.

The typical starting dose of ivabradine is 5 mg twice daily, which can be adjusted to 2.5-7.5 mg twice daily based on heart rate response. Ivabradine works by selectively inhibiting the If current in the sinoatrial node, reducing heart rate without affecting blood pressure or contractility. The 2022 AHA/ACC/HFSA guideline for the management of heart failure recommends ivabradine for patients with heart failure with reduced ejection fraction who have a resting heart rate of at least 70 beats per minute and are in sinus rhythm, despite optimal medical therapy 1.

Key points to consider when prescribing ivabradine include:

• The patient should have a resting heart rate of at least 70 beats per minute
• The patient should be in sinus rhythm
• The patient should have heart failure with reduced ejection fraction
• The patient should remain symptomatic despite optimal medical therapy
• The typical starting dose is 5 mg twice daily, with adjustments based on heart rate response.

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 [CI]: 0.75,0.90, p < 0. 0001)

The beautiful and SHIFT trials for ivabradine are not explicitly mentioned in the provided text, except for the SHIFT trial.

• The SHIFT trial was a randomized, double-blind trial that compared ivabradine and placebo in patients with heart failure.
• The primary endpoint was a composite of the first occurrence of either hospitalization for worsening heart failure or cardiovascular death.
• Ivabradine reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis 2. There is no information about the beautiful trial in the provided text.

From the Research

Beautiful Trial

• The BEAUTIFUL trial 3 was a randomized, double-blind, placebo-controlled trial that aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction.
• The trial found that ivabradine did not affect the primary composite endpoint, but it did reduce secondary endpoints such as admission to hospital for fatal and non-fatal myocardial infarction and coronary revascularisation in a subgroup of patients with heart rates of 70 bpm or greater.
• The BEAUTIFUL trial was designed to evaluate the superiority of ivabradine over placebo in reducing cardiovascular events in patients with stable coronary artery disease and left ventricular systolic dysfunction 4.

Shift Trial

• The SHIFT trial is mentioned in the context of a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials 5.
• This analysis found that ivabradine was associated with a 13% relative risk reduction for the composite of cardiovascular mortality or heart failure hospitalization, and a 19% relative risk reduction for hospitalization for new onset or worsening heart failure.
• The SHIFT trial is not described in detail in the provided evidence, but it is mentioned as a major outcome trial of a specific heart rate-reducing agent.

Key Findings

• Ivabradine may be useful in reducing major cardiovascular events in patients with stable coronary artery disease and left ventricular systolic dysfunction who have heart rates of 70 bpm or greater 3, 5.
• Ivabradine was associated with a reduction in hospitalization for myocardial infarction and coronary revascularisation in patients with limiting angina 6.
• A meta-analysis of ivabradine trials found that unselective use of ivabradine in patients with stable coronary artery disease is not supported by evidence and can be associated with new-onset atrial fibrillation, bradycardia, and drug-related nuisance adverse events 7.