I funny Channel Inhibitors: An Emerging Option for Heart Failure

Excerpt

1. I_funny (I_f), or funny current, channel inhibitors are a class of drugs with heart rate reducing properties (negative chronotropic drugs) and ivabradine is the first representative of this drug class; it was recently tested for the treatment of heart failure (HF).

2. Based on currently available evidence, it can be interpreted that ivabradine may have a role in the treatment of patients who have a certain form of HF. So for patients with symptomatic HF with reduced ejection fraction (HFrEF) (EF ≤ 35%); that is, with the lower-left part of their heart not contracting well, with a heart rate of 70 beats per minute (bpm) or higher and for patients who are unable to tolerate optimal beta-blocker dosing. Of note, patients with HFrEF who have a heart rate greater than 77 bpm may be the ones to derive the most benefit from initiating ivabradine therapy.

3. Ivabradine was evaluated in more than 10 clinical trials for a number of cardiovascular (CV) uses including coronary artery disease, angina, myocardial infarction, and HF. While an initial HF study, BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), did not find significant improvement in cardiac outcomes with ivabradine, findings from a prespecified subgroup of patients with a heart rate of 70 bpm or higher suggested a correlation between the resting heart rate and the risk of CV events; this observation led to further investigation of ivabradine for the treatment of HF.

4. The clinical development of ivabradine continued with the SHIFT (Systolic Heart failure treatment with the I_f inhibitor ivabradine Trial) study. This study targeted patients with HFrEF, in sinus rhythm (i.e., normal heartbeat) and with a heart rate of 70 bpm or higher. The phase 3 trial evaluated the morbidity and mortality benefits of ivabradine as an add-on therapy to standard treatment for HF, including the use of a beta-blocker if tolerated, compared with placebo. Results showed that when ivabradine is added on to guidelines-based background therapy, there is a statistically significant decrease of 18% in the rate of primary end point (composite of CV death or hospital admission for worsening HF) compared with placebo.

5. Of note, 89% of patients enrolled in the SHIFT trial were on beta-blockers. However, despite aiming to treat patients at the guidelines-specified target dose for beta-blockers, only 56% of patients were on at least 50% of the target dose and, 26% of patients were at target dose. The most common reasons for suboptimal dosing of beta-blocking therapy were hypotension and fatigue.