Heart failure (HF) is a major chronic clinical syndrome affecting approximately 5.1 million Americans.¹ It is a major cause of morbidity and mortality with an annual economic burden of $32 billion.² HF is among the leading causes of hospitalization in patients above 65 years of age. About 25% of patients admitted for HF are readmitted within 30 days and about 30% by 60-90 days post discharge. Among the strategies to reduce HF hospitalizations, treatment with evidence-based drugs and device therapies are of major importance. However, over the last decade, there have been no new breakthroughs in the pharmacologic management of this condition.

Recently, ivabradine was approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic HF. Ivabradine is the first drug with a novel mechanism of action acting by selective inhibition of the pacemaker I_f "funny" channel, which is responsible for the autonomic capacity of the sinoatrial (SA) node. I_f channels are upregulated in atrial tissue of patients with HF. Ivabradine works by reduction of the diastolic depolarization slope in the SA node, thereby decreasing heart rate via direct sinus node inhibition without direct effects on myocardial contractility and intracardiac conduction. The drug is approved for patients with stable, symptomatic chronic HF with left ventricular ejection fraction (LVEF) ≤35% who are in sinus rhythm with resting heart rate ≥70 beats per minute (bpm) and are also taking beta-blockers at the highest tolerated dose.

As a first-in-class agent, ivabradine was reviewed under the FDA's priority review program. This process involves the expedited review of drugs that are intended to treat a serious disease or condition and may provide a significant improvement over currently available therapy. It was also granted the Fast Track Designation, which helps facilitate the development and expedite the review of drugs to treat serious or life-threatening conditions and fill an unmet medical need. For products that have been designated as Fast Track, the FDA may review portions of a marketing application on a rolling basis.

The safety and efficacy of ivabradine was studied in an industry-sponsored clinical trial of 6,505 participants. The Systolic Heart failure treatment with the I_f inhibitor Ivabradine Trial (SHIFT) was a multinational, randomized, double-blinded, placebo-controlled trial published in 2010.³ The study included patients with symptomatic chronic HF of four or more weeks' duration with LVEF ≤35%, who had been admitted to the hospital for worsening HF within the previous 12 months, and who were in sinus rhythm and with a resting heart rate of ≥70 bpm. Patients were randomized to receive treatment with ivabradine or placebo. The starting dose of the study drug was 5 mg twice daily. After a 14-day titration period, the dose was increased to 7.5 mg twice daily, unless the resting heart rate was 60 bpm or lower. The dose was adjusted throughout the study to 7.5, 5, or 2.5 mg twice daily according to resting heart rate and tolerability. At randomization and throughout the study, participants were required to be on guideline-directed medical therapy for HF. When a participant was not on a guideline-directed dose of a beta-blocker, the investigator was required to provide justification. The major adverse effects noted on ivabardine were mild with 5% having symptomatic bradycardia and 3% having visual side effects (phosphenes). There was a higher incidence of atrial fibrillation in patients on ivabradine; therefore, caution was recommended in continuing ivabradine in patients who develop atrial fibrillation.

Ivabradine significantly reduced the primary composite endpoint of cardiovascular death and hospitalization for worsening HF by 18%. This finding is mainly attributable to ivabradine's favorable effect on HF hospitalizations (16 % vs. 21 %; hazard ratio [HR] 0.74, 0.66–0.83; p <0.0001) and HF deaths (3 % vs. 5 %; HR 0.74, 0.58–0.94, p = 0.014). Cardiovascular deaths and all-cause mortality were not affected by ivabradine.

One of the limitations of the SHIFT study was the number of patients on guideline-directed target doses of beta-blockers as compared to landmark trials on beta-blockers.⁴ In the SHIFT study, only 26% patients were at target dose of beta-blockers, 56% were at >50% of target dose of beta-blockers, and 11% were on no beta-blocker. The main reason cited for the inability to reach target dose was hypotension even though the mean systolic blood pressure at enrollment was 122 in the ivabradine sub-group. The main question posed was whether the effects of improvement in the primary endpoint was driven by ivabradine or influenced by a relatively low percentage of patients on target beta-blocker doses. In a post-hoc analysis of the SHIFT study carried out by the manufacturer, the effects of Ivabradine were compared across five categories of beta-blocker intake (no beta-blocker, <25% target dose, 25-50% target dose, 50-100% target dose and ≥100% target dose of beta-blockers). There were similar trends in efficacy for ivabradine compared with placebo for the outcomes of hospital admission for worsening HF and cardiovascular death across the beta-blocker categories, and further statistical analysis demonstrated that the treatment effect of ivabradine could be explained by the magnitude of heart rate reduction rather than the beta-blocker dose.⁵ However, the results should be interpreted with caution due to it being a sub-group analysis of a study.

Another important question is how many patients would benefit from this new agent? In a recent study, 1,000 consecutive outpatients attending specialist HF clinics were examined for guideline-directed medical therapy based on the European Society of Cardiology and National Institute of Health and Care Excellence, UK guidelines. The study demonstrated that 16% of patients were eligible for beta-blocker uptitration and 12% for treatment with ivabardine.^6,7,8 Notably, the opportunity to uptitrate beta-blockers was missed in a majority of these patients.

In conclusion, ivabradine will be a useful tool in the armamentarium for chronic HF as adjuvant to beta-blockers in a small sub-group of chronic HF patients. However, it is important to note that beta-blockers have proven mortality benefit in chronic HF and the availability of ivabradine should not prevent initiation and uptitration of beta-blockers. Based on evidence from clinical trials, ivabradine should only be prescribed to patients who are already on the maximal-tolerated beta-blocker dose with a heart rate that remains 70 or higher. Thus, ivabradine may prove useful in patients in sinus rhythm who are intolerant of beta-blockers due to hypotension, fatigue, or reactive airway disease.

References

1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013;127:e6–e245.
2. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation 2011;123:933-44.
3. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-85.
4. Teerlink JR. Ivabradine in heart failure—no paradigm SHIFT...yet. Lancet 2010; 376:847-9.
5. Swedberg K, Komajda M, Böhm M, et al. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol 2012;59:1938-45.
6. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803-69.
7. Dierckx R, Cleland JG, Parsons S, et al. Prescribing patterns to optimize heart rate: analysis of 1,000 consecutive outpatient appointments to a single heart failure clinic over a 6-month period. JACC Heart Fail 2015;3:224-30.
8. National Institute for Health and Care Excellence (NICE). Ivabradine for treating chronic heart failure (NICE website). 2012. Available at: http://www.nice.org.uk/guidance/TA267. Accessed 6/1/15.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Implantable Devices, EP Basic Science, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Chronic Heart Failure

Keywords: Adrenergic beta-Antagonists, Atrial Fibrillation, Benzazepines, Blood Pressure, Bradycardia, Cost of Illness, Diastole, Heart Failure, Systolic, Heart Rate, Hospitalization, Hypotension, Incidence, Outpatients, Pharmaceutical Preparations, Phosphenes, Random Allocation, Research Personnel, Sinoatrial Node, Stroke Volume, Systole, United States Food and Drug Administration

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