A Phase 4, Open-Label, Single-Arm Study Assessing the Efficacy and Safety of Ivabradine in African American Patients with Heart Failure and Reduced Ejection Fraction

David E Lanfear, Kelsey R Neaton, Chen Lu, Yimeng Liu, Ricardo E Dent-Acosta, David E Lanfear, Kelsey R Neaton, Chen Lu, Yimeng Liu, Ricardo E Dent-Acosta

Abstract

Introduction: There are limited data on ivabradine therapy in black patients and none in African Americans. We performed an open-label, prospective study at two centers in the United States. African American patients with heart failure (HF) (N = 30), left ventricular ejection fraction ≤ 35%, and in sinus rhythm with resting heart rate (HR) ≥ 70 bpm received ivabradine 2.5-7.5 mg twice daily for 57 days.

Methods: The primary endpoint was change in HR from baseline to day 57, compared with the -5 bpm change observed in the absence of ivabradine in the placebo group of the SHIFT study. The safety endpoint was treatment-emergent adverse events (TEAEs). Exploratory endpoints were change from baseline to day 57 in 6-minute walk test (6MWT) distance, HR difference during a 6MWT (i.e. HR at minute 6 - resting HR), and physical activity counts.

Results: At day 57, the estimated least squares mean change from baseline in HR was -9.5 bpm (95% CI -13.0, -6.0). The estimated mean treatment difference with ivabradine versus a presumed -5 bpm change from baseline HR, as seen in the placebo group of the SHIFT study, was -4.5 bpm (95% CI -8.0, -1.0; p = 0.013). The mean (SE) changes in 6MWT distance and HR difference during the 6MWT were 16.3 (10.8) meters and 2.3 (3.7) bpm, respectively. Ivabradine therapy did not result in greater physical activity. TEAEs were reported in 11 (36.7%) patients.

Conclusion: These data support ivabradine use in African American patients with HF with reduced ejection fraction who meet typical treatment criteria.

Trial registration: ClinicalTrials.gov identifier, NCT03456856.

Keywords: Efficacy; Heart failure; Ivabradine; Safety.

Figures

Fig. 1
Fig. 1
Mean change in heart rate and total estimated number of steps taken from baseline to end of treatment. Reference line is plotted at −5 bpm as the change in HR from baseline observed in the placebo group in the SHIFT study. Vertical lines represent the 95% confidence intervals around the means. Missing values were not imputed. Total estimated number of steps taken is defined as the sum of daily total estimated steps taken in 7 days prior to/on the target study day. bpm beats per minute, HR heart rate

References

    1. Francis GS. Pathophysiology of chronic heart failure. Am J Med. 2001;110(Suppl 7A):37S–46S. doi: 10.1016/S0002-9343(98)00385-4.
    1. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70:776–803. doi: 10.1016/j.jacc.2017.04.025.
    1. Sidney S, Quesenberry CP, Jr, Jaffe MG, et al. Recent trends in cardiovascular mortality in the United States and public health goals. JAMA Cardiol. 2016;1(5):594–599. doi: 10.1001/jamacardio.2016.1326.
    1. Parikh KS, Greiner MA, Suzuki T, et al. Resting heart rate and long-term outcomes among the African American population: insights from the Jackson Heart Study. JAMA Cardiol. 2017;2:172–180. doi: 10.1001/jamacardio.2016.3234.
    1. Beta-Blocker Evaluation of Survival Trial Investigators. Eichhorn EJ, Domanski MJ, Krause-Steinrauf H, Bristow MR, Lavori PW. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344(22):1659–1667. doi: 10.1056/NEJM200105313442202.
    1. Lanfear DE, Hrobowski TN, Peterson EL, et al. Association of beta blocker exposure with outcomes in heart failure differs between African American and white patients. Circ Heart Fail. 2012;5(2):202–208. doi: 10.1161/CIRCHEARTFAILURE.111.965780.
    1. Amgen Inc. CORLANOR® (ivabradine) [package insert]. U.S. Food and Drug Administration website. . Revised Apr 2019. Accessed Aug 2020.
    1. Fox K, Ford I, Steg PG, Tendera M, Ferrari R, BEAUTIFUL Investigators Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807–816. doi: 10.1016/S0140-6736(08)61170-8.
    1. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875–885. doi: 10.1016/S0140-6736(10)61198-1.
    1. Ortega RF, Yancy CW, Mehran R, Batchelor W. Overcoming lack of diversity in cardiovascular clinical trials: a new challenge and strategies for success. Circulation. 2019;140(21):1690–1692. doi: 10.1161/CIRCULATIONAHA.119.041728.
    1. Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371(12):1091–1099. doi: 10.1056/NEJMoa1406430.
    1. Böhm M, Robertson M, Ford I, et al. Influence of cardiovascular and noncardiovascular co-morbidities on outcomes and treatment effect of heart rate reduction with ivabradine in stable heart failure (from the SHIFT Trial) Am J Cardiol. 2015;116(12):1890–1897. doi: 10.1016/j.amjcard.2015.09.029.
    1. Savelieva I, Camm AJ. If inhibition with ivabradine: electrophysiological effects and safety. Drug Saf. 2008;31(2):95–107. doi: 10.2165/00002018-200831020-00001.
    1. Yancy CW, Januzzi JL, Jr, Allen LA, et al. 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure with Reduced Ejection Fraction: a Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;71(2):201–230. doi: 10.1016/j.jacc.2017.11.025.
    1. Tillman F, Kim J, Makhlouf T, Osae L. A comprehensive review of chronic heart failure pharmacotherapy treatment approaches in African Americans. Ther Adv Cardiovasc Dis. 2019;13:1753944719840192. doi: 10.1177/1753944719840192.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit