Does Ivabradine Decrease Cardiovascular Deaths in Heart Failure Patients?



      Ivabradine, a heart rate-slowing drug used to treat heart failure and (in Europe) angina, had varying impacts upon cardiovascular events in its 3 large outcome trials. Food and Drug Administration (FDA) analyses may explain the reasons for the variability.


      An FDA reviewer analyzed the raw data from the 3 trials using logistic regressions to assess interactions between ivabradine and other drugs and forest plots to display dose responses.


      Ivabradine in its SHIFT heart failure trial shows a significant interaction with loop diuretics with a beneficial impact upon cardiovascular deaths (odds ratio 0.61; 95% confidence interval, 0.42-0.87, P = .007). This favorable effect is supported by similar interactions in the other 2 trials (BEAUTIFUL, SIGNIFY) and by a dose response for loop diuretics interacting with ivabradine in the SHIFT and BEAUTIFUL trials. The interaction is not related to heart failure severity.


      Ivabradine used concomitantly with a loop diuretic has a beneficial impact upon cardiovascular death.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Swedberg K.
        • Komajda M.
        • Böhm M.
        • et al.
        Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study.
        Lancet. 2010; 376: 875-885
        • Fox K.
        • Ford I.
        • Steg P.G.
        • Tendera M.
        • Ferrari R.
        Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
        Lancet. 2008; 372: 807-816
        • Fox K.
        • Ford I.
        • Steg P.G.
        • Tardif J.-C.
        • Tendera M.
        • Ferrari R.
        Ivabradine in stable coronary artery disease without clinical heart failure.
        N Engl J Med. 2014; 371: 1091-1099
        • McMurray J.J.V.
        It is BEAUTIFUL we should be concerned about, not SIGNIFY: is ivabradine less effective in ischaemic compared with non-ischaemic LVSD?.
        Eur Heart J. 2015; 36: 2047-2049
        • Beltrame J.F.
        Ivabradine and the SIGNIFY conundrum.
        Eur Heart J. 2015; 36: 3297-3299
        • Agewall S.
        • Atar D.
        Interpreting clinical trials: the “beautiful” case.
        Fundam Clin Pharmacol. 2009; 23: 261-262
      1. Marciniak TA. Cross-discipline team leader memo, ivabradine (Corlanor), NDA 206-143. Available at: Published December 18, 2014. Accessed December 14, 2015.

        • Messerli F.H.
        • Rimoldi S.F.
        • Bangalore S.
        Ivabradine in coronary heart disease-the emperor has no clothes.
        Am J Cardiol. 2017; 120: e15
        • Rimoldi S.F.
        • Messerli F.H.
        • Cerny D.
        • et al.
        Selective heart rate reduction with ivabradine increases central blood pressure in stable coronary artery disease Hypertens Dallas Tex 1979. 2016; 67: 1205-1210
        • Morgan T.
        • Lauri J.
        • Bertram D.
        • Anderson A.
        Effect of different antihypertensive drug classes on central aortic pressure.
        Am J Hypertens. 2004; 17: 118-123
        • Hancox J.C.
        • Melgari D.
        • Dempsey C.E.
        • Brack K.E.
        • Mitcheson J.
        • Ng G.A.
        hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes.
        Ther Adv Drug Saf. 2015; 6: 177-179
        • Mert K.U.
        • Mert G.O.
        • Morrad B.
        • Tahmazov S.
        • Mutlu F.
        • Cavusoglu Y.
        Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias.
        Kardiol Pol. 2017; 75: 786-793
        • Frommeyer G.
        • Weller J.
        • Ellermann C.
        • et al.
        Ivabradine reduces digitalis-induced ventricular arrhythmias.
        Basic Clin Pharmacol Toxicol. 2017; 121: 526-530
        • Kleinbongard P.
        • Gedik N.
        • Witting P.
        • Freedman B.
        • Klocker N.
        • Heusch G.
        Pleiotropic, heart rate-independent cardioprotection by ivabradine.
        Br J Pharmacol. 2015; 172: 4380-4390
      2. McKee S. UK launch for Novartis’ breakthrough heart drug. PharmaTimes. Available at: Published January 20, 2016. Accessed January 2, 2019.

      3. Amgen. Corlanor (ivabradine) prescribing information. Available at: Published 2015. Accessed February 17, 2017.

        • Marciniak T.A.
        Eplerenone treatment of aortic stenosis. [letter].
        Am Heart J. 2009; 157: e15
        • Pitt B.
        • Zannad F.
        • Remme W.J.
        • et al.
        The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
        N Engl J Med. 1999; 341: 709-717
      4. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-e239.

      5. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an 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. 2016;68(13):1476-1488.

      6. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975.