Physicians' Academy for Cardiovascular Education

Short-term treatment with ivabradine improves exercise capacity in patients with HFpEF

Literature - Kosmala W, Holland DJ, Roje A et al. - J Am Coll Cardiol. Published online July 31, 2013

Effect of If-channel Inhibition on Hemodynamics and Exercise Tolerance in Heart

Failure with Preserved Ejection Fraction: A Randomized Trial

Kosmala W, Holland DJ, Roje A et al.,
J Am Coll Cardiol. Published online July 31, 2013. doi:10.1016/j.jacc.2013.06.043


Patients with heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) suffer from symptoms of dyspnea and exercise intolerance. Current therapeutic recommendations focus on controlling associated comorbidities, especially hypertension, diabetes, coronary artery disease and obesity [1]. New strategies beyond the management of underlying etiologies are welcome.
The latest heart failure guidelines for HF with reduced LV ejection fraction included ivabradine, a selective sinus node If channel inhibitor that reduces heart rate, devoid of negative inotropic effect, which was shown to decrease mortality and morbidity in the SHIFT trial [2,3].
Especially in the early stages of HFpEF high heart rates during exercise reduce time for diastolic filling and promote increased LV filling pressure and exercise intolerance. Therapeutic measures that prolong the LV filling phase may optimise transmitral flow, which reduces raised filling pressure and the resultant dyspnea. Beta-adrenoreceptor blockade has been trialled in HFpEF, but the negative inotropic effect is unfavourable.
Ivabradine might be a good means to control exertion-associated tachycardia without harming myocardial contractility. Previously, ivabradine has been shown to improve myocardial diastolic properties [4-8]. This prospective, blinded, placebo-controlled trial therefore studied the effects of treatment with ivabradine on exercise capacity and LV function, in patients with HFpEF.

Main results

  • Patients treated for 7 days with ivabradine 5 mg b.i.d. had in increase in exercise capacity, while the control group showed no change. In ivabradine treated patients, change in Metabolic Equivalents (METs) was greater than in controls (1.5+1.2 vs. 0.4+1.2, P=0.001), as was the peak in VO2 (3.0+3.6 vs. 0.4+2.7 ml/kg/min, P=0.003).
  • The treatment group also showed improved resting LV lusitropic function, as indicated by higher septal e’, without accompanying change in resting E/e’ or circulating BNP, indicating that it was not due to increased preload.
  • Resting heart rate was lower after ivabradine treatment. There was no change in heart rate response to exercise.  Workload-corrected chronotropic response showed a slower increase in heart rate during exercise in the treatment group than in the placebo group.
  • There were no differences in effect of slowing of heart rate between patients with grade I or grade II diastolic dysfunction, as judged by BNP, METs, peak VO2 and exercise increment of E/e’. Subdivision according to resting heart rate and normal or reduced response to exercise gave similar results.


Short-term treatment with the If channel inhibitor ivabradine improves exercise capacity in patients with HFpEF. A reduction of the exercise-induced increase in LV filling pressure (E/e’ ratio) was seen, and a slower increase in heart rate during exercise. Since patients with HFpEF often only have symptoms on exertion, treatments targeting abnormal exercise hemodynamics may be useful. These data therefore call for further testing of ivabradine in larger and longer clinical trials in patients with HFpEF.


1. Owan TE, Hodge DO, Herges RMet al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251-9.
2. McMurray JJ, Adamopoulos S, Anker SD, et al.; ESC Committee for Practice Guidelines. 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 Heart J 2012;33:1787-847.
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. Reil JC, Hohl M, Reil GH, et al. Heart-rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction. Eur Heart J 2012 Jul 24. doi: 10.1093/eurheartj/ehs218.
5. Fang Y, Debunne M, Vercauteren M, et al. Heart-rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia. J Cardiovasc Pharmacol 2012;59:260-7.
6. Busseuil D, Shi Y, Mecteau M, et al. Heart-rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis. Cardiology 2010;117:234-42.
7. Becher PM, Lindner D, Miteva K, et al. Role of heart-rate reduction in the prevention of experimental heart failure: comparison between If-channel blockade and β-receptor blockade. Hypertension 2012;59:949-57.
8. Colin P, Ghaleh B, Hittinger L, et al. Differential effects of heart-rate reduction and β-blockade on left ventricular relaxation during exercise. American Journal of Physiology - Heart and Circulatory Physiology 2002;282:H672-H9.

Find this article on Pubmed