Physicians' Academy for Cardiovascular Education

CV benefit of ivabradine maintained in HF patients with or without renal dysfunction

Literature - Voors et al., Eur J Heart Fail. 2014 - Eur J Heart Fail. 2014 Feb 7


The effect of heart rate reduction with ivabradine on renal function in patients with chronic heart failure: an analysis from SHIFT

Voors AA, van Veldhuisen DJ, Robertson M, on behalf of the SHIFT investigators
Eur J Heart Fail. 2014 Feb 7. doi: 10.1002/ejhf.59


Renal dysfunction is common in patients with heart failure (HF), as well as worsening renal function (WRF). WRF is associated with an increased risk of adverse outcomes [1-3].
SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) evaluated the heart-rate-lowering agent ivabradine, when given on top of guideline-recommended treatments, in patients in sinus rhythm with chronic systolic HF and heart rate >70 bpm. Ivabradine is a specific inhibitor of the If current in the sinoatrial node [4]. Addition of ivabradine gave a significant reduction in a composite of hospitalization for worsening heart failure or cardiovascular (CV) death [5,6].
These results suggest a beneficial haemodynamic effect of ivabradine, which may protect against worsening of renal function. This analysis investigated the association between heart rate and renal function, and the effects of ivabradine on renal function and clinical outcome, in 6160 individuals enrolled in the multi-center randomised, double-blind, placebo-controlled SHIFT trial.

Main results

  • 5 bpm increments in baseline heart rate were independently associated with 5% increments in risk of developing WRF (HR: 1.05, 95%CI: 1.02-1.08, P=0.003). Other independent predictors of WRF were increasing age, relatively lower haemoglobin levels, history of diabetes and peripheral artery disease, use of an ARB, and non-Caucasian race.
    WRF as a time-varying covariate was a strong and independent predictor of occurrence of the primary endpoint of CV death or hospitalisation due to HF (HR: 1.38, 95%CI: 1.15-1.64, P<0.0010) and of all-cause mortality (HR: 1.42, 95%CI: 1.16-1.72, P<0.001).
  • eGFR>60 mL/min/kg was associated with a significantly lower occurrence of the primary endpoint when compared to eGFR<60 mL/min/kg (HR: 0.74, 95%CI: 0.66-0.83, P<0.001) and all-cause mortality (HR: 0.81, 95%CI: 0.70-0.95, P=0.009).
  • No difference was seen in renal function between ivabradine and placebo-treated patients after 24 months.
  • Groups with eGFR above and below 60 mL/min/kg had had similar dosage of ivabradine, which was associated with similar placebo-corrected changes in heart rate at day 28.
    Ivabradine was associated with a significant reduction of the primary composite endpoint in patients with renal dysfunction (HR: 0.82, 95%CI: 0.68-0.97, P=0.023) and in patients without renal dysfunction (HR: 0.81, 95%CI: 0.71-0.91, P<0.001). Hospitalisation for WRF was also similarly reduced with ivabradine, in patients with and without renal dysfunction.
    Ivabradine significantly reduced the risk of death for worsening of heart failure in patients without renal dysfunction (HR: 0.68, 95%CI: 0.47-0.98, P=0.04). No interaction of treatment effect and renal dysfunction was seen for CV death, HF death, all-cause death.


Renal function remained remarkably stable in clinically stable patients with systolic HF and in sinus rhythm, and with a heart rate of >70 bpm. Progressively increasing heart rate prior to therapy is associated with increased risk of worsening renal function, but slowing heart rate had a neutral effect on renal function during 2 years of follow-up in patients with chronic HF.
The beneficial effect of ivabradine on clinical cardiac outcomes was maintained in patients with or without renal dysfunction, without affecting renal function.  
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1. Damman K, Valente MA, Voors AA, et al. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J 2013.
2. Damman K, Navis G, Voors AA, et al.. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail 2007;13:599–608.
3. Smith GL, Lichtman JH, Bracken MB,et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006;47:1987–1996.
4. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharmacol Res 2006;53:399–406.
5. Swedberg K, Komajda M, Böhm M, et al. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail 2010;12:75–81.
6. Swedberg K, Komajda M, Böhm M, et al. SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–885.

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