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SHIFT: Effects of ivabradine on cardiovascular events in patients with moderate to severe chronic heart failure and left ventricular systolic dysfunction

Heart Failure

Michel Komajda, FESC
Presenter | see Discussant report Webcasts become available 24h after the presentation
Komajda, Michel

List of Authors:
Michel Komajda ; Karl Swedberg ; Michael Boehm ; Jeffrey S. Borer ; Ian Ford ; Ariane Dubost-Brama ; Guy Lerebours ; Luigi Tavazzi


Chronic heart failure (HF) is associated with high mortality and morbidity. Elevated resting heart rate is a risk factor for adverse outcomes. We hypothesized that reduction of heart rate by the selective sinus node inhibitor ivabradine could improve outcomes in HF.

In this randomized, double-blind, placebo-controlled multinational study, patients were eligible if they had symptomatic HF and left ventricular ejection fraction ≤35%, were in sinus rhythm with heart rate >=70 bpm, had a hospitalization for HF within the previous 12 months and were on stable background therapy including a beta-blocker when tolerated. Overall, 6505 patients were randomly assigned to ivabradine (N=3241) titrated maximally to 7.5 mg twice daily or matching placebo (N=3264). The primary endpoint was the composite of cardiovascular death or hospital admission for worsening HF.

Median follow-up was 22.9 months. In total, 793 (24.5%) patients in the ivabradine group and 937 (28.7%) patients in the placebo group had a primary endpoint (HR, 0.82, 95% CI 0.75–0.9, p<0.0001). The effects were driven mainly by hospital admissions for worsening HF, which were reduced from 20.6% to 15.9% (HR, 0.74, 95% CI 0.66–0.83, p<0.0001) and deaths due to HF (HR, 0.74, 95% CI 0.58–0.94, p=0.014). There were fewer cardiovascular deaths (HR, 0.91, 95% CI 0.80–1.03) and all-cause deaths (HR, 0.90, 95% CI 0.80–1.02) in the ivabradine group. Ivabradine reduced all-cause hospital admissions (HR, 0.89, 95% CI 0.82–0.96, p=0.003) and was well-tolerated. The findings were consistent across several prespecified subgroups, though patients who had relatively high heart rate had the greatest reductions in the primary endpoint with ivabradine.

Our results support the importance of achieving heart rate reduction with ivabradine to improve clinical outcomes in HF and confirm the important role of heart rate in the pathophysiology of HF.

Inder Anand
Discussant | see Presenter abstract Webcasts become available 24h after the presentation
Anand, Inder
(United States of America)


High resting heart rate (HR) is strongly related with mortality and other adverse cardiovascular (CV) outcomes in the general population and in patients with CAD and Heart Failure (HF). The SHIFT investigators tested the hypothesis that reducing resting HR with the selective sinus-node inhibitor ivabradine in patients with HF and systolic dysfunction improves cardiovascular outcomes.

They studied 6558 patients with HF, EF < 35% in sinus rhythm with baseline resting HR > 70 bpm, who were well treated with 90% on beta-blockers (BB), ACEi and over 60% on aldosterone blockers. They found that use of ivabradine caused approximately a 9-bpm decrease in HR compared to placebo over the duration of the trial. This was associated with an 18% reduction in the risk of the primary endpoint of CV mortality and hospitalization for HF that was largely driven by a 26% decrease in the risk of hospitalization for HF. Greater benefit was seen in patients HR >77 bpm, independent of BB dose. Ivabradine had no serious adverse effects.

Potential Weaknesses and Limitations
This study raises an important question: whether the SHIFT patients were receiving optimal BB background therapy? Although the use of BB was high, only 26% of the patients were prescribed target doses of BB by the investigators, despite being encouraged to up-titrate drugs to the doses used in the clinical trials. In clinical practice, because of concerns of side effects, lower doses of BB are used, similar to those reported in SHIFT. Nevertheless, it is appropriate to question whether higher doses of BB could have achieved similar outcomes to SHIFT? In a meta-regression of 23 beta-blocker HF trials involving over 19,000 patients, mortality benefit was related to the magnitude of HR reduction and not to the dose of BB used.(1) The reduction in mortality hazard with ivabradine for an average 9-bpm decrease in HR is consistent with the prediction from the meta-analysis. In clinical trials, higher doses of BB have not been shown in to reduce heart rate further. In SHIFT, the reduction in HR was no different in the entire cohort ¯15.4 bpm) compared to those on > 50% target dose of BB ¯15.5 bpm). Therefore, it is unlikely that higher BB doses would have decreased the heart rate further or altered the outcomes. Moreover, all previous drug or device HF trials that led to the approval of specific therapies were done in patients receiving background therapy as prescribed by the investigators and no force titration was attempted. Hence SHIFT should be judged on the merits of its findings in the population studies.
Which patients are likely to be candidates for ivabradine? Unfortunately, a quarter of the HF population would be excluded because of the presence of atrial fibrillation where ivabradine is unlikely to have an effect. Recent HF trial databases and HF registries inform us that over 50% of HF patients have resting HR greater than 70 bpm and approximately 40% have HR over 77 bpm, where most of the beneficial effects of ivabradine were seen. The use of devices was low in SHIFT because of inclusion criteria and geography. However, these patients need not be excluded if they meet the other inclusion criteria and pacing rates are set appropriately low. Therefore, approximately 40% of all HF patients with LV systolic dysfunction receiving standard of care HF therapies might benefit from the addition of ivabradine.

In conclusion, the SHIFT investigators should be congratulated for conducting a very important study. SHIFT confirms the importance of HR in the pathophysiology of HF and supports the concept that reduction in HR contributes significantly to beneficial outcomes in patients with HF. In patients with systolic HF in SR with HR >70 bpm, receiving usual clinical care and unable to tolerate higher doses of BB, the addition of the pure HR reducing agent ivabradine is likely to improve HF outcomes.


1. McAlister et al Ann Intern Med 2009;150:784-794


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Hot Line I - Heart failure and left ventricular dysfunction
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.