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SHIFT: Heart rate in heart failure: risk marker or risk factor? A sub-analysis of the SHIFT trial

Heart Failure

Michael Boehm, FESC
Presenter | see Discussant report Webcasts become avaialble 24h after the session
Böhm, Michael
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List of Authors:

Böhm Michael, Swedberg Karl, Komajda Michel, Borer Jeffrey, Ford Ian, Dubost-Brama Ariane, Lerebours Guy, Tavazzi Luigi


Background: Elevated resting heart rate is a marker of cardiovascular risk. We hypothesized that heart rate is also a risk factor for cardiovascular events in heart failure (HF) and tested this hypothesis by investigating their relationship using pure heart rate–lowering with ivabradine in the SHIFT trial on top of contemporary background therapy.

Methods: In this randomized trial including 6505 patients with chronic HF in sinus rhythm with heart rate ≥70 bpm, we analysed cardiovascular outcomes in the placebo and ivabradine groups divided by quintiles of baseline heart rate. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes.

Results: The primary composite endpoint of cardiovascular death and hospital admission for worsening HF will be explored in the placebo group in relation to quintiles of heart rate at baseline. The increase in risk for 1- and 5-bpm increases in baseline heart rate will also be presented. Furthermore, cardiovascular outcomes will be evaluated for the heart rate achieved with ivabradine at 28 days, i.e. after uptitration of study drug. The results will improve the understanding of the role of shifting HF patients to lower heart rate profiles with ivabradine on cardiac outcomes. The goal was to provide information on whether elevated resting heart rate is a risk factor, and not simply a risk marker, in chronic HF.

John Kjekshus
Discussant | see Presenter abstract Webcasts become avaialble 24h after the session
Kjekshus, John
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Elevated resting heart rate is a marker of risk for coronary artery disease, especially acute myocardial infarction and sudden death. Increased heart rate augments myocardial oxygen requirement and shorten the diastolic interval for myocardial inflow. This may cause myocardial ischemia and electric instability in established coronary disease. Previous studies have shown that β-receptor blockade after acute myocardial infarction reduces all cause mortality in proportion to the reduction in heart rate. β-receptor blockade also benefit prognosis in patients with heart failure (HF). However, the application of β-receptor blockade in HF patients is often limited by intolerance to the drug and poor heart rate reduction. The SHIFT study is therefore an important contribution to our understanding of the importance of heart rate as a marker and a risk factor and as a target for HF treatment.

The SHIFT investigators studied the effect of ivabradine in 6505 patients. Ivabradine is a novel selective sinus node inhibitor that can lower heart rate by 10-15 bpm independent of concurrent β-receptor blockade. Ivabradine was titrated to 7.5 mg twice daily or placebo. In the ivabradine group heart rate fell by 15.4 bpm compared with pre-treatment, when corrected for change in the placebo group, the net reduction with ivabradine was 10.9 bpm. The primary endpoint ( cardiovascular death or hospital admission for worsening HF) was reduced from 28.7% to 24.5%. (HR, 0.82, 95% CI 0.75–0.9, p<0.0001). Follow up was 22.9 months. The effects were driven mainly by hospital admissions for worsening HF which was reduced by 26%. The directional changes were consistent in all prespecified subgroups, with fewer cardiovascular and all-cause deaths.

However, the effect on sudden death was neutral which is in accordance with the use of concurrent β-receptor blockade in 90% of all the patients. A total of 26 patients are needed to be treated for 1 year to prevent one cardiovascular death or one hospital admission for HF. The SHIFT study is well planed, the groups balanced and the results are consistent. There were 21% withdrawals among patients randomised to ivabradine and 18.5% the placebo groups, well in line with other heart failure studies. On a whole the drug was well tolerated with very few dropouts due to adverse reactions, especially few due to visual disturbances which are a well known side effect to the drug. As expected there were observed more symptomatic and asymptomatic bradycardia in the ivabradine group, but less than 1% had to be withdrawn for this reason, equally distributed among symptomatic and asymptomatic patients. The investigators should be congratulated with en excellent study.

The results support the importance of achieving heart rate reduction with ivabradine when added to β-receptor blocker to improve the clinical outcomes in HF and the study confirm the important role of heart rate in the pathophysiology of HF.


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Clinical Trial Update II
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.