Elsevier

The Lancet

Volume 376, Issue 9744, 11–17 September 2010, Pages 886-894
The Lancet

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Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(10)61259-7Get rights and content

Summary

Background

Raised resting heart rate is a marker of cardiovascular risk. We postulated that heart rate is also a risk factor for cardiovascular events in heart failure. In the SHIFT trial, patients with chronic heart failure were treated with the selective heart-rate-lowering agent ivabradine. We aimed to test our hypothesis by investigating the association between heart rate and events in this patient population.

Methods

We analysed cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this randomised trial, divided by quintiles of baseline heart rate in the placebo group. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly.

Findings

In the placebo group, patients with the highest heart rates (≥87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2·34, 95% CI 1·84–2·98, p<0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes. Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3–19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85–1·06, p=0·352).

Interpretation

Our analysis confirms that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure.

Funding

Servier, France.

Introduction

Resting heart rate is a strong predictor of cardiovascular mortality and morbidity in the general population,1 as well as in patients with hypertension,2 coronary artery disease,3 and chronic heart failure.4, 5 Heart rate is directly associated with atherogenesis in disease models6, 7 and patients.8 These results suggest that the slower the heart rate, the lower the cardiovascular complications.9 Failing human myocardium has a negative force-frequency association10, 11 and is energetically starved.12 Previous evidence suggests that heart-rate reduction can improve contractility13 and improve energy supply while reducing expenditure.14 This finding suggests that heart-rate reduction per se could improve cardiovascular outcomes in heart failure.

This hypothesis was tested in the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), which investigated the effect of isolated heart-rate reduction on clinical outcomes in heart failure. The results of SHIFT showed that heart-rate reduction with ivabradine significantly reduced adverse clinical outcomes in a population with symptomatic heart failure and heart rates of 70 beats per min (bpm) or more.15 Ivabradine slows the heart by selective If current inhibition and, unlike β blockers, has no known cardiovascular effects other than heart-rate reduction.16 Therefore, these results support the notion that heart rate is not only a risk marker, but also a risk factor for patients with heart failure. To further assess these findings, we analysed outcomes in the SHIFT population according to baseline heart rates and heart rates achieved at 28 days of treatment with ivabradine.

Section snippets

Study design and participants

The design of the SHIFT study has been described previously.15, 17 In brief, SHIFT was a randomised, double-blind, placebo-controlled, multinational trial that included 6505 patients with symptomatic chronic heart failure and a left-ventricular ejection fraction (LVEF) of 35% or lower and in sinus rhythm with heart rates of 70 bpm or higher. They had been admitted to hospital for heart failure within the 12 months before randomisation. Average age was 60·4 (SD 11·4) years, 4970 (76%) were men,

Results

Table 1 shows baseline demographic and clinical characteristics of the total SHIFT population grouped by quintiles of heart rate at baseline in the placebo group. Patients in the high heart-rate groups were younger and were more likely to be current smokers than were those with lower heart rates. They had lower LVEF and higher NYHA classes, and were more likely to have heart failure of non-ischaemic cause. High heart rates were also associated with lower use of β blockers and

Discussion

Our results show that in patients with heart failure, who were in sinus rhythm with heart rates of 70 bpm or higher, there is a continuous direct association between baseline heart rate and outcomes. The risk is modified and significantly decreased by ivabradine. The effect of ivabradine on heart rate was most pronounced in patients with high baseline values and correspondingly high reductions in heart rate due to ivabradine treatment.

Our finding that pretreatment heart rates are related to

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