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SHIFT: Selective heart rate reduction with Ivabradine improves left ventricular remodeling and function: insights from the SHIFT-Echocardiography sub-study

Heart Failure (HF)

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Jean-Claude Tardif Jean-Claude Tardif (Canada)

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List of Authors:
Jean-Claude Tardif, Eileen O'Meara, Michel Komajda, Michael Bohm, Jeffrey S. Borer, Ian Ford, Luigi Tavazzi, Karl Swedberg, on behalf of the SHIFT Investigators.


The SHIFT echocardiographic substudy evaluated the effects of ivabradine on left ventricular (LV) remodelling in heart failure (HF).

Methods: Eligible patients had chronic HF and systolic dysfunction [LV ejection fraction (LVEF) ≤35%], were in sinus rhythm and had resting heart rate ≥70 bpm. Patients were randomly allocated to ivabradine or placebo, superimposed on background therapy for HF. Complete echocardiographic data at baseline and 8 months were available for 411 patients (ivabradine 208, placebo 203).

Results: Treatment with ivabradine reduced left ventricular end-systolic volume index (LVESVI, primary substudy endpoint) versus placebo [–7.0±16.3 versus –0.9±17.1 mL/m2; difference (SE), –5.8 (1.6), 95% CI –8.8 to –2.7, P<0.001]. The reduction in LVESVI was independent of beta-blocker use, HF aetiology, and baseline LVEF. Ivabradine also improved LV end-diastolic volume index (–7.9±18.9 versus –1.8±19.0 mL/m2, P=0.002) and LVEF (+2.4±7.7 versus –0.1±8.0%, P<0.001). The incidence of the SHIFT primary composite outcome (cardiovascular mortality or hospitalization for worsening HF) was higher in patients with LVESVI above the median (59 mL/m2) at baseline (HR 1.62, 95% CI 1.03 to 2.56, P=0.04). Patients with the largest relative reductions in LVESVI had the lowest event rates.

Conclusion: Ivabradine reverses cardiac remodelling in patients with heart failure and left ventricular systolic dysfunction.

Discussant | see Presenter abstract

Burkert Mathias Pieske (Austria)

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Despite optimal therapy, morbidity and mortality in heart failure with reduced ejection fraction remains high. Elevated resting heart rate emerged as a risk factor for poor outcome in heart failure, and beneficial effects of beta-blockers were in part attributed to their heart-rate lowering effects. Ivabaradine is a direct sinus node inhibitor with few side effects. In the large SHIFT trial (1), heart rate lowering with Ivabradine in heart failure patients with EF<35% and a resting heart rate equal to or above 70 bpm resulted in a significant reduction in the combined primary endpoint of cardiovascular death or hospital admission for heart failure (HR, 0.82, p<0.0001). Tardif and coworkers now present the echocardiographic substudy of the SHIFT-trial (2) that assessed the effect of Ivabradine on LV volumes and function and compared these parameters to outcome.

Main findings:

This predefined substudy included 611 out of 6505 patients from SHIFT or in other words, 9.3% of the entire cohort studied in SHIFT. 96 ivabradine- and 104 placebo-treated patients had to be excluded, mainly due to incomplete or unreadable echo-recordings which left 208 patients in the ivabradine- and 203 in the placebo-group for analysis. The echoes were analysed centrally and the investigations were done at baseline and after 8 months with the primary endpoint of change of left ventricular systolic volume index (LVESVI) . At baseline, patients were on stable standard heart failure medication (92% beta blockers with 56% taking 50% or more of the recommended dose; 96% on an ACEI/ARB, 72% on aldosterone antagonists). Eight months of ivabradine-treatment resulted in a 7ml/m2 reduction of LVESVI as compared to 0.9ml/m2 in the placebo-group and an increase in left ventricular ejection fraction (a secondary endpoint) of 2.4% without changes (-0.1%) in the placebo group, with highly significant ifferences between Ivabradine and placebo. These effects compare to previous reports on reverse remodeling with beta blockers or ACE-inhibitors. A LVESVI above the median at study entry was associated with a significantly higher number of events during the whole SHIFT trial period.

Strength of the study

This is a well conducted relatively large echo substudy that used an echo core lab with central echo readings. It convincingly shows the potential of Ivabradine to induce reverse remodeling and improve cardiac function after 8 months of therapy. Of note, this effect was of clinically relevant size and could be observed on top of standard heart failure therapies also associated with reverse remodeling. The study allows some mechanistic insight into the beneficial effect of Ivabradine in heart failure patients and also underscores the importance of reverse remodeling to improve outcome.

Limitations of the study

A relatively large number of patients initially included into the substudy could not be used for final analysis, largely because of incomplete or unreadable echos. Also, only 29% of patients were on target doses of beta blockers. Though heart rate reduction per se appears a compelling underlying mechanism for reverse remodeling with Ivabradine, anxillay effects, such as blockade of If channels wich are overexpressed in failing cardiomyocyes, may also play a role. Importantly, SHIFT included only patients in sinus rhythm and at resting heart rates ≥70/min. In this subgroup, a substantial reduction of LVESVI (by 15% or more) was observed only in about 1/3 of patients.


Ivabradine induces substantial reverse remodeling in patients with SR, elevated heart rates and on a standard background heart failure therapy. Ivabradine should strongly be considered as add-on medication in this patient population.


1. Swedberg K et al., Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo- controlled study. Lancet 2010;376:875-885
2. Tardif J-C et al., Effects of selevtive heart rate reduction with Ivabradine on left ventricular remodeling and function: results from the echocardiography SHIFT substudy. Eur Heart J 2011; doi:10.1093/eurheartj/ehr311


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Clinical Trial Update II - Rate and rhythm

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.