Borer JS, Böhm M, Ford I, et al.
Am J Cardiol. 2014;113:497-503. doi: 10.1016/j.amjcard.2013.10.033.

Background

The Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) study demonstrated that heart rate reduction with the If inhibitor, ivabradine, significantly improved clinical outcomes in patients with chronic systolic HF. [1] This post hoc analysis of SHIFT explores the efficacy and safety of ivabradine in patients with severe HF (NYHA class IV and/ or LVEF≤20%). Severe HF (NYHA class IV) is associated with relatively poor outcomes (28% mortality rate at 1 year vs 7% and 15% for NYHA classes II and III, respectively). [2,3] Severity of HF can also be described in terms of left ventricular systolic function. Trial data indicate a 39% increase in all-cause mortality rate for each 10% decrement in left ventricular ejection fraction (LVEF) below normal; most HF-related deaths occur in patients with the lowest LVEF (defined as ≤22%). [4,5] Patients with severe HF are the most difficult to treat and are also the most in need of better-than conventional treatment for HF (careful optimization of treatment may not be sufficiently effective [6,7]).
In this post hoc analysis, the effect of ivabradine on outcomes according to the severity of HF at baseline was assessed. Patients with severe HF were defined as all patients in NYHA class IV and NYHA classes II or III with LVEF≤20%. The complementary group of patients with less severe HF were those in classes II or III with LVEF >20%. To test the relevance of the results in patients with severe HF according to this definition, the following subgroups were also analyzed: patients in NYHA class IV; patients in NYHA classes II or III with LVEF≤20%; patients in NYHA classes II or III with LVEF≤15%; and patients in NYHA class IV with LVEF≤15%, and the effect in patients with severe or less severe HF and heart rate at rest≥75 beats/min at baseline.
The primary outcome was the composite of cardiovascular death or hospitalization for worsening HF. Other end points included the individual components of the primary end point, all-cause death, HF death, and hospitalization for any cause.

Main results

• In the placebo group, the rate of primary composite end point was 42% for the patients with severe HF versus 27% for the less severe HF group (p <0.001).
• The effect of ivabradine did not reach statistical significance versus placebo in patients with severe HF, but there were substantial nominal reductions in relative risk for the primary composite end point (16%, p = 0.16), all-cause death (22%, p = 0.096), cardiovascular death (22%, p = 0.11), HF death (37%, p = 0.067), and hospitalization for worsening HF (17%, p = 0.21).
• In the group with severe HF and heart rate ≥75 beats/min, ivabradine was associated with significant reductions versus placebo in risk for the primary composite end point (25%, p = 0.045), all-cause death (34%, p = 0.018), cardiovascular death (32%, p = 0.034), HF death (59%, p = 0.005), and hospitalization for worsening HF (30%, p = 0.042).
• In the group with severe HF, 38% of ivabradine-treated patients improved in NYHA class versus 29% of placebo-treated patients (p = 0.009).
• Ivabradine had an acceptable safety profile, largely indistinguishable from that of placebo

Conclusion

The effect of ivabradine in reducing outcomes, including the primary outcome, all-cause death, HF death, and hospitalization for worsening HF, is consistent in patients with severe and less severe HF,
with no significant statistical interaction between the results in the 2 groups.
The inclusion of ivabradine in the regimen of patients with severe HF is safe and can improve outcomes, even when β blockers are also administered.

References

1. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875e885.
2. McMurray JJ. Clinical practice. Systolic heart failure. N Engl J Med 2010;362:228e238.
3. Muntwyler J, Abetel G, Gruner C, Follath F. One-year mortality among unselected outpatients with heart failure. Eur Heart J 2002;23:1861e1866.
4. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006;27:65e75.
5. Solomon SD, Anavekar N, Skali H, et al. Influence of ejection fraction on cardiovascular outcomes in a broad spectrum of heart failure patients. Circulation 2005;112:3738e3744
6. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787e1847.
7. McMurray JJ. Clinical practice. Systolic heart failure. N Engl J Med 2010;362:228e238.

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