Ivabradine safely reduces cardiovascular risk in the elderly with heart failure
Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights from the SHIFT study
Tavazzi L, Swedberg K, Komajda M, et al.; on behalf of the SHIFT Investigators.
Eur J Heart Fail. 2013 Jun 26. [Epub ahead of print]
BackgroundAgeing often influences drug metabolism and pharmacological effects, possibly affecting efficacy and safety. Heart failure (HF) predominantly affects the elderly , since heart rhythm disturbances may occur as a result of age-related alterations in sinus node function [2,3].
Ivabradine is a heart rate-reducing drug that acts selectively on If channels of the sinus node . It has been tested in a large population with chronic HF and LV systolic dysfunction in the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT), which showed that ivabradine was associated with a reduction in major cardiovascular (CV) outcomes [5,6]. Mean age of the SHIFT population (60.4 + 11.4 years) was similar to those of populations in landmark RCTs of ACE inhibitors and beta-blockers in chronic HF patients with reduced LVEF [7,8]. Real world HF patients appear to have a mean age of 67 years . This analysis therefore aimed to determine the effect of ivabradine on clinical outcomes, safety and tolerability across the whole age spectrum of the SHIFT population. Data of 3241 patients who were randomised to ivabradine and 3264 who received placebo were analysed.
- For each 1 beat per minute (bpm) increase in heart rate, the relative risk of the primary endpoint increased by 3.6 in the age group of <53, by 3.1 in 53-60 year-olds, by 3.2 in 60-69 year-olds and 2.2% in patients >69 years old (all P<0.0001). Thus, the effect of heart rate on the occurrence of the primary endpoint decreased with age (P value for interaction: 0.015).
- Heart rate achieved at 28 days in the different age groups differed considerably between the ivabradine arm and the placebo arm. Generally, in the ivabradine arm the lowest percentage of people in each age group had bpm>75, while in the placebo arm the largest proportions had bpm>75.
- The relative risk of CV death or hospital admission for worsening HF was significantly reduced by 38% in the ivabradine group as compared to placebo in the youngest patients (<53 years, HR: 0.62, 95%CI: 0.50-0.78, P<0.001), and by 16% in patients >69 years old (HR: 0.84, 95%CI: 0.71-0.99, P=0.035). Relative risk of hospital admissions for worsening of HF was reduced by 45% (HR:0.55, 95%CI:0.42-0.72, P<0.001) in the youngest group and by 20% in the oldest group (HR:0.80, 95%CI: 0.65-0.98, P=0.028).
- The incidence of adverse events increased with age, but did not significantly differ between ivabradine and placebo in any of the age groups, except in the youngest group (34% for ivabradine vs. 41% for placebo, P=0.008).
- Adverse effects associated with ivabradine use, such as symptomatic bradycardia, asymptomatic bradycardia and phosphenes, occurred more often with ivabradine than in the placebo group, but the rates did not change with age.
ConclusionIvabradine safely reduced cardiovascular death and hospital admission for worsening of HF in both young (<53 years) and elderly (>69 years) HF patients. Thus, it can safely be administered to patients with chronic HF of all ages, although the relative risk of cardiovascular death appeared to decrease
most in young patients.
1.Maggioni AP, DahlstromU, Filippatos G, et al.(ESC-HF Pilot). Eur J Heart Fail 2010;12:1076–1084.
2. de Marneffe M, Gregoire JM, Waterschoot P, Kestemont MP. The sinus node function: normal and pathological. Eur Heart J 1993;14:649–654.
3. de Marneffe M, Jacobs P, Haardt R, Englert M. Variations of normal sinus node function in relation to age: role of autonomic influence. Eur Heart J 1986;7:662–672.
4. DiFrancesco D, Camm AJ. Heart rate lowering by specific and selective If current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs 2004;64:1757–1765.
5. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled trial. Lancet 2010;376:875–885.
6. Swedberg K, Komajda M, Böhm M et al. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f)Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail 2010;12:75–81.
7. Ferrari R. Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) Study. Arch Intern Med 2006;166:659–666.
8. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial todetermine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with Heart Failure (SENIORS). Eur Heart J 2005;26:215–225.
8. Lazzarini V, Mentz RJ, Fiuzat M, et al. Heart failure in elderly patients: distinctive features and unresolved issues. Eur J Heart Fail 2013