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]

Background

Ageing often influences drug metabolism and pharmacological effects, possibly affecting efficacy and safety. Heart failure (HF) predominantly affects the elderly [1], 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 I_f channels of the sinus node [4]. 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 [1]. 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.

Main results

• 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.

Conclusion

Ivabradine 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.

References

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