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. 2016 Jun 23:4:58-63.
doi: 10.1016/j.conctc.2016.06.003. eCollection 2016 Dec 15.

Heart rate modulation in stable coronary artery disease without clinical heart failure: What we have already learned from SIGNIFY?

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Heart rate modulation in stable coronary artery disease without clinical heart failure: What we have already learned from SIGNIFY?

Gian Piero Perna et al. Contemp Clin Trials Commun. .

Abstract

An elevated heart rate is a marker of cardiovascular risk in patients with stable coronary artery disease. Ivabradine selectively inhibits the "f" current in the sinus node and reduces heart rate without any modifications of blood pressure, myocardial contractility and arteriolar resistance. However the addition of ivabradine to standard therapy to reduce heart rate did not improve outcomes in the recent SIGNIFY trial. Moreover, a significant interaction between the effect of ivabradine among subgroups with and without angina was detected, with a worse outcome in patients in CCS class >II at baseline. The explanation for this surprising finding despite a significant reduction in angina and myocardial revascularization procedures is uncertain. A J-curve for heart rate was not demonstrated. We speculate a significant interference on adverse events (mainly atrial fibrillation and consequently acute coronary syndromes) and on the outcome of unfavorable interactions between ivabradine and diltiazem, verapamil and strong inhibitors of CYP3A4 (4.6% of the total population). Indeed, when these patients are excluded from subgroup analysis, the harmful effect of Ivabradine among patients with severe angina disappears. In conclusion, heart rate is a marker of risk but is not a risk factor and/or a target of therapy in patients with stable coronary artery disease and preserved ventricular systolic function. Standard doses of ivabradine are indicated for treatment of angina as an alternative or in addition to beta-blockers, but should not be administered in association with CYP3A4 inhibitors or heart rate-lowering calcium-channel blockers.

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Figures

Fig. 1
Fig. 1
Hazard ratios and 95% confidence interval for the primary endpoint (composite of death from cardiovascular causes or nonfatal MI) in the overall population and in prespecified angina subgroups in SIGNIFY trial.
Fig. 2
Fig. 2
Effects of Ivabradine vs. Placebo on angina control and coronary revascularization.
Fig. 3
Fig. 3
Determinants of prognosis in stable Coronary Artery Disease: a complex interplay between clinical, anatomical, functional, and pathophysiological factors.
Fig. 4
Fig. 4
Relationship between “on treatment” heart rate and major adverse cardiac events (MACE) in Angina patients (Ivabradine Group). HR: hazard ratio. CI: confidence interval.
Fig. 5
Fig. 5
Distribution of primary endpoint occurrence according to Ivabradine dose. The 10 mg bid dose is not approved by European Medicines Agency (EMA).
Fig. 6
Fig. 6
Theoretical relationship between the dose of a drug and the response (in terms of clinical efficacy and toxic effect).
Fig. 7
Fig. 7
Primary end-point occurrence in angina subgroup analysis of SIGNIFY Trial. A: When the overall population is considered, a statistically significant interaction is detected between subgroups with or without severe angina. B: When patients receiving Diltiazem/Verapamil (1135) or strong CYP3A4 inhibitors (262) are excluded from analysis, the difference between groups and the harmful effect of Ivabradine among patients with severe angina disappear.

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