Addition of zatebradine, direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angin taking extended-release nifedipine: results of multicenter, randomized, double-blind, placebo-controlled, parallel-group study

Objectives. We examined the antianginal and anti-ischemic effects of oral zatebradine, direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angin pectoris taking extended-release nifedipine. Background. Heart rate reduction is considered an important pharmacologic mechanism for providing anginal pain relief and anti-ischemic action in patients with chronic stable angina, suggesting benefit for sinus node-inhibiting drugs. Methods. In single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once day) were randomized to receive zatebradine (5 mg twice day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angin at baseline, and after randomization they performed serial exercise test 3 h after each dose for 4 weeks. Results. Zatebradine reduced rest heart rate both at 4 weeks ([mean ± SEM] 12.9 ± 1.23 vs. 2.3 ± 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 ± 1.2 vs. 3.4 ± 1.2 [placebo] beats/min, p < 0.0001). Despite the significant effects on heart rate at rest and exercise, there were no additional benefits of zatebradine from placebo baseline in measurements of total exercise duration, time to 1-mm ST segment depression or time to onset of angina. Subjects taking zatebradine also had more visual disturbances as adverse reactions. Conclusions. Zatebradine seems to provide no additional anti-anginal benefit to patients already receiving nifedipine, and it raises questions regarding the benefit of heart rate reduction alone as an antianginal approach to patients with chronic stable angina.