723-1 Selective Reduction of Heart Rate with the Sinus Node Inhibitor Zatebradine (ULFS 49) Does not Lead to the Expected Improvements in Exercise Duration in Patients with Angina Pectoris

Abstract

Zatebradine is a novel compound blocking selectively the i F -channel in the sinus node, which is believed to be the pacemaker current. Its effect on heart rate is believed to be very selective, without any other effects on the myocardium. Since it is widely believed that the beneficial effects of betablockers are due to their heart rate reducing properties, selective reduction of heart rate without negative inotropy should result in prolongation of exercise duration and reduction in myocardial ischemia in patients with angina pectoris. To investigate this hypothesis we performed a multicenter, randomized, double-blind, placebo-controlled, dose ranging study with zatebradine. Patients (n-237) with reproducible exercise induced angina pectoris with evidence of myocardial ischemia ( ≥ 1mm ST-segment depressionI received either placebo, 2.5, 5.0 or 7.5 mg zatebradine for 4 weeks. Symptom limited exercise tests were repeated at 3 and 12 hours post dose after 4 weeks of treatment. Change from Baseline Placebo Zatebradine 3 h pa 12 h pa 2.5 mg 5.0 mg 7.5 mg 3 h 12 h 3 h pa 12 h pa 3 h pa 12 h pa Total ETD (s) 30 30 33 25 42 28 50 38 Time 1 Min (s) 24 34 27 33 57 * 34 57 48 HR Rest (bpm) 1.8 0.5 -6.4 *** -6.2 *** -12.1 *** -8.0 *** -20.5 *** -13.7 *** HR Ex (bpm) 3.8 3.8 -5.9 *** -5.5 *** 10.9 *** -9.6 *** -19.2 *** -14.4 *** EXSBP (mmHg) -2.3 -04 6.4 ** 3.2 5.4 * 4.1 3.4 60 h = hours, p.a. = post administration,s = seconds. ETD = exercise test duration, HR = heart rate. EX = Exercise, SSP = Systolic Blood Pressure * p < 0.05 ** p < 0.01 *** p < 0.001 Zatebradine is a powerful agent that reduces heart rate dosedependently over at least 12 hours. The observed heart rate reduction did not translate into the expected improvements of exercise performance or reduction of myocardial ischemia suggesting that the anti-ischemic effect of heart rate limitation should be reconsidered.