title: Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group.
abstract: OBJECTIVE
  We examined the antianginal and anti-ischemic effects of oral zatebradine, a direct sinus node inhibitor that has no blood pressure-lowering or negative inotropic effects in patients with chronic stable angina 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 a benefit for sinus node-inhibiting drugs.
  
  
  METHODS
  In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60). All subjects had reproducible treadmill exercise-induced angina at baseline, and after randomization they performed a 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 antianginal 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.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, New York, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: Frishman
authors.forename: C J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: R J
authors.initials: RJ
authors.lastname: Weiss
authors.forename: W M
authors.initials: WM
authors.lastname: Baiker
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D001552:Benzazepines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002908:Chronic Disease; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005080:Exercise Test / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009543:Nifedipine / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; D003692:Delayed-Action Preparations; D009543:Nifedipine; C043636:zatebradine