title: Efficacy and safety of a once-daily graded-release diltiazem formulation dosed at bedtime compared to placebo and to morning dosing in chronic stable angina pectoris.
abstract: BACKGROUND
  The efficacy and safety of a once-daily graded-release diltiazem hydrochloride (GRD) formulation dosed at 10 PM in doses of 180, 360, and 420 mg were compared with placebo and with GRD 360 mg dosed once daily at 8 AM in patients (n = 311) with chronic stable angina pectoris.
  
  
  METHODS
  This was a 3-week multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled trial. Standard Bruce protocol treadmill stress test was performed at baseline and end point between 6 and 8 PM (trough for evening doses) and between 7 and 11 AM (trough for morning doses).
  
  
  RESULTS
  All GRD evening doses showed a significant (P < or = .0201) increase in total duration of exercise at trough and a greater significant increase (P < or = .0002) at peak, compared with placebo. The GRD 360-mg evening dose showed the greatest increase at trough. In contrast, GRD 360-mg morning dose showed an increase in total duration of exercise at trough that was not significantly different (P = .0555) from placebo AM. GRD 360-mg evening dose showed a 4-fold placebo-adjusted improvement compared with GRD 360-mg morning dose between 7 and 11 AM. Significant increases (P < or = .0240) in time to onset of angina were obtained for all evening doses at trough and peak. All GRD doses were well tolerated, and incidence of adverse events for all GRD groups combined was less than that for placebo.
  
  
  CONCLUSIONS
  Bedtime GRD significantly increases exercise tolerance in patients with angina pectoris over the 24-hour dosing interval. A greater 4-fold placebo-adjusted improvement occurred between 7 and 11 AM compared with the same morning dose, coinciding with the period of increased cardiovascular risk. GRD was safe and well tolerated.
authors.affiliation: Department of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. glasser@epi.umn.edu
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Glasser
authors.forename: Theophilus J
authors.initials: TJ
authors.lastname: Gana
authors.forename: Luz G
authors.initials: LG
authors.lastname: Pascual
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Albert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004110:Diltiazem / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000627:therapeutic use
chemical_list: D002317:Cardiovascular Agents; D003692:Delayed-Action Preparations; D004110:Diltiazem; D005996:Nitroglycerin