title: Effects of intermittent transdermal nitroglycerin on occurrence of ischemia after patch removal: results of the second transdermal intermittent dosing evaluation study (TIDES-II).
abstract: OBJECTIVE
  We sought to evaluate the effects of intermittent transdermal nitroglycerin (TD-NTG) on the occurrence of ischemia during patch-off hours in patients with stable angina pectoris receiving a beta-adrenergic blocking agent or calcium antagonist, or both.
  
  
  BACKGROUND
  The current recommendations for the use of intermittent TD-NTG may be associated with the occurrence of rebound ischemia.
  
  
  METHODS
  This was a multicenter, randomized, double-blind, placebo-controlled, crossover trial with three study periods. Tolerability to TD-NTG was assessed in Period I. Seventy-two patients were assigned to receive either double-blind transdermal placebo or maximally tolerated TD-NTG for 2 weeks (Period II) and were then crossed over to the alternative treatment for another 2 weeks (Period III). The patients were instructed to apply medication daily at 8 AM, to remove it at 10 PM and to note symptoms and sublingual nitroglycerin (SL-NTG) use in a diary. The occurrence of ischemia was assessed from patient-perceived angina, symptom-limited exercise treadmill test (ETT) and 48-h ambulatory electrocardiographic (AECG) monitoring.
  
  
  RESULTS
  Transdermal NTG (0.2 to 0.4 mg/h) significantly reduced the magnitude of ST segment depression at angina onset during ETT compared with placebo. Total angina frequency was not significantly different between TD-NTG (mean [+/-SD] 3.2 +/- 4.2) and placebo (3.3 +/- 5.2). During patch-off hours, angina frequency increased with TD-NTG (1.1 +/- 2.1) compared with placebo (0.7 +/- 1.6) (p = 0.03). Similar trends for an increase in ischemia after TD-NTG were also observed from AECG analyses. Specifically, ischemia frequency tended to be lower during patch-off hours for placebo than with TD-NTG (0.05 +/- 0.09 vs. 0.08 +/- 0.20 episodes/h, respectively, p = 0.08), even though frequency of ischemia tended to be higher during patch-on hours for placebo than with TD-NTG (0.12 +/- 0.19 vs. 0.07 +/- 0.15 episodes/h, respectively, p = 0.11). During placebo, ischemia frequency decreased 58% (patch-on to patch-off, p = 0.01) compared with a 14% increase with TD-NTG. These changes attenuate the usual circadian variation in ischemia.
  
  
  CONCLUSIONS
  An increase in ischemia frequency during patch-off hours after use of intermittent TD-NTG was perceived by patients, and this subjective finding was supported by a corresponding trend for AECG ischemia to increase during these same hours.
authors.affiliation: Colleges of Medicine and Pharmacy, University of Florida, Gainesville, USA. pepine.med@shands.ufl.edu
authors.forename: C J
authors.initials: CJ
authors.lastname: Pepine
authors.forename: L M
authors.initials: LM
authors.lastname: Lopez
authors.forename: D M
authors.initials: DM
authors.lastname: Bell
authors.forename: E M
authors.initials: EM
authors.lastname: Handberg-Thurmond
authors.forename: R G
authors.initials: RG
authors.lastname: Marks
authors.forename: S
authors.initials: S
authors.lastname: McGorray
mesh_terms: D000279:Administration, Cutaneous; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D015716:Electrocardiography, Ambulatory; D005080:Exercise Test; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000139:chemically induced*; D005996:Nitroglycerin / Q000008:administration & dosage* / Q000009:adverse effects*; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; D005996:Nitroglycerin