Intermittent transdermal nitrates do not improve ischemia in patients taking beta-blockers or calcium antagonists: potential role of rebound ischemia during the nitrate-free period.
OBJECTIVE
This study was conducted to determine whether rebound ischemia occurs during nitrate-free periods with intermittent cutaneous nitroglycerin therapy in patients with angina pectoris who are receiving background antianginal therapy.


BACKGROUND
Rebound angina has been suggested to be a complication of the nitrate-free period with long-term cutaneous nitroglycerin therapy given intermittently to prevent tolerance.


METHODS
Fifty-two patients with stable effort angina taking either a beta-adrenergic blocking agent (n = 25) or diltiazem (n = 22) or their combination (n = 5) completed a randomized, double-blind, placebo-controlled crossover study of cutaneous nitroglycerin patches (50 mg). Active or placebo patches were worn for 1 week, applied at 8 AM and removed at 10 PM to provide a 10-h daily nitrate-free (or placebo-free) period. During the last 48 h of each study phase, a Holter monitor was used to detect ischemia.


RESULTS
Only 31 patients experienced ischemia during either phase of the study (23 during the patch-off period). A total of 463 ischemic episodes were recorded: 246 during placebo and 217 during nitroglycerin (p = 0.8, for per patient comparison). The majority (88%) of ischemic episodes were silent. Mean (+/- SEM) duration of ischemia during the total 48-h period was similar during active and placebo phases (35.5 +/- 15.0 min/24 h for active therapy vs. 29.7 +/- 9.8 for placebo, p = 0.8). This was due to an increase in duration of ischemia with active therapy during the patch-off period (46.9 +/- 17.9 min/24 h for active therapy vs. 22.5 +/- 9.2 for placebo, p = 0.07) and a decrease during the patch-on period (27.5 +/- 14.0 min/24 h for active therapy vs. 34.5 +/- 11.0 min/24 h for placebo, p = 0.16). The pattern of diurnal distribution of ischemic episodes differed between active and placebo phases. During placebo there was a nadir in the incidence of ischemia in the overnight patch-off period, with a significantly lower incidence between midnight and 6 AM (25 episodes) compared with the mean number of episodes during the three other 6-h periods (73 episodes, p < 0.001). During the nitroglycerin patch-off period, there was a loss of this overnight nadir, with the same incidence of ischemia between midnight and 6 AM (53 episodes) as the mean number of episodes for the three other 6-h periods (54 episodes).


CONCLUSIONS
The majority of patients taking background antianginal therapy experienced no ischemia during the patch-off period. In the 44% of patients with ischemia during this period, there was a nonsignificant increase in the duration of ischemia with active therapy. Although this result was statistically inconclusive, the change in the distribution of diurnal ischemia offers suggestive evidence that rebound ischemia may be a problem with regard to intermittent cutaneous nitroglycerin.
Freedman
S B
SB
Hallstrom Institute of Cardiology, University of Sydney, Royal Prince Alfred Hospital, Australia.
Daxini
B V
BV
Noyce
D
D
Kelly
D T
DT
D000279:Administration, Cutaneous; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D001262:Atenolol / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002940:Circadian Rhythm / Q000502:physiology; D018592:Cross-Over Studies; D004110:Diltiazem / Q000627:therapeutic use; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D015716:Electrocardiography, Ambulatory; D005080:Exercise Test; D005260:Female; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000175:diagnosis / Q000503:physiopathology*; D005996:Nitroglycerin / Q000008:administration & dosage* / Q000627:therapeutic use
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D001262:Atenolol; D004110:Diltiazem; D005996:Nitroglycerin; D008790:Metoprolol