Intermittent transdermal nitrates do not improve ischemi in patients taking beta-blockers or calcium antagonists: Potential role of rebound ischemi during the nitrate-free period

Objectives. This study was conducted to determine whether rebound ischemi occurs during nitrate-free periods with intermittent cutaneous nitroglycerin therapy in patients with angin pectoris who are receiving background antianginal therapy. Background. Rebound angin has been suggested to be complication of the nitrate-free period with long-term cutaneous nitroglycerin therapy given intermittently to prevent tolerance. Methods. Fifty-two patients with stable effort angin taking either beta-adrenergic blockign agent (n = 25) or diltiazem (n = 22) or their combination (n = 5) completed 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 and removed at 10 to provide 10-h daily nitrate-free (or placebo-free) period. During the last 48 h of each study phase, Holter monitor was used to detect ischemia. Results. Only 31 patients experienced ischemi during either phase of the study (23 during the patch-off period). 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 ischemi 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 ischemi 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 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 nadir in the incidence of ischemi in the ovenight patch-off period, with significantly lower incidence between midnight and 6 (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 loss of this overnight nadir, with the same incidence of ischemi between midnight and 6 (53 episodes) as the mean number of episodes for the three other 6-h periods (54 episodes). Conclusions. The majority of patients taking background anti-anginal therapy experienced no ischemi during the patch-off period. In the 44% of patients with ischemi during this period, there was nonsignificant increase in the duration of ischemi with active therapy. Although this result was statistically inconclusive, the change in the distribution of diurnal ischemi offers suggestive evidence that rebound ischemi may be problem with regard to intermittent cutaneous nitroglycerin.