Freedman S B, Daxini B V, Noyce D, Kelly D T
Hallstrom Institute of Cardiology, University of Sydney, Royal Prince Alfred Hospital, Australia.
J Am Coll Cardiol. 1995 Feb;25(2):349-55. doi: 10.1016/0735-1097(94)00416-n.
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.
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.
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.
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).
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.
本研究旨在确定在接受背景抗心绞痛治疗的心绞痛患者中，间歇性皮肤应用硝酸甘油治疗的无硝酸酯间期是否会发生反弹性缺血。
有观点认为，长期间歇性皮肤应用硝酸甘油治疗以预防耐受性时，反弹性心绞痛是无硝酸酯间期的一种并发症。
52例稳定型劳力性心绞痛患者，其中服用β-肾上腺素能阻滞剂的有25例，服用地尔硫䓬的有22例，联合服用两者的有5例，完成了一项关于皮肤硝酸甘油贴片（50 mg）的随机、双盲、安慰剂对照交叉研究。活性或安慰剂贴片佩戴1周，上午8点贴敷，晚上10点取下，以提供每日10小时的无硝酸酯（或无安慰剂）间期。在每个研究阶段的最后48小时，使用动态心电图监测仪检测缺血情况。
仅31例患者在研究的任一阶段发生缺血（23例发生在贴片取下期）。共记录到463次缺血发作：安慰剂期246次，硝酸甘油期217次（每位患者比较，p = 0.8）。大多数（88%）缺血发作是无症状的。在整个48小时期间，活性治疗期和安慰剂期缺血的平均（±标准误）持续时间相似（活性治疗组为35.5±15.0分钟/24小时，安慰剂组为29.7±9.8分钟/24小时，p = 0.8）。这是由于活性治疗在贴片取下期缺血持续时间增加（活性治疗组为46.9±17.9分钟/ /24小时，安慰剂组为22.5±9.2分钟/24小时，p = 0.07），而在贴片贴敷期减少（活性治疗组为27.5±14.0分钟/24小时，安慰剂组为34.5±11.0分钟/24小时，p = 0.16）。活性治疗期和安慰剂期缺血发作的昼夜分布模式不同。在安慰剂期，夜间贴片取下期缺血发生率有一个最低点，午夜至凌晨6点之间的发生率（25次发作）明显低于其他三个6小时时间段的平均发作次数（73次发作，p < 0.001）。在硝酸甘油贴片取下期，夜间最低点消失，午夜至凌晨6点之间的缺血发生率（53次发作）与其他三个6小时时间段的平均发作次数（54次发作）相同。
大多数接受背景抗心绞痛治疗的患者在贴片取下期未发生缺血。在该期间有44%发生缺血的患者中，活性治疗使缺血持续时间有不显著的增加。虽然这一结果在统计学上无定论，但昼夜缺血分布的变化提供了提示性证据，表明反弹性缺血可能是间歇性皮肤应用硝酸甘油的一个问题。
