Effects of Intermittent Transdermal Nitroglycerin on Occurrence of Ischemi After Patch Removal: Results of the Second Transdermal Intermittent Dosing Evaluation Study (TIDES-II)

Objectives. We sought to evaluate the effects of intermittent transdermal nitroglycerin (TD-NTG) on the occurrence of ischemi during patch-off hours in patients with stable angin pectoris receiving 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 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 image, to remove it at 10 image and to note symptoms and sublingual nitroglycerin (SL-NTG) use in diary. The occurrence of ischemi 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 angin onset during ETT compared with placebo. Total angin frequency was not significantly different between TD-NTG (mean [±SD] 3.2 ± 4.2) and placebo (3.3 ± 5.2). During patch-off hours, angin 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 ischemi after TD-NTG were also observed from AECG analyses. Specifically, ischemi 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 ischemi 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, ischemi frequency decreased 58% (patch-on to patch-off, p = 0.01) compared with 14% increase with TD-NTG. These changes attenuate the usual circadian variation in ischemia. Conclusions. An increase in ischemi frequency during patch-off hours after use of intermittent TD-NTG was perceived by patients, and this subjective finding was supported by corresponding trend for AECG ischemi to increase during these same hours.