Effects of intermittent transdermal nitroglycerin on occurrence of ischemia after patch removal: results of the second transdermal intermittent dosing evaluation study (TIDES-II)

Colleges of Medicine and Pharmacy, University of Florida, Gainesville, USA. pepine.med@shands.ufl.edu

OBJECTIVES: 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.

This article has been cited by other articles:

				T. Munzel, A. Daiber, and T. Gori Nitrate Therapy: New Aspects Concerning Molecular Action and Tolerance Circulation, May 17, 2011; 123(19): 2132 - 2144. [Full Text] [PDF]

				A. Fukatsu, T. Hayashi, A. Miyazaki-Akita, H. Matsui-Hirai, Y. Furutate, A. Ishitsuka, Y. Hattori, and A. Iguchi Possible usefulness of apocynin, an NADPH oxidase inhibitor, for nitrate tolerance: prevention of NO donor-induced endothelial cell abnormalities Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H790 - H797. [Abstract] [Full Text] [PDF]

				T. Munzel Does nitroglycerin therapy hit the endothelium? J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1102 - 1105. [Full Text] [PDF]

				E. R. Azevedo, A. M. Schofield, S. Kelly, and J. D. Parker Nitroglycerin withdrawal increases endothelium-dependent vasomotor response to acetylcholine J. Am. Coll. Cardiol., February 1, 2001; 37(2): 505 - 509. [Abstract] [Full Text] [PDF]

				T. Munzel, H. Mollnau, M. Hartmann, C. Geiger, M. Oelze, A. Warnholtz, A. H. Yehia, U. Forstermann, and T. Meinertz Effects of a nitrate-free interval on tolerance, vasoconstrictor sensitivity and vascular superoxide production J. Am. Coll. Cardiol., August 1, 2000; 36(2): 628 - 634. [Abstract] [Full Text] [PDF]