Avoidance of tolerance and lack of rebound with intermittent dose titrated transdermal glyceryl trinitrate. The Transdermal Nitrate Investigators.

Abstract

Objectives-To investigate the efficacy of transdermal glyceryl trinitrate given continuously and with a nocturnal nitrate free period.Design-Double blind placebo controlled study with two parallel limbs.Setting-Multicentre trial.Patients-52 patients randomised to receive either continuous treatment (23 patients) or intermittent treatment with an individually titrated dose (29 patients) for 14 days: both treatments were compared with placebo in a crossover fashion.Intervention-Continuous treatment with 10 mg per 24 hours of transdermal glyceryl trinitrate or intermittent transdermal glyceryl trinitrate titrated to give an arbitrary 10 mm Hg drop in systolic blood pressure (mean dose 18-2 mg) given over approximately 16 hours.Main outcome measure-Treadmill exercise stress testing and ambulatory monitoring of the ST segment after 14 days' treatment.Results-After 14 days' intermittent treatment resting supine and standing systolic blood pressure fell by 7 5 mm Hg (95% confidence interval 2-7 to 12-2) and 9 0 mm Hg (95% CI 3-4 to 14-5) respectively (p < 0-01); resting heart rate was unchanged. Mean heart rate at 1 mm ST segment depression rose by 11 9 beats/ min (CI 1-1 to 23-7) (p < 0-05), mean time to onset of angina increased by 59 seconds

Intermittent or continuous transdermal nitroglycerin: Still an issue, or Is the case closed?

“…Also, Demots and Glasser observed that intermittent therapy caused a so-called zero-hour effect, apparent as a reduced exercise capacity (compared with placebo-treated patients) at the time just before the daily patch application [15]. Other studies, however, have not been able to demonstrate increased angina frequency during the patch-off hours [34,43,45,46], and in the new large intermittent transdermal nitroglycerin study by Parker et al, a significant zero-hour effect could not be demonstrated [43]. A recent study indicates that a rebound effect with reduced exercise tolerance is most prominent 2-6 hours after patch removal [47], and the problem may hence be underestimated in studies testing just before renewed application, that is, 12 hours after removal.…”

Avoiding nitrate tolerance.

“…The best currently available estimate for the incidence of rebound with intermittent patch therapy, based on the published data in randomised studies totalling over 500 patients, suggests that rebound angina may occur in 2-4% of patients. Reassuringly, there is no evidence for any exacerbation of silent ischaemia during overnight patch withdrawal (Fox et al, 1991).…”

“…Although continuous therapy may be of some value, benefits are substantially less than during intermittent therapy. Numerous studies, totalling over 500 randomised patients, have demonstrated the benefits of intermittent patch therapy over continuous (Cowan et al, 1987;De Milliano et al, 1989;DeMots & Glasser, 1989;Fox et al, 1991;Luke et al, 1987;Scardi et al, 1991;Schaer et al, 1988). For this reason, where possible, intermittent therapy is preferable to continuous.…”

“…Six of 10 patients had anginal symptoms at this time. However, many other studies have failed to show any evidence whatsoever for rebound (Cowan et al, 1987;Fox et al, 1991;Luke et al, 1987;Scardi et al, 1991;Schaer et al, 1988). The best currently available estimate for the incidence of rebound with intermittent patch therapy, based on the published data in randomised studies totalling over 500 patients, suggests that rebound angina may occur in 2-4% of patients.…”

Eccentric Dosing of Nitrates Does Not Increase Cardiac Events in Patients with Healed Myocardial Infarction

“…Intermittent nitrate therapy increases exercise duration and maintains anti-ischemic effects, without significant evidence of nitrate tolerance or rebound phenomenon (17,(49)(50)(51)(52). Although intermittent nitrate therapy has proved superior to continuous therapy, intermittent therapy may be associated with rebound myocardial ischemia during the nitrate-free period.…”