Sustained High‐Dose Nitroglycerin Transcutaneous Patch Therapy in Angina Pectoris: Evidence for Attenuation of Effect Over Time

Frishman, William H.; Giles, Thomas D.; Greenberg, Steven M.; Heiman, Mark; Raffidal, Louise; Soberman, Judith E.; Laifer, Larry; Nadelmann, Jeremy; Lazar, Eliot J.; Strom, Joel A.

doi:10.1002/j.1552-4604.1989.tb03285.x

Cited by 12 publications

(7 citation statements)

References 24 publications

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“…Second, as discussed in our meta-analysis [25], lack of effect is mostly reported when tested at the end of a patch application period. There are, however, double-blind studies that report no improvement in exercise duration also in the hours just after patch application [1,3,16,31,32,39]. None of these studies included more than 10-12 patients, however, and four of them used suboptimal doses, that is, 10 mg/24 hr or below [3,16,31,32].…”

Section: Intermittent Versus Continuous Treatmentmentioning

confidence: 97%

“…What about the other trials that report no effect of continuous treatment on exercise duration [1,3,16,31,32,[36][37][38][39]? First, one must acknowledge that nitrate tolerance exists as a clinical problem, and that attenuation of efficacy develops during continuous therapy.…”

Section: Intermittent Versus Continuous Treatmentmentioning

confidence: 99%

“…During continuous therapy, nitrate tolerance cannot be overcome with high doses; on the contrary, complete tolerance was observed in studies with very high doses [14,39]. Maintained efficacy has been observed 2-5 hours after patch renewal in studies using 0.4-0.8 mg/hr (10-20 mg/24 hr) [17][18][19][20]34,35,56].…”

Section: Optimal Dosesmentioning

confidence: 99%

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

Klemsdal

Gjesdal

1996

Cardiovasc Drug Ther

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After a decade of controversy and debate, many experts have now concluded that continuous nitroglycerin patch treatment leads to complete tolerance development and therefore cannot be recommended for any angina patient. This conclusion is largely based on the disappointing results of the large Transdermal Nitroglycerin Cooperative Study, in which continuous patch treatment in doses of 15-105 mg daily failed to increase exercise duration more than placebo after 2 and 8 weeks of treatment. However, other well-designed studies recently reported maintained efficacy during continuous treatment, and the differences in results has remained unexplained. The disagreeing data may be better understood if certain facts are considered: (1) The cooperative study tested a patient population with a very low first-dose treatment response--only 34 seconds (or 10-12%) improvement compared with placebo. At the end of the study, 25% of the patients terminated exercise for reasons other than angina, and a reduced nitrate responsiveness had developed, even in the placebo group. (2) Patients who demonstrate a large first-dose nitrate responsiveness tend to be less susceptible to tolerance development. (3) Even during continuous therapy, maintained efficacy is often observed in exercise tests done 2-5 hours after patch renewal, while typically no effect is seen at the end of the application period. Attenuation of the initial effects is seen with all long-acting nitrate treatment regimens, but the degree of tolerance varies with the patient population, the efficacy parameter (exercise test vs. attack counts), the timing of the efficacy test, the patch dose, and whether or not nitrate-free (-low) intervals are used. In general, intermittent patch therapy is superior to continuous therapy in improving exercise duration, but even continuous therapy may retain some effect. Rebound phenomena do occur but are clinically relevant only in a minority of the patients. Rebound phenomena are not a problem during continuous therapy, which therefore may be of value in patients with frequent and/or nocturnal angina attacks. Patients experiencing angina during exercise only and with low first-dose effects are likely to benefit more from intermittent therapy. Doses of 0.6-0.8 mg/hr (15-20 mg/24 hr) are usually optimal, and the efficacy is comparable with that observed after oral nitrates.

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Section: Intermittent Versus Continuous Treatmentmentioning

confidence: 97%

Section: Intermittent Versus Continuous Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

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

Klemsdal

Gjesdal

1996

Cardiovasc Drug Ther

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“…In the same study, higher doses proved to be of no benefit, not even acutely during the first 24 hours [25]. The data in several small studies using higher doses are confiicting and do not allow any firm conclusions [6,16,19,21]. Thus, there is little evidence supporting treatment with doses exceeding 20 mg/24 hr.…”

Section: Optimal Dosingmentioning

confidence: 99%

“…Several studies demonstrate that continuous nitrate treatment in high doses will produce a high degree of nitrate tolerance, regardless of whether the administration is transdermal or intravenous, and similar for isosorbide dinitrate given orally qid [21,25,35,36]. The question that has remained unanswered is to what extent patch treatment in doses of 5-20 mg/24 hr will cause tolerance.…”

Section: Pharmacokinetic Considerationsmentioning

confidence: 99%

The effect of transdermal nitroglycerin on exercise tolerance in relation to patch application time?a meta-analysis

Klemsdal

Gjesdal

1992

Cardiovasc Drug Ther

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Disagreeing results have been reported in the many studies on continuous treatment with nitroglycerin patches. The effects on exercise tolerance are partly studied at the end of a 24-hour application period, and partly examined only a few hours after patch renewal. The present meta-analysis estimates the overall efficacy of nitroglycerin patches in trials with and without concomitant antianginal therapy, and investigates if the treatment effect depends on the patch application time. A computed search (MEDLINE) identified 110 publications, of which 17 trials on nitrate patch monotherapy and six trials on combined therapy satisfied the inclusion criteria. Data on "exercise duration" and "ST-segment depression" were converted to a standardized treatment effect size d, and pooled to an overall treatment effect size d+. In tests 2-5 hours after patch renewal, moderate but significant effects of nitrate monotherapy were observed; d+ was 1.20 with regard to "ST-segment depression" and 0.39 with regard to "exercise duration" (both p < 0.0001). In contrast, 24 hours after patch application, the values for d+ were 0.09 (not significant) and 0.36 (p < 0.01), respectively. When adding the results from the six trials on combined therapy, d+ with regard to "exercise duration" was reduced to 0.28 (p < 0.0001) 2-5 hours after renewal and to 0.17 (p = 0.04) after 24 hours. Thus, the efficacy of continuous nitroglycerin patch treatment is moderate but evident during exercise tests 2-5 hours after patch renewal; however, it is reduced after 24 hours of patch application.

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Effects of sublingual nitroglycerin in patients receiving transdermal nitroglycerin for coronary artery disease: Prevention of cross‐tolerance

Naito

Mastsuda

Yorozu

et al. 1991

Clinical Cardiology

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Summary:The systemic hemodynamic and coronary dilative responses to sublingual nitroglycerin were studied in patients receiving transdermal nitroglycerin. A total of 48 patients with coronary artery disease were divided into 4 groups: 12 patients receiving 1 tablet of sublingual nitroglycerin without transdermal nitroglycerin (Group I), 12 patients receiving 1 tablet of sublingual nitroglycerin with 12-hour-daily intermittent therapy of transdermal nitroglycerin (Group 2), 12 patients receiving 1 tablet of sublingual nitroglycerin with continuous therapy of transderma1 nitroglycerin (Group 3), and 12 patients receiving 2 tablets of sublingual nitroglycerin with continuous therapy of transdermal nitroglycerin (Group 4). Before and during administration of sublingual nitroglycerin, aortic pressure, left ventricular pressure, and coronary artery diameter were examined at diagnostic cardiac catheterization in all patients. During sublingual nitroglycerin, the decreases of aortic systolic pressure and left ventricular end-diastolic pressure were greater in Group 1,2, and 4 than in Group 3. Dilation of coronary arteries by sublingual nitroglyerin tended to be greater in Group 1,2, and 4 than in Group 3. Thus, the effects of sublingual nitroglycerin for the relief of ischemia might be more prominent in patients with intermittent therapy of transdermal nitroglycerin than in those with continuous therapy. The increased dose of sublingual nitroglycerin for the relief of ischemia might be more effective in patients with continuous therapy of transdermal nitroglycerin.

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Sustained High‐Dose Nitroglycerin Transcutaneous Patch Therapy in Angina Pectoris: Evidence for Attenuation of Effect Over Time

Cited by 12 publications

References 24 publications

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

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

The effect of transdermal nitroglycerin on exercise tolerance in relation to patch application time?a meta-analysis

Effects of sublingual nitroglycerin in patients receiving transdermal nitroglycerin for coronary artery disease: Prevention of cross‐tolerance

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