Lack of rebound during intermittent transdermal treatment with glyceryl trinitrate in patients with stable angina on background beta blocker.

Holdright, Diana R.; Katz, Richard J.; Wright, C A; Sparrow, Jane; Sullivan, A K; Cunningham, A D; K, Fox

doi:10.1136/hrt.69.3.223

Cited by 10 publications

(5 citation statements)

References 21 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Harmful Effects In the Nitrate-free Periods?mentioning

confidence: 98%

“…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. It has been suggested that concomitant therapy (e.g., beta-blockers) could be protective in the nitrate-free period [46], but this has not been tested out specifically in any study.…”

Section: Harmful Effects In the Nitrate-free Periods?mentioning

confidence: 99%

“…Both the neurohumoral response and the withdrawal phenomena are likely to increase with increasing doses. However, clinically significant withdrawal phenomena appear to affect only a small proportion of the patients, and this problem cannot prohibit a general recommendation of intermittent therapy [15,34,43,45,46].…”

Section: Harmful Effects In the Nitrate-free Periods?mentioning

confidence: 99%

See 2 more Smart Citations

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

Klemsdal

Gjesdal

1996

Cardiovasc Drug Ther

View full text Add to dashboard Cite

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.

show abstract

Section: Harmful Effects In the Nitrate-free Periods?mentioning

confidence: 98%

Section: Harmful Effects In the Nitrate-free Periods?mentioning

confidence: 99%

Section: Harmful Effects In the Nitrate-free Periods?mentioning

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

View full text Add to dashboard Cite

show abstract

“…Observational studies of explosives industries workers confirm an increased relative risk of sudden cardiac death during off‐duty periods [19]. Chronic beta‐blocker administration for stable angina protects against ‘rebound vasoconstriction’ in patients treated with intermittent nitrate patches [20]. The mechanism through which beta‐blockers exert their protective effect could include a dampening down of the effects of increased vasoconstrictor levels found in nitrate tolerance [21].…”

Section: Nitrate Tolerancementioning

confidence: 99%

Nitrate tolerance and the links with endothelial dysfunction and oxidative stress

Fayers

Cummings

Shaw

et al. 2003

Brit J Clinical Pharma

View full text Add to dashboard Cite

Identification of nitric oxide as the molecule responsible for endothelial dependant vasodilatation has led to an explosion of interest in endothelial function. Oxidative stress has been identified as an important factor in the development of tolerance to organic nitrates. This review examines the evidence supporting this recently developed theory and how mechanisms of nitrate tolerance may link with the wider picture of primary nitric oxide resistance.

show abstract

“…Intermittent use of nitrate patches providing a daily nitrate-free interval of 12 hours at night is effective for 8-12 hours, provided an adequate patch size delivering at least 7.5 mg of nitroglycerin per 12 hours is used. The patient remains unprotected at night and during the early hours of the morning, and if this is of concern, one should either use an aiternative antianginal agent or a beta-blocker concomitantly with the patches [65].…”

Section: Current Recommendations For Use Of Nitratesmentioning

confidence: 99%

Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure

Thadani

1997

Cardiovasc Drug Ther

View full text Add to dashboard Cite

Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhdryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinical concern. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and antiischemic effects of nitrates for 10-14 hours during the daytime can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120-240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10-12 hours each day). Only the patch on and off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients with 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also de...

show abstract

Lack of rebound during intermittent transdermal treatment with glyceryl trinitrate in patients with stable angina on background beta blocker.

Abstract: Objective-To assess whether intermittent transdermal treatment with glyceryl trinitrate causes clinically significant rebound in patients maintained on a blockers for stable angina pectoris.Design

Cited by 10 publications

References 21 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?

Nitrate tolerance and the links with endothelial dysfunction and oxidative stress

Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure

Contact Info

Product

Resources

About