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Sublingual Nitrates for Patients as a Default in the Post-ACS Discharge Pack: Is It Time for a Rethink?

Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.121.058008Circulation. 2022;145:791–792

    The current era of management for coronary artery disease and acute coronary syndromes (ACS) is guided by high-level evidence from large-scale, prospective clinical trials. Although certain therapies such as early invasive therapy, dual antiplatelet therapy, and angiotensin-converting enzyme inhibition have clear prognostic benefits, use of sublingual glyceryl trinitrate therapy (GTN) after discharge appears to be guided by historic studies. The first reported use of GTN for the treatment of angina pectoris was in 1867. Despite the limited data, use of sublingual GTN after ACS is strongly embedded within guidelines, with 2 to 3 million patients per year from the United States and Europe alone being discharged after ACS with their bottle of spray or sublingual tablets to be used as required. This article aims to relook at this global “habit” in the setting of routine revascularization for ACS.

    The most accepted mechanism of GTN action is vasodilatation mediated by activation of soluble guanylate cyclase and production of cyclic guanosine monophosphate in vascular smooth muscle. In the setting of ACS, GTN-induced vasodilation of epicardial vessels and resistance vessels as well as collateral vessels may acutely improve myocardial perfusion until revascularization can be achieved. The current European Society of Cardiology guidelines, released in 2020, give a class I recommendation for the use of nitrates (sublingual or intravenous) for the treatment of ACS without persistent ST elevation in the setting of ischemic symptoms without contraindications.1 Similarly, the American Heart Association/American College of Cardiology guidelines provide a class I recommendation for the use of nitrates for management of both acute non–ST-segment–elevation myocardial infarction and ST-segment–elevation myocardial infarction in patients with “ongoing ischemic pain, except in the setting of treatment with phosphodiesterase inhibitors (PDE).”2 In all cases, recommendations are based on level C evidence and indicated for patients with ongoing ischemia before percutaneous intervention, with the authors stating that “the rationale for nitrate use in NSTE [non-ST elevation]-ACS is extrapolated from pathophysiological principles and clinical observations, experimental studies, and clinical experience.”2

    The studies cited in the ACS guidelines have largely been conducted in the pre-percutaneous coronary intervention era and have evaluated long-acting nitrate formulations. These studies include the ISIS-4 study3 and the GISSI-3 trial.4 In the ISIS-4 study, 1 month of oral controlled-release mononitrate was compared with placebo. In this study, there was no significant difference in mortality between the 2 groups, no reduction in postinfarction angina, and no reduction in reinfarction rates. There was a significantly higher incidence of hypotension and headaches in the nitrate therapy arm.3 The GISSI-3 trial was a multicenter randomized clinical trial designed to assess the efficacy of lisinopril, transdermal GTN, and their combination in improving survival and ventricular function after acute myocardial infarction. This trial showed that compared with control, the systematic administration of transdermal GTN did not show any independent effect on the survival or ventricular function. There was also no significant effect on the incidence of reinfarction, but a small reduction in rates of postinfarction angina (20.0% versus 21.2%; P=0.033).4

    The data supporting use of GTN after ACS are limited to long-acting GTN, with no study found addressing the potential efficacy and safety of sublingual GTN for patients discharged after ACS with successful revascularization (on the basis of a broad search on PubMed and Embase). Evidence supporting use of nitrate therapy for symptom improvement after ACS is not guided by abundant robust clinical trials, with studies limited to its use in stable angina. We were unable to find any studies reporting patient-reported experience or outcome measures that may be important to consider.

    Having found limited evidence for the widespread practice of discharging patients with ACS with sublingual GTN (or equivalent), we also considered the potential harm and cost. Adverse events include headaches, hypotension that may lead to syncope, cutaneous flushing, and reflex tachycardia. Caution should particularly be applied in the setting of concomitant use of PDE inhibitors, right ventricular infarction, aortic stenosis, and hypertrophic cardiomyopathy, where the hemodynamic effect of GTN may reduce cardiac output. This may augment the hemodynamic challenges related to the myocardial infarction itself, and the hemodynamic-altering properties of evidence-based β-blockade and angiotensin-converting enzyme inhibition.

    Last, the economic cost of GTN should be considered, particularly in view of the scale of its use and lack of demonstrated benefit in the current era. An estimated 780 000 patients with ACS are admitted in the United States each year,1 and estimates of between 670 000 and 2.4 million patients with ACS annual admissions across Europe. Applying this estimated incidence, and assuming as estimated US$25 per prescription, the cost of the medication is US$19 500 000 and US$60 000 000 annually across the United States and Europe, respectively. These are rough estimates, without accounting for hospital presentations related to side effects or renewed prescriptions related to short shelf life. Futility also needs to be considered. In clinical practice, there are many patients who do not “reach” for their sublingual nitrate until it is out of date, many months after their discharge. Furthermore, there are a substantial number of patients who renew their prescriptions despite never having required them.

    Although potential harm and economic costs exist, there is potential for sublingual GTN to prevent presentations with angina for certain subgroups of patients. Indeed, consistent with the benefits of a more targeted approach, the TRANSLATE ACS registry5 indicates that the incidence of recurrent angina is close to 30% at 6 weeks, with higher incidence of recurrence in patients with previous ACS and previous revascularization. These presentations may have implications on quality of life as well as economic costs. Patients who may benefit from sublingual GTN prescription include patients with residual coronary artery disease associated with risk of myocardial ischemia, patients with previous revascularization or ACS, patients with ongoing symptoms before discharge, and patients with symptoms on follow-up after discharge.

    To guide future recommendations, qualitative research to examine patient perspective, a randomized study of not prescribing sublingual GTN on discharge and evaluating rehospitalization rates, and a formal cost-effectiveness analysis may be valuable and relevant to the guidelines.

    Conclusions

    In the current revascularization era, judicious use of sublingual GTN may be indicated and beneficial for the patient with ACS with residual coronary artery disease at risk of recurrent ischemia; however, the routine prescription of sublingual GTN to all patients discharged after ACS must be questioned.

    Article Information

    Disclosures G.A.F. reports personal consulting fees from CSL, Janssen, Amgen, and Boehringer Ingelheim and grants from Abbott Diagnostic outside the submitted work. In addition, G.A.F. has a patent for Biomarkers and Oxidative Stress that was awarded in May 2017 in the United States (US9638699B2) issued to Northern Sydney Local Health District. The other authors report no conflicts.

    Footnotes

    The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

    For Sources of Funding and Disclosures, see page 792.

    Circulation is available at www.ahajournals.org/journal/circ

    Correspondence to: Gemma A. Figtree, MBBS, DPhil, Royal North Shore Hospital, Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Level 12, Kolling Institute of Medical Research, 10 Westbourne Street, St Leonards, 2065, Australia. Email

    References

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