Intracoronary nitroglycerin: recognizing coronary spasm first and foremost to avoid unnecessary coronary stents

KEYWORDS:

• Coronary angiography
• coronary artery disease
• coronary spasm
• coronary stents
• nitroglycerin
• percutaneous coronary intervention

Approximately, 1.2 million percutaneous coronary interventions (PCIs) for treatment of coronary artery disease (CAD) are performed annually in the United States [1]. Although the procedure is safe, complications can still occur, including vascular access complications, arrhythmias, myocardial infarction, stroke, and in rare cases death. Over the past decade, concerns were raised by both the medical community and the lay press regarding overuse of stents in certain patients with CAD. Unnecessary stenting exposes the patient to the risk of complications without providing any added benefit. Current cardiovascular guidelines and Appropriate Use Criteria provide direction regarding which patients are most likely to benefit from PCI [2]. However, diagnostic challenges and dilemmas still exist in patients with seemingly significant angiographic CAD. Coronary artery spasm (CAS) is one such challenge.

First described in 1959 by Prinzmetal et al., CAS is a variant type of angina, which, unlike the classic form of stable angina, occurs at rest and is associated with transient ST-segment elevations [3]. Printzmetal hypothesized that the mechanism underlying this presentation was an increase in vasomotor tone that caused temporary constriction of a large epicardial artery. The advent of coronary angiography revealed that CAS was indeed the cause of variant angina and confirmed Prinzmetal’s original hypotheses that the sudden, reversible increase in vasomotor tone can occur both at the site of a stenosis and in normal appearing coronary arteries [4]. Recent studies have shown that up to 40% of patients with stable angina have angiographically normal coronary arteries, many of whom will demonstrate CAS on provocative testing [5]. Patients with symptomatic CAS face serious consequences including ischemia, myocardial infarction, malignant arrhythmias, and sudden cardiac death [3].

CAS is an underappreciated but important cause of chest pain syndromes. Unlike coronary atherosclerosis which often requires consideration for PCI, CAS can typically be treated with calcium channel blockers and nitrates. However, studies have demonstrated that atherosclerotic CAD and CAS often coexist [6], creating a diagnostic dilemma during angiographic evaluation of patients presenting with angina. Since misidentification of CAS can lead to inappropriate PCI, ruling out vasospasm is important in the patients who present with stable angina as well as those with unstable or rest angina. Studies have shown that CAS in the setting of nonobstructive CAD is the underlying mechanism in up to 25% of patients presenting with stable angina and 49% of patients presenting with acute coronary syndrome [7].

In a recent case series, we highlighted the importance of intracoronary nitroglycerin (IC NTG) administration during diagnostic catheterization prior to PCI [8]. In this study, six patients between the ages of 46 and 57 were referred for PCI after presenting with angina and angiographically significant stenoses (>70%). None of the patients had ST-segment elevation on electrocardiography. IC vasodilators, including NTG, adenosine, or calcium channel blockers, were not administered to these patients at the time of diagnostic coronary angiography. However, in all patients, repeat angiography following administration of IC NTG prior to planned PCI demonstrated resolution of the target stenosis. PCI was deferred and all six patients were successfully treated with calcium channel blockers with or without long-acting nitrates. The study highlighted that CAS should be suspected especially in patients with angiographically significant stenosis who are young, have a history of smoking, or have a history of migraines [8]. An important observation of our study was that severe CAS can be present at the time of coronary angiography even without ongoing angina or electrocardiographic changes.

In an example of the significant adverse consequences of unrecognized CAS, Mohammed and colleagues [9] performed a retrospective review of patients with left main coronary artery (LMCA) disease (>50%) who had undergone coronary artery bypass surgery and had subsequent follow-up coronary angiography. Of 385 patients, 16 (4.1%) demonstrated LMCA stenosis <25% on repeat angiography, suggesting the presence of unrecognized CAS at the time of preoperative coronary angiography. Factors predisposing to LMCA spasm included increased catheter-to-Left Main (LM) diameter ratio, catheter-to-LM wall contact, and an acute catheter-to-LM angle [9]. The authors concluded that even with angiographically significant LMCA stenosis, attempts to ameliorate possible spasm are a reasonable routine in hemodynamically stable patients in order to avoid potentially unnecessary cardiac surgery. Other investigators have suggested an even higher incidence of unrecognized left main coronary spasm in patients referred for coronary bypass surgery [10]. Since these series on unrecognized CAS are relatively small, single-center, retrospective studies, larger prospective studies would be welcome to further the scientific grounds for promoting the routine use of IC NTG during coronary angiography.

The use of IC NTG has drawbacks and unknowns. Even local administration of NTG may have systemic effects, most notably hypotension. It is especially important to avoid nitrates in patients who have recently taken phosphodiesterase-5 inhibitors used for erectile dysfunction or pulmonary hypertension. Many patients undergoing cardiac catheterization for chest pain may be treated with nitrates and/or calcium channel blockers beforehand. The published studies do not address the potential effects of prior vasodilator therapy on the incidence of CAS in these patients. Another unknown is whether CAS is less likely to be diagnosed in patients undergoing cardiac catheterization via the radial artery. Since intravascular NTG and calcium channel blockers are typically given during radial artery catheterization, the systemic effects of these drugs could potentially treat any ongoing CAS (which would then be no longer apparent on subsequent coronary angiography).

In patients with CAS who do not have obstructive atherosclerotic disease, long-term prognosis with medical therapy alone is favorable [11]. While coronary stenting for refractory CAS has been reported in isolated cases, PCI is not generally recommended in the absence of severe atherosclerotic disease. In such patients, PCI does not eliminate the need for continued calcium channel blocker therapy since spasm may occur outside of the stented area [12]. Furthermore, spasm in one segment of the coronary vasculature increases the risk of spasm occurring in a different segment. In one prospective study of 45 patients who underwent repeat provocative testing with IC acetylcholine following the initial diagnosis of spasm, 77% demonstrated inducible spasm either at a different site within the same vessel or in an altogether different coronary artery [12].

In conclusion, in patients with apparent significant angiographic lesions, it is imperative to rule out coronary spasm before embarking on revascularization procedures. Simple administration of IC NTG can unmask the presence of CAS in patients presenting with chest pain and angiographically significant lesions. This serves to avoid unnecessary stenting by preventing misdiagnosis of CAS as fixed atherosclerotic disease. Current PCI guidelines emphasize the importance of periprocedural antiplatelet and anticoagulant agents, but they fail to mention any role for IC NTG during diagnostic cardiac catheterization or before PCI. Perhaps, we need to relearn the lessons taught in older textbooks [13] since the routine use of IC NTG is apparently overlooked all too often in clinical practice and in practice guidelines. It is time to reassert the fundamental role of IC NTG so that it is no longer the ‘forgotten stepchild of cardiovascular guidelines’ [8]. IC NTG should be an integral part of coronary angiography and intervention. The gauntlet has been thrown down. Should IC NTG be included in future revisions of PCI guidelines?

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.