Nitrates in the management of acute coronary syndrome

INTRODUCTION — Sublingual, intravenous, and oral nitrate preparations are used in the management of acute coronary syndromes. Most of the published data come from patients with myocardial infarction (MI), but the conclusions would apply to patients with unstable angina.

The role of nitrates in the management of acute coronary syndrome, which includes ST-elevation and non-ST elevation MI, as well as unstable angina, will be reviewed here. The role of nitrate therapy in patients in the emergency department suspected of having chest pain due to myocardial ischemia and the overall management of the patient with an MI are discussed separately. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department", section on 'Immediate emergency department interventions' and "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

MECHANISMS OF ACTION — Potential mechanisms by which nitrates can relieve ischemic pain include:

●Dilatation of large coronary arteries and arterioles (>100 millimicrons [nanometers] in diameter), which may lead to increased perfusion of ischemic zones.

●Dilatation of the venous system with decreased preload, reduction in ventricular volume, and a fall in pulmonary capillary wedge pressure. This effect is useful in patients with pulmonary congestion.

●Systemic arterial dilatation, which decreases afterload, also occurs but to a lesser degree. These changes lower wall stress and oxygen consumption and can reverse a restrictive filling pattern [1].

●Termination of an episode of variant angina. (See "Vasospastic angina".)

●Enhanced collateral blood flow.

Nitrates produce these effects by entering vascular smooth muscle cells and combining with sulfhydryl groups to form nitric oxide and eventually S-nitrosothiols (figure 1). The nitroso-thiols stimulate guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), which causes smooth muscle relaxation by decreasing intracellular calcium levels. (See "Nitrates in the management of chronic coronary syndrome", section on 'Mechanism of action'.)

SIDE EFFECTS AND CAUTION — The primary adverse effects induced by nitrate therapy include hypotension (especially in patients with ventricular ischemia or hypovolemia), headache, and tachycardia. Hypovolemia or nitrate-induced hypotension respond promptly to volume replacement. Despite presumed correction of preload by the infusion of saline, the antiischemic effect of nitroglycerin persists.

Prolonged infusion of high dose nitroglycerin may lead to the development both of methemoglobinemia (which can be treated with intravenous methylene blue) and of heparin resistance. In addition, commercial preparations of intravenous nitroglycerin contain alcohol (0.01 to 0.14 mL/mg of nitroglycerin). Thus, a substantial alcohol load may be delivered to the patient. (See "Methemoglobinemia".)

Nitrates in all forms should be avoided in patients with one or more of the following [2]:

●Systolic blood pressure less than 90 mmHg or ≥30 mmHg below baseline. Nitrates may induce symptomatic hypotension and can lead to hemodynamic decompensation in the setting of cardiac ischemia.

●Marked bradycardia (heart rate less than 50 beats per minute) or tachycardia (heart rate greater than 100 beats per minute). In this setting nitrates may cause hemodynamic decompensation.

●Known or suspected right ventricular infarction. Nitrates should be avoided because of the increased risk of inducing hypotension. (See "Right ventricular myocardial infarction".)

●Patients who have taken a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours (or perhaps as long as 48 hours with tadalafil). Nitrates may induce severe hypotension. (See "Sexual activity in patients with cardiovascular disease".)

●Hypertrophic cardiomyopathy. Nitrates can induce or increase outflow tract obstruction, even in those not known to have a resting gradient. (See "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction" and "Hypertrophic cardiomyopathy: Management of patients without outflow tract obstruction", section on 'Chest discomfort'.)

●Severe aortic stenosis. A sudden decrease in blood pressure can lead to cardiovascular collapse.

In view of their lack of survival benefits, nitrates should not be used in preference to beta blockers for the management of chronic, refractory chest pain [2]. In addition, the chronic administration of nitroglycerin should not preclude therapy with beta blockers and angiotensin converting enzyme inhibitors. The latter drugs improve survival, a benefit not seen with nitroglycerin. (See 'GISSI-3 trial' below.)

SUBLINGUAL NITROGLYCERIN — Sublingual nitroglycerin is the therapy of choice for acute anginal episodes and for prophylaxis of activities known to elicit angina. It is administered to the patient with acute MI to improve symptoms, lower blood pressure, improve pulmonary congestion, and, in some cases, to help in the diagnosis of coronary artery spasm. (See "Vasospastic angina", section on 'Initial therapy'.)

For the patient presenting to the emergency department with chest pain that may be due to cardiac ischemia, sublingual nitroglycerin is commonly administered at a dose of 0.4 mg every five minutes for a total of three doses. Up to 0.6 mg as a single dose may be given to patients with refractory angina, particularly those with hypertension. After the administration of sublingual nitroglycerin, assessment should be made about the need for intravenous nitroglycerin.

INTRAVENOUS NITROGLYCERIN — Intravenous nitroglycerin is typically initiated in patients with persistent ischemic chest pain despite three sublingual nitroglycerin tablets and other adjunctive therapies.

Dosing — An intravenous infusion permits titration of therapy according to the blood pressure response.

●The goal of intravenous nitroglycerin therapy is relief of symptoms or a mean arterial blood pressure 10 percent below baseline in normotensive patients and up to 25 to 30 percent in hypertensive patients. The blood pressure lowering should be gradual with careful attention to signs or symptoms of hypoperfusion. The systolic pressure should not fall below 90 mmHg or by more than 30 mmHg.

●The initial infusion rate is 5 to 10 mcg/min.

●If the above goals are not met, the infusion rate is gradually increased at approximately 10-minute intervals by 5 to as much as 20 mcg/min.

●In general, the dose should not exceed 400 mcg/min.

The infusion is indicated for the first 48 hours for persistent ischemia, heart failure, or hypertension. Intravenous, oral, or topical nitrates can be given after 48 hours for recurrent or persistent indications. At any time, the administration of nitroglycerin should not preclude therapy with beta blockers and angiotensin converting enzyme inhibitors.

Efficacy — Despite extensive clinical use, there is remarkably little objective information documenting the effectiveness of intravenous nitroglycerin in unstable angina. Several small trials have evaluated the ability of an open-label infusion of nitroglycerin to reduce the frequency of ischemic chest pain; symptomatic relief was noted in each of the reports [3,4]. One randomized trial of 167 patients found that, compared to placebo, intravenous nitroglycerin reduced the frequency and duration of ischemic episodes [5]. In addition, a single randomized trial compared the intravenous, oral, and transdermal nitroglycerin preparations [6]. There was no difference in response among the preparations with regard to symptomatic improvement. However, the small size of this study (40 patients) makes it difficult to draw definitive conclusions.

GISSI-3 trial — In the third Gruppo Italiano per lo Studio dell Sopravvivenza nell'Infarto Miocardico (GISSI-3), 19,394 patients with acute MI between 1991 and 1993 were randomly assigned in a two-by-two factorial design to intravenous nitroglycerin followed by a nitrate patch or placebo, as well as to lisinopril or placebo [7]. Intravenous nitroglycerin was infused within the first 24 hours, starting at 5 mcg/min and increasing until the systolic blood pressure fell by 10 percent, avoiding systolic pressure below 90 mmHg. Nitrate patch and lisinopril were maintained for six weeks and the patients were followed for six months from the date of randomization.

The results were analyzed by intention to treat; however, 57 percent of the placebo group received short-term nitrate therapy for angina or heart failure and approximately 11 percent received long-term nitrate therapy. Most of the patients were treated with other appropriate therapies for MI at the time of the trial such as thrombolysis (72 percent), aspirin (84 percent), and beta blockers (31 percent).

The primary study end point of mortality at six weeks demonstrated no significant benefit of nitrate therapy. However, the subset of patients receiving lisinopril and nitrates had the lowest mortality in the trial (odds ratio 0.83 versus 0.88 for lisinopril alone), suggesting a possible additive beneficial effect of nitroglycerin to lisinopril. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".)

The nitrate patch was discontinued at six weeks. Six month follow-up continued to show no difference in mortality (18.4 versus 18.9 percent) or left ventricular dysfunction in the patients who received nitrate therapy [8].

Nitrate tolerance — The major concern with a continuous infusion of nitroglycerin is the development of nitrate tolerance that occurs in most patients within 24 hours. In GISSI-3, for example, the blood pressure lowering effect of intravenous nitroglycerin was lost within 24 hours [7]. However, prolonged nitroglycerin infusions are not generally needed in acute coronary syndromes, since patients with ST elevation are either rapidly given fibrinolytic therapy or taken directly to the catheterization laboratory, while many patients with non-ST elevation acute coronary syndromes go to the catheterization laboratory within the first 48 hours. (See "Nitrates in the management of chronic coronary syndrome", section on 'Nitrate tolerance'.)

ORAL AND TRANSDERMAL NITRATES — Oral and transdermal nitrates have a limited role in an acute coronary syndrome. Outpatient oral nitrates may be appropriate in the minority of patients who do not attain complete relief of angina after revascularization. (See "Nitrates in the management of chronic coronary syndrome", section on 'Commonly used nitrate preparations'.)

As with intravenous nitroglycerin, there is no evidence that oral nitrate therapy after acute coronary syndrome reduces mortality. This issue was evaluated in the ISIS-4 trial [9]. Longer-term nitrate therapy may help to prevent left ventricular remodeling, but angiotensin converting enzyme (ACE) inhibitors are likely to be more effective for this purpose.

Dosing — Nitrates used for this purpose include isosorbide dinitrate (starting at 10 mg three times daily and increasing to 40 mg three times daily as necessary, given at 8 AM, 1 PM, and 6 PM), isosorbide mononitrate (starting at 30 mg/day in the morning and increasing to 120 mg/day as necessary), or a transdermal Nitroglycerin patch (starting at 0.2 mg/hr and increasing to 0.6 mg/hr with removal of the patch at 6 to 8 PM). These regimens provide an adequate nitrate-free interval to prevent complete nitrate tolerance. (See "Nitrates in the management of chronic coronary syndrome", section on 'Nitrate tolerance'.)

Long-term therapy — Long-term nitrate therapy is associated with a modest hemodynamic benefit in patients with a low left ventricular ejection fraction [10]. However, in the era of ACE inhibitors and angiotensin II receptor blockers, nitrate therapy for this purpose would be considered only in patients unable to take an angiotensin inhibitor. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials" and "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST-elevation myocardial infarction (STEMI)".)

SUMMARY AND RECOMMENDATIONS

●Nitrate therapy has an important role in the management of patients with an acute coronary syndrome, despite the absence of a mortality benefit. It can be of value in reducing or potentially eliminating pain (either initial or recurrent) due to myocardial ischemia, improving symptoms of pulmonary congestion, lowering blood pressure in hypertensive patients, and aiding in the diagnosis and management of the rare patient who presents with variant angina (coronary artery spasm).

●Nitrates are part of combined modality therapy for symptoms or signs of myocardial ischemia, heart failure, and hypertension in the patient with an acute coronary syndrome. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the acute management of ST-elevation myocardial infarction".)

●There are several important adverse effects of nitrate therapy. Avoid nitrates in patients with systolic blood pressure <90 mmHg or ≥30 mmHg below baseline, marked bradycardia or tachycardia, known or suspected right ventricular infarction, phosphodiesterase inhibitor use within the last 24 to 48 hours, hypertrophic cardiomyopathy, or severe aortic stenosis. (See 'Side effects and caution' above.)

•The development of hypotension in patients with volume depletion, right ventricular infarction, or recent use of a phosphodiesterase inhibitor for erectile dysfunction (eg, sildenafil).

•The prevention of optimal dosing of beta blockers or morphine sulfate due to its blood pressure lowering effect.