ORIGINAL ARTICLES

GLYCERYL TRINITRATE IN ANGINA PECTORIS

We sought to determine if the duration of pain or other features of the history predict major adverse cardiac events (MACE) in patients with chest pain in the emergency department (ED).

This was a prospective cohort study of patients presenting to a single ED with chest pain. Consenting patients filled out a survey about their symptoms. After 6 weeks, we assessed patients for MACE via chart review and direct contact. We used this data to calculate the likelihood ratios (LRs) of a number of historical features for acute myocardial infarction (MI) (primary endpoint) and MACE within 6 weeks (secondary endpoint). We planned a priori to analyze patients who reported chest pain for ≤1 min or continuously for ≥24 h.

We enrolled 1002 patients, and 83.6% had successful 6-week follow up. Regarding chest pain lasting for ≤1 min, the positive LR was 0.95 (95% CI 0.24 to 3.80) for acute MI and 0.67 (95% CI 0.17 to 2.72) for MACE within 6 weeks. The positive LRs of continuous pain lasting ≥24 h for acute MI and MACE within 6 weeks were 0.15 (95% CI 0.04 to 0.58) and 0.36 (95% CI 0.18 to 0.74), respectively. Amongst other historical features assessed, radiation to the right arm was the strongest positive predictor of acute MI.

Patients with continuous chest pain for ≥24 h are unlikely to have an acute MI. Chest pain lasting ≤1 min does not exclude acute MI.

The use of nitroglycerin in the treatment of angina pectoris began not long after its original synthesis in 1847. Since then, the discovery of nitric oxide as a biological effector and better understanding of its roles in vasodilation, cell permeability, platelet function, inflammation, and other vascular processes have advanced our knowledge of the hemodynamic (mostly mediated through vasodilation of capacitance and conductance arteries) and nonhemodynamic effects of organic nitrate therapy, via both nitric oxide–dependent and –independent mechanisms. Nitrates are rapidly absorbed from mucous membranes, the gastrointestinal tract, and the skin; thus, nitroglycerin is available in a number of preparations for delivery via several routes: oral tablets, sublingual tablets, buccal tablets, sublingual spray, transdermal ointment, and transdermal patch, as well as intravenous formulations. Organic nitrates are commonly used in the treatment of cardiovascular disease, but clinical data limit their use mostly to the treatment of angina. They are also used in the treatment of subsets of patients with heart failure and pulmonary hypertension. One major limitation of the use of nitrates is the development of tolerance. Although several agents have been studied for use in the prevention of nitrate tolerance, none are currently recommended owing to a paucity of supportive clinical data. Only 1 method of preventing nitrate tolerance remains widely accepted: the use of a dosing strategy that provides an interval of no or low nitrate exposure during each 24-h period. Nitric oxide’s important role in several cardiovascular disease mechanisms continues to drive research toward finding novel ways to affect both endogenous and exogenous sources of this key molecular mediator.

The prophylactic and therapeutic anti-ischemic efficacy of isosorbide dinitrate (ISDN) oral spray was assessed in 10 patients with coronary artery disease and stable angina pectoris. The patients entered a randomized crossover study of ISDN spray and placebo, involving bicycle exercise testing. Each patient underwent 2 exercise tests at least 4 hours apart. Immediately before initiation of exercise they received either ISDN spray or placebo and crossed over during the other test. ISDN spray delayed the onset of anginal pain by about 40%, from a mean of 5.1 ± 1.4 minutes with placebo to 7.2 ± 1.3 minutes with the active drug (p < 0.001). Time of onset of ST-segment depression was also significantly prolonged, from 7.1 ± 1.5 minutes with placebo to 10.2 ± 1.2 minutes with ISDN (p < 0.001). The patients achieved a higher double product at onset of pain with ISDN than with placebo. The drug also reduced the time of disappearance of pain after discontinuation of exercise from 3.2 ± 0.7 to 2.1 ± 0.8 minutes (p < 0.001), and the time of disappearance of electrocardiographic changes from 4.2 ± 0.6 to 2.5 ± 0.8 minutes (p < 0.005). These findings indicate that oral ISDN spray is an effective prophylactic for exercise-induced angina. Its rapid onset of action makes it especially suitable for usage immediately before exercise.

The expanding applications of nitroglycerin and nitrate esters—in congestive heart failure, in the reduction of infarct size in myocardial infarction and in the long-term prophylaxis of angina—have enhanced the clinical importance of these drugs. This article reviews some of the significant recent investigations of the nitrates and makes specific recommendations regarding clinical use.

The effect of sublingual (0.2 mg.) nitroglycerin (TNG) was studied in anesthetized dogs before and after coronary occlusion. Coronary artery occlusion was accomplished by embolization of the circumflex branch of the left coronary artery. TNG was administered before embolization and again at one minute, one, two, and six hours after embolization. TNG treatment did not significantly increase the number of arrhythmias or deaths compared to untreated animals with coronary occlusion. Hemodynamic and blood biochemical parameters were measured 5 to 15 minutes after TNG treatment. At this time of measurement, blood pressures (AO, LV, LA, PA, RV, RA), cardiac output, pulmonary and systemic resistances, and left ventricle work were not significantly different in the TNG-treated group compared to the animals with coronary occlusion but no TNG treatment. In the first five minutes after TNG administration, aortic pressure is reduced. Blood samples withdrawn five minutes after TNG treatment are not significantly different from the untreated animals in Po₂, Pco₂, pH, glucose, lactate, pyruvate, free fatty acids, LDH, CPK, and SGOT. It is concluded that TNG is not detrimental to animals with acute coronary occlusion and that TNG has a transient, short-duration effect.