Can chest pain relief by nitroglycerin predict active CAD?

hest pain is one of the most common symptoms encountered in the emergency department.1 Although the characteristics of the pain, coronary artery disease (CAD) risk factors, and blood markers are all helpful in the evaluation of chest pain, a small number of patients with acute myocardial infarction (MI) are missed in the emergency department, and a large number of patients with low-risk chest pain are admitted for further evaluation, at considerable expense and inconvenience.2

Relief of chest pain with nitroglycerin is often taken as a sign that the pain is cardiac in origin.3,4 Nitroglycerin has myriad effects, however, including relief of esophageal spasm,5 and thus the response to nitroglycerin may not have the diagnostic value that some attribute to it.

Patients and methods

We studied 459 patients who presented to the emergency department and were admitted with an initial diagnosis of “rule out MI,” “chest pain,” or the equivalent. They all had active chest pain in the ambulance or in the emergency department and had been given nitroglycerin. The pain level was recorded on a scale of 1 to 10 before and after administration of nitroglycerin. We then followed the patients through their hospitalization and contacted them by telephone at 4 months.

We defined pain relief as a 50% or greater decrease in self-reported pain intensity following a single 0.4-mg dose of spray or sublingual nitroglycerin. The primary outcome was the presence of active CAD, which was defined as an increased serum troponin T level; 70% or greater stenosis on coronary angiogram; positive results on a stress test, with or without imaging; or typical symptoms in the setting of known severe disease in the absence of further testing.

Results

Of the 459 patients enrolled in the study, 181 (39%) had chest pain relief with nitroglycerin, and 278 (61%) did not. There were no significant differences in baseline characteristics between the two groups. Other medications given concurrently with the nitroglycerin were similar between the two groups. Additionally, it was shown that, in 141 patients (31%), the chest pain was caused by active CAD; however, 275 patients (60%) were shown not to have active CAD. For 43 patients (9%), we were not able to identify a definitive cause of the chest pain.

Of the 141 patients whose chest pain was caused by active CAD, nitroglycerin provided relief in 49 (35%). For the 275 subjects whose chest pain was not due to active CAD, however, nitroglycerin provided chest pain relief in 113 patients (41%). These findings show that there was no diagnostic value to chest pain relief with nitroglycerin in the overall population. The Figure shows the sensitivity and specificity of chest pain relief by nitroglycerin (A; leftmost bars), along with the positive and negative likelihood ratios that chest pain would be relieved by nitroglycerin (B; leftmost bars). The likelihood ratios cross 1.0, which means that chest pain relief with nitroglycerin is not useful in differentiating active CAD from other diagnoses.

We also examined the diagnostic value of chest pain relief in subgroups. As can be seen in the Figure, for patients who were shown not to have MI during the index admission (troponin negative), who had a history of CAD, and who did not have a history of CAD, the sensitivity and specificity of chest pain relief with nitroglycerin for active CAD were poor, and the likelihood ratios all crossed 1.0. This indicates that, even when the analysis was limited to these specific subgroups, chest pain relief by nitroglycerin was not use-ful in distinguishing active CAD from other sources of acute chest pain.

We also examined other definitions of pain relief. By varying either the percentage of pain change or an absolute reduction in pain level to define “pain relief,” we showed that no matter what definition was used, the likelihood ratios at each cutoff point were close to 1.0. This indicates that no matter what definition of pain relief was used, chest pain relief by nitroglycerin did not aid in the diagnosis of CAD.

Although the diagnosis of chest pain was the primary outcome in this study, we also examined outcomes at 4 months to determine if chest pain relief by nitroglycerin held any prognostic value. As can be seen in the Table, there were no significant differences in the rates of death, MI, or revascularization between the patients who did and did not have pain relief (50% or greater reduction in self-reported pain) with nitroglycerin.

Discussion

The results of this study clearly show that chest pain relief with nitroglycerin does not aid in diagnosis and prognosis and should not be used in the triage of patients with chest pain who present to the emergency department. Our findings also held true when the analysis was limited to patients who did not have MI, had a known history of CAD, or had no known history of CAD.

Pain relief also held no prognostic value in terms of 4-month outcomes. Even when the definition of pain relief was varied according to percentage of pain reduction or an absolute number of units of pain reduction, there was no diagnostic or prognostic value.

Given that pain relief with nitroglycerin has been used as a criterion for CAD, how can our findings be explained? Nitroglycerin has many effects on the body, causing vasodilation of all vascular beds.6 It is a first-line treatment for esophageal spasm, which is high on the list of differential diagnoses for chest pain in patients in the emergency department.5 Additionally, there is probably a substantial placebo effect to nitroglycerin in the emergency department, as this is usually the first intervention given to patients with chest pain. Whether or not the pain is cardiac in origin, patients may report a decrease in pain intensity simply as an effect of the attention and any intervention.

There are several limitations to our study. One is that we examined the effect of the first dose of nitroglycerin only. We chose this approach because the first nitroglycerin dose is usually given before other medications and interventions, such as oxygen, aspirin, and beta blocking agents. In many patients, the first nitroglycerin dose is insufficient to cause relief of pain, no matter what the cause, but by the second or third dose, the pain has been relieved. However, by this point, several other medications have typically been given, and distinguishing the effect of the nitroglycerin from the other interventions is difficult.

Although our study was done in a prospective manner, it was observational. Additional cardiac testing, which formed the basis for deciding whether a patient had active CAD, was pursued at the option of the physicians caring for the patients after discharge and thus was not standardized. The pain was also based on the patient’s self-report using the simple 0- to 10-point scale. Although self-reported pain is not an ideal system,7 it does reflect clinical practice, and it was recorded in real time while the patients were having the pain; therefore, we believe that it accurately reflected the intensity of the pain.

The study was conducted solely with patients who presented to the emergency department with chest pain. Although our results strongly support the conclusion that chest pain relief with nitroglycerin holds little diagnostic or prognostic value in the emergency department setting, they do not address chest pain relief from nitroglycerin in other settings. We suspect that there is substantial overlap between patients with chest pain presenting to the emergency department and those presenting to physicians’ offices and that chest pain relief with nitroglycerin is most likely not useful in this setting, either.

Conclusion

In the emergency department setting, chest pain relief from nitroglycerin does not predict active CAD and does not predict outcomes at 4 months. Response of chest pain to nitroglycerin should not be used to guide triage in the emergency department and does not yield any information about the underlying disease process.