Unanswered Questions for Management of Acute Coronary Syndrome: Risk Stratification of Patients With Minimal Disease or Normal Findings on Coronary Angiography

Background  The prognostic implication of chest pain associated with normal or near-normal findings on angiography is still unknown. We explored outcomes and methods of risk stratification in patients with nonobstructive coronary artery disease in the setting of non–ST-segment elevation acute coronary syndromes.

Methods  Data were pooled from 3 Thrombolysis in Myocardial Infarction (TIMI) trials (TIMI 11B, TIMI 16, and TIMI 22). Angiographic data were available on 7656 patients with non–ST-segment elevation acute coronary syndromes. The primary end point of this analysis was the composite of the rates of death, myocardial infarction, unstable angina requiring rehospitalization, revascularization, and stroke at 1-year follow-up. Outcomes were evaluated by mean of the TIMI risk score for developing at least 1 component of the primary end point.

Results  Angiographic findings showed that 710 (9.1%) of 7656 patients had nonobstructive coronary artery disease; 48.7% of these had normal coronary arteries (0% stenosis), and 51.3% had mild coronary artery disease (>0% to <50% stenosis). A primary end-point event occurred in 101 patients (12.1%). It is noteworthy that a 2% event rate of deaths and myocardial infarctions had occurred in these patients at the 1-year follow-up. Event rates of death and myocardial infarction increased significantly as the TIMI risk score increased from 0.6% for a score of 1 to 4.0% for a score greater than 4.

Conclusions  Patients with non–ST-segment elevation acute coronary syndromes with nonobstructive coronary artery disease detected by angiography have a substantial risk of subsequent coronary events within 1 year. The risk is not univariately high, and the TIMI risk score helps to reveal patients at high risk.

In clinical practice, chest pain in the presence of non-obstructive coronary artery disease (CAD) remains an unsolved problem.^1,2 Thousands of patients are told that they have no significant heart disease following demonstration of normal or near-normal arteries on coronary angiography and often are offered no treatment beyond reassurance.^3-6 Physicians agonize endlessly over the discrepancy between observed and expected angiographic findings in the subset of patients at greater risk, namely, those presenting with acute coronary syndromes (ACS). Their consternation is largely justified; ACS may result from disruption of modestly stenotic vulnerable plaques, is often not detectable by angiography, and may lead to thrombotic complication.^7,8 However, available outcome data are limited to a few cohort studies that used special tests are not routinely employed, (ie, intravascular ultrasonography⁹ and intracoronary acetylcholine testing).^10-13

The aims of this study were (1) to evaluate outcomes at the 1-year follow-up of patients without critical coronary stenosis as assessed by routine angiography in a large cohort of patients with non–ST-segment elevation (NSTE)–ACS drawn from international multicenter trials and (2) to evaluate the relative importance of simple clinical and biochemical variables in the risk stratification of these patients.

Because no published clinical trials on ACS provided outcome data sorted by angiographic groups (those with obstructive CAD vs those with nonobstructive CAD), we contacted 4 authors regarding 7 studies^14-20 and received data from 3 studies: the Thrombolysis in Myocardial Infarction (TIMI) 11B, Orbofiban in Patients with Unstable coronary Syndromes (OPUS)-TIMI 16, and PRavastatin Or atorVastatin Evaluation and Infection Therapy (PROVE IT)-TIMI 22 trials.^15,16,20

The study design and the main results of the TIMI 11B, OPUS–TIMI 16, and PROVE IT–TIMI 22 trials have been previously reported.^15,16,20 These trials have similar inclusion criteria. In brief, the TIMI 11B trial enrolled 3910 patients (from 1996 to 1998) to determine whether treatment with enoxaparin sodium was superior to treatment with unfractionated heparin. All patients were required to have had ischemic discomfort of at least 5 minutes’ duration at rest within 24 hours before randomization. The OPUS–TIMI 16 trial enrolled 10 302 patients (from 1997 to 1998) to study an oral glycoprotein IIb/IIIa inhibitor in the long-term treatment outcome of ACS. Inclusion criteria were ischemic discomfort at rest lasting 5 minutes, with onset within 72 hours of randomization. The PROVE IT–TIMI 22 trial enrolled 4162 patients (from 2000 to 2001) to establish the effect of intensive therapy vs standard statin therapy. To be included in the study, a patient had to have been hospitalized for acute myocardial infarction or ischemic discomfort lasting at least 15 minutes within the preceding 10 days. Clinical data were pooled from the 3 trials for all patients with NSTE-ACS for whom angiographic data were available. Patients with prior percutaneous coronary intervention or those who had had bypass surgery were excluded. We performed an exploratory analysis on outcomes at the 1-year follow-up. Angiographic assessments were performed at the local level.

The primary end point of this analysis was the composite of the rates of death, myocardial infarction, stroke, revascularization, and unstable angina requiring rehospitalization. End points were mutually exclusive and hierarchical as listed in the previous paragraph. By hierarchical, we mean that death, whenever it occurred in the study time frame, displaced any earlier nonfatal events.

The TIMI risk score for patients with NSTE-ACS is a risk assessment tool comprised of 7 independent clinical risk indicators that are evaluated at presentation.²¹ The 7 predictor variables are age older than 65 years, 3 cardiovascular risk factors (family history of coronary disease, diabetes mellitus, hypertension, hypercholesterolemia, or current smoking), previous CAD (>50% stenosis at angiography), severe anginal symptoms (2 episodes in preceding 24 hours), use of aspirin in the last 7 days, ST-segment deviation greater than 0.05 mV, and elevated concentrations of serum cardiac markers of necrosis. For each patient, the score is calculated as the simple sum of the number of risk indicators that are present (range, 0-7). Cutoff points for positive biomarkers were 0.01 ng/mL for cardiac troponin T and 0.1 ng/mL for troponin I.¹⁹

In our study, the highest TIMI risk score was only 6, because 1 component (stenosis >50% at angiography) was 0 by definition in patients without obstructive lesions.

Patients with nonobstructive CAD were grouped as those with normal findings on angiography (0% lumen stenosis in all vessels) and those with mild CAD (>0% but <50% lumen stenosis). We used adjusted baseline models to determine whether differences between groups were independent. Statistical testing was performed with the χ² test for categorical variables and the Wilcoxon rank sum test for continuous variables. Estimates of the hazard ratios and associated 95% confidence intervals were obtained with the use of the Cox proportional hazards model.

Data were analyzed by the TIMI Data Coordinating Center (Brigham and Women's Hospital and Harvard Medical School, Boston, Mass), which also handled our queries.

Angiographic data were available for 7656 patients with NSTE-ACS. A total of 6955 patients had obstructive CAD, and 701 (9.1%) had nonobstructive CAD (48.7% with normal coronary arteries and 51.3% with mild CAD).

The Kaplan-Meier estimates of 1-year event rates for patients with obstructive lesions were 3.9% for deaths, 6.9% for nonfatal myocardial infarction, 11.2% for either myocardial infarction or death, 12.8% for revascularization, 18.8% for unstable angina requiring rehospitalization, 1.1% for stroke, and 32.7% for composite cardiovascular events.

The Kaplan-Meier event rates for the primary end points are shown in Table 1. In the overall population with nonobstructive CAD, recurrent ischemia was the most frequent end point (10.1%). Death and myocardial infarction occurred in 2.1% of patients. In angiographic subgroups, the primary end points occurred in 15.1% of patients with mild CAD and in 9.4% of those with normal findings on angiography (P<.05). Patients with mild CAD were more likely to have undergone revascularization during 1-year follow-up (1.6% vs 0%, P = .02). Death, nonfatal myocardial infarction, and unstable angina requiring rehospitalization occurred less frequently in the group with normal findings on angiography than in the group with mild CAD, but the differences were not statistically significant. The Figure shows the primary end-point event rate in patients with normal findings on angiography and those with mild CAD at 7, 30, and 180 days and at the 1-year follow-up. The difference was significant (P<.05) only at the 1-year follow-up.

A primary end-point event at 1-year follow-up occurred in 75 patients. Patients with and without a primary end-point event matched well with regard to age, sex, risk factors, and treatment of the index event (Table 2). Presence of ST-segment deviation and biochemical markers was not significantly different. There was a higher incidence of unstable angina as the index event in patients with the primary end point (P<.05). Patients in whom the primary end point did not subsequently develop were more likely to have a TIMI risk score of 0 to 2 (P = .003).

The analysis excluded patients with missing values for assessing the TIMI risk score. Of the 710 patients with NSTE-ACS, 665 were eligible for TIMI risk score evaluation.

Most (65%) of the patients with nonobstructive CAD had a score ranging from 1 to 3. Because of the small number of patients with very high risk scores, those with a score of 4 or higher were combined. Event rates (Table 3) of patients with nonobstructive CAD increased significantly as the TIMI risk score increased from 4.9% for a score of 0 to 14.7% for a score of 4 or higher than 4 (P<.01). Rates for death and myocardial infarction ranged from 0.6% for a score of 1 to 4.1% for a score of 4 or higher than 4 (P<.05).

The assumption that nonobstructive CAD carries a good prognosis is not based on hard data, and, to our knowledge, this is the first examination of it in a large study.^3-6 The study described herein demonstrates that the assumption turns out to be incorrect, at least in those patients presenting with an ACS.

We performed a post hoc analysis of 3 published randomized clinical trials (TIMI 11B, OPUS–TIMI 16, and PROVE IT–TIMI 22), involving 7656 patients with NSTE-ACS for whom angiographic data were available.

The prevalence of nonobstructive CAD in this population with ACS was 9.1%. Slightly more than half of the 701 affected patients had mild CAD (defined as those with less than 50% stenosis, whereas the remainder had normal, smooth coronary arteries found on angiography. The primary outcome measure was the combined 1-year rates of death, myocardial infarction, unstable angina requiring rehospitalization, revascularization, and stroke. The incidence rate of events was 9.4% in patients with ACS and with normal arteries found on angiography and 15.5% in those with less than 50% stenosis. Even more disturbing, however, were the rates of the most serious outcomes, death and myocardial infarction. The overall incidence was 2.1% at 1 year, with a 1.2% rate among patients with normal coronary arteries found on angiography and 3.3% in those with mild CAD. These findings are not in agreement with the notion that chest pain with normal or near-normal findings on coronary angiography implies benign prognosis, at least in those patients presenting with ACS.

Because the event rate of patients with nonobstructive CAD was very high, physicians should classify virtually every patient admitted with a clinical diagnosis of ACS to a disease category, even if the angiographic evaluation is absolutely negative. We fear that the potential perplexity that this message might cause among primary care physicians is considerable and deserves some considerations.

First, this study is a retrospective analysis of patients with ACS rather than stable CAD and thus is not comparable with similar series reported in previous articles on chest pain with normal or near-normal findings on angiography.^3-6 An acute coronary event marks a patient for a long-term high risk of recurrence, independent of what the coronary anatomy ultimately looks like.²² Second, in ACS the event rate of patients without obstructive CAD is high, but these patients have a relatively lower incidence of events compared with patients whose diagnosis fits the definition of obstructive CAD in the same clinical setting. Angiographic findings, therefore, remain one of the important determinants of prognosis. Third, our data do not suggest that all patients with a diagnosis of nonobstructive CAD are at high risk of subsequent cardiac ischemic events. Conversely, it reinforces the idea that patients with nonobstructive CAD are a rather heterogeneous population. Patients with NSTE-ACS and nonobstructive CAD may have a wide spectrum of risk for cardiac ischemic events, and they would benefit from methods of risk stratification.

To date, attempts to risk stratify such patients have mainly focused on special investigations not routinely used, such as intravascular ultrasonography⁹ or endothelial function testing.^10-13 Available outcome data with these relatively new techniques are limited to a few cohort studies and need further evaluation.

In the study described herein, ACS patients with nonobstructive CAD with and without a primary study end point were evenly matched in terms of baseline demographic characteristics as well as treatment. There was a higher incidence of unstable angina as the index event and a higher prevalence of TIMI risk scores of 3 or higher in patients with the primary end point. The TIMI risk score was derived and validated in a selected randomized trial population of patients with unstable angina and myocardial infarction without ST-segment elevation.²¹ When we applied the TIMI risk score to the 665 eligible patients, the associated 1-year risk rate of death or nonfatal myocardial infarction climbed from 0.6% (in those with a TIMI score of 1) to 4.1% (in those with a score of 4 or higher). The 0.6% rate in death or myocardial infarction seen in patients with a TIMI score of 1 is the expected rate in the general population of low-risk asymptomatic subjects.²³ An event rate of 2.8% (TIMI score of 3) to 4.1% (TIMI score of 4) for death and myocardial infarction at 1-year follow-up is unacceptably high for this supposedly low-risk population.

Although elevated concentrations of serum cardiac markers and the presence of electrocardiographic changes are considered to be excellent risk stratification tools in the appropriate clinical setting, little is known about their prognostic value for patients without obstructive CAD. Previous studies on this issue were small (fewer than 110 patients) and had low statistical power (fewer than 5 end points).^24,25

In our study, a large percentage (40% [278 of 701]) of patients showed elevated cardiac biomarkers. As well, many patients (412 [59%] of 701) showed electrocardiographic changes. Comparing patients who did have vs those who did not have subsequent coronary events, the former were more likely to have electrocardiographic changes (68.8 vs 57.8%) but not to have more elevated serum cardiac markers.

The present analysis, therefore, highlights the principle that no single variable can accurately predict the risk for nonobstructive CAD in patients with NSTE-ACS. In this subset of patients, biochemical markers of myocardial injury, such as troponin T, and troponin I, are valuable only in combination with electrocardiographic findings and clinical features. Accordingly, the TIMI risk score has a greater statistical power in discriminating patients who are having vs those who are not having subsequent coronary events.

Although we have described angiographically occult CAD as a potential mechanism for coronary events in patients with ACS and normal or near-normal findings on cardiac angiography, consideration also should be given to other causes such as angiograms that are inadequate or misinterpreted by visual analysis, myocardial infarction caused by coronary spasm,²⁶ microembolization,²⁷ and a misdiagnosis of ACS in patients with a variety of different clinical entities, such as myocarditis²⁸ and Takatsubo cardiopathy,²⁹ among others. Obviously, the same diagnostic uncertainties may affect those patients diagnosed as having obstructive CAD and the overall populations of the ACS trials. We do not have data to quantify the relative contribution of these factors. However, queries about the use of angiography by visual estimation seem to be clinically irrelevant. No matter how precisely measured, the angiogram of a complex lesion poorly represents the real lumen size.³⁰ Accordingly, interpretation of angiography by visual analysis is still considered by most catheter laboratories to be the gold standard for defining coronary anatomy and represents, therefore, the real clinical world.

Some limitations must be noted. First, clinical trials usually select high-risk patients. The 3 TIMI trials enrolled a population of patients presenting with classic, typical, ischemic discomfort at rest. Patients are more likely to experience subsequent coronary events if they present typically.³¹ Therefore it could be asked whether the rate of events would be the same in an unselected population of patients who are representative of general clinical practice. Most patients in the general population are different. Admissions are often related to atypical symptoms of chest pain and continued seeking of medical care. Second, the decision to perform coronary angiography was performed at the local level. It is not known whether there was any bias in the referral pattern.

In conclusion, patients presenting with typical symptoms of ACS but without critical obstruction on visual angiography have a prognosis that is not as benign as previously thought. Although the mean risk was high even for death and myocardial infarction (2.1% after 1 year), most events were driven by repeated admission for unstable angina (10.1%). The risk is not univariately high, and thus the TIMI risk score helps to predict the likelihood of patients to develop coronary events.

Correspondence: Raffaele Bugiardini, MD, Dipartimento di Medicina Interna, Cardioangiologia, Epatologia (Padiglione 11), University Alma Mater of Bologna, Via Massarenti 9, 40138 Bologna, Italy (raffaele.bugiardini@unibo.it).

Accepted for Publication: April 16, 2006.

Financial Disclosure: None reported.