The clinical features and prognosis of patients with ST-segment elevation myocardial infarction (STEMI) and no significant coronary artery disease (CAD) have not been well studied. We examined the outcomes of patients with STEMI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial according to the presence or absence of significant CAD. “No-CAD” was defined by the absence of any lesion with a diameter stenosis of ≥30% on quantitative coronary angiography of the baseline coronary angiogram. Of 3,602 patients, 127 (3.5%) had no-CAD. Of these, 86 (67.7%) had angiographically normal coronary arteries, and 41 (32.3%) had mild disease (diameter stenosis <30%). Eight patients had previously been treated with coronary artery bypass grafting. Compared to patients with CAD, patients with no-CAD were younger, had a lower body mass index, were more frequently black, had a lower prevalence of smoking and previous angina, and had a greater left ventricular ejection fraction. Cardiac enzymes were elevated in fewer patients with no-CAD than in those with CAD (63.2% vs 98.7%, p <0.001). At 3 years of follow-up, the patients with no-CAD versus CAD had lower rates of major adverse cardiovascular events (7.7% vs 22.2%, p = 0.002), net adverse clinical events (major adverse cardiovascular events or major bleeding not related to coronary artery bypass grafting, 12.5% vs 26.9%, p = 0.005), and postprocedure coronary revascularization (0% vs 19.5%, p <0.001). The differences in the rates of death or reinfarction, stroke, and major bleeding were not statistically significant. In conclusion, 3.5% of patients with STEMI had no significant CAD. The 3-year prognosis for these patients was favorable compared to that of patients with STEMI and with obstructive CAD.
Previous studies have demonstrated that approximately 3% of patients with acute myocardial infarction have angiographically normal coronary arteries. Although the prognosis of these patients is thought to be good, this has been based on limited data from registries and retrospective studies. In the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, the proportion of patients admitted with acute coronary syndrome with mild or even no significant obstructive coronary artery disease (CAD) was 12%. In these patients, the prognosis was good, and additional treatment with the potentially bleeding-inducing drug eptifibatide did not give any statistically significant benefit. The importance of an accurate diagnosis is thus of vast importance because of the use of adjunctive drug therapy that can be associated with potential bleeding risk. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study, quantitative coronary angiography (QCA) was performed at an independent angiographic core laboratory on the baseline films from all patients. Using that trial database, we, therefore, sought to (1) determine the proportion of patients presenting with ST-segment elevation myocardial infarction (STEMI) who had no significant CAD; (2) characterize these patients compared to patients with significant CAD; and (3) compare the late outcomes in patients with versus without significant CAD.
Methods
The HORIZONS-AMI study was a prospective, open-label, multicenter, randomized, controlled trial of patients with STEMI undergoing primary percutaneous coronary intervention (PCI). The study incorporated 2 × 2 factorial randomization to the direct thrombin inhibitor bivalirudin alone versus heparin plus a glycoprotein IIb/IIIa inhibitor and paclitaxel-eluting stents versus bare metal stents in an eligible subset of patients. The trial was sponsored and managed by the Cardiovascular Research Foundation, a nonprofit organization, with grant support from Boston Scientific (Natick, Massachusetts) and The Medicines Company (Parsippany, New Jersey). The institutional review board or ethics committee at each participating center approved the study, and all patients gave written informed consent (Clinical Trial Registration no. NCT00433966 ; http://www.clinicaltrials.gov ).
The HORIZONS-AMI trial design has been previously described. In brief, 3,602 consecutive patients aged ≥18 years who presented within 12 hours of symptom onset with ST-segment elevation of ≥1 mm in ≥2 contiguous leads, new left bundle branch block, or true posterior myocardial infarction on the electrocardiogram were considered for enrollment.
Eligible patients were randomly assigned in the emergency department, or before, to treatment with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor or bivalirudin alone in a 1:1 ratio. Subsequently, among patients undergoing PCI, the patients were randomized to TAXUS Express (Boston Scientific) paclitaxel-eluting stents or Express (Boston Scientific) bare metal stents in a 3:1 ratio. Creatine phosphokinase with MB bands were assessed at baseline and at 8, 16, and 24 hours after the index procedure. Clinical follow-up was performed at 30 days, 6 months, and 1, 2, and 3 years in all patients, except for those who had neither significant CAD by QCA nor increased cardiac enzymes, in which case the 30-day follow-up examination only was performed.
All baseline angiograms were analyzed by an angiographic core laboratory that was unaware of the randomization assignment and clinical outcomes. QCA was performed using standardized techniques, as previously described. QCA was performed for every lesion in the coronary tree with a reference vessel diameter ≥1.5 mm. For the present analysis, we defined significant CAD as any lesion with a diameter stenosis of ≥30% by QCA. Thus, patients without significant CAD (i.e., normal coronary arteries or only mildly diseased coronary arteries when assessed with angiography), henceforth referred to as “no-CAD,” had no lesion with a diameter stenosis of ≥30%. For patients with previous coronary artery bypass grafting (CABG), we defined significant CAD as any lesion with a diameter stenosis of ≥30% in any grafts or native vessels distal to anastomosis by QCA.
For the present analysis, we sought to compare the early (30-day) and late (3-year) rates of death, reinfarction, major bleeding not related to CABG, and revascularization of any vessel for ischemia subsequent to the index procedure in patients with CAD versus no-CAD. The definitions of the adverse events have been previously described. All events were adjudicated by an independent clinical events committee that was unaware of the treatment assignment.
Categorical variables were compared using the chi-square test or Fisher’s exact test. Continuous variables are expressed as the median and interquartile ranges and were compared using the Wilcoxon rank sum test. Kaplan-Meier methods were used to derive the event rates at follow-up and to plot the time-to-event curves. Comparisons were made using the log-rank test. All statistical tests were 2-tailed. Statistical significance was set at p = 0.05.
Results
Of the 3,602 patients enrolled in the HORIZONS-AMI trial, 127 (3.5%) had no-CAD. Of these, 16 patients had undergone previous PCI and 8 patients had undergone previous CABG (all grafts were patent without significant disease). A statistically significant difference was found between the groups regarding nonprotocol preprocedural heparin use with less use in the no-CAD group (55.1% vs 64.9, p = 0.02); however, no difference was found regarding either oral or parenteral antithrombotic pretreatment. Of the 127 patients, 86 (67.7%) had angiographically normal coronary arteries and 41 (32.3%) had mild disease (<30%). Compared to patients with CAD, those with no-CAD were younger, had a lower body mass index, were more frequently black, had a lower prevalence of smoking and previous angina, had a greater prevalence of previous CABG, had a greater incidence of apical ballooning syndrome, and had a greater left ventricular ejection fraction ( Table 1 ). A nonsignificant trend was found for the patients with no-CAD to be women. No significant differences were found between the groups in the rates of hypertension, hyperlipidemia, diabetes, interval from symptom onset to hospital presentation, or aspirin and thienopyridine use before admission.
| Variable | CAD | p Value | |
|---|---|---|---|
| No (n = 127) | Yes (n = 3,475) | ||
| Age (yrs) | 0.002 | ||
| Median | 57.6 | 60.3 | |
| IQR | 47.0, 67.5 | 52.5, 69.9 | |
| Women | 29.9% | 23.1% | 0.08 |
| Black | 7.1% | 1.8% | <0.001 |
| Height (cm) | 0.62 | ||
| Median | 172.0 | 172.0 | |
| IQR | 165.0, 177.8 | 166.0, 178.0 | |
| Body mass index (kg/m 2 ) | 0.002 | ||
| Median | 26.1 | 27.1 | |
| IQR | 23.7, 28.1 | 24.6, 30.3 | |
| Previous myocardial infarction | 11.8% | 10.9% | 0.74 |
| Previous percutaneous coronary intervention | 12.6% | 10.7% | 0.49 |
| Previous coronary bypass | 6.3% | 2.8% | 0.03 |
| Family history of premature coronary artery disease | 30.7% | 29.4% | 0.75 |
| Previous angina pectoris | 13.4% | 21.8% | 0.02 |
| Medically treated hypertension | 58.3% | 53.3% | 0.27 |
| Medically treated hyperlipidemia | 40.9% | 43.1% | 0.62 |
| Smoker | 45.7% | 64.3% | <0.001 |
| Diabetes mellitus | 15.7% | 16.5% | 0.82 |
| Peripheral vascular disease | 2.4% | 4.5% | 0.25 |
| Thrombocytopenia | 0.8% | 0.3% | 0.30 |
| Renal insufficiency | 3.9% | 2.9% | 0.42 |
| Baseline medications | |||
| Aspirin | 24.4% | 23.6% | 0.83 |
| Thienopyridine | 3.1% | 2.8% | 0.78 |
| Calcium channel blocker | 10.2% | 10.4% | 0.96 |
| Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker | 31.5% | 23.7% | 0.04 |
| Insulin | 4.7% | 4.2% | 0.76 |
| Oral hypoglycemic | 10.2% | 9.8% | 0.88 |
| Diuretics | 13.4% | 11.2% | 0.44 |
| Digoxin | 1.6% | 0.8% | 0.29 |
| Hormonal replacement therapy | 1.6% | 2.2% | >0.99 |
| Amiodarone | 0.8% | 0.4% | 0.44 |
| Cyclooxygenase inhibitors | 1.6% | 0.7% | 0.26 |
| Mean ST-segment elevation | 2.14 ± 1.03 | 3.18 ± 2.10 | <0.001 |
| Symptom onset to study hospital presentation (min) | 0.32 | ||
| Median | 137.5 | 129.5 | |
| IQR | 75, 300 | 75, 235 | |
| Apical ballooning syndrome | 10 (7.9%) | 2 (0.1%) | <0.0001 |
| Left ventricular ejection fraction (%) | <0.001 | ||
| Median | 60 | 50 | |
| IQR | 55, 65 | 42, 59 | |
After angiography, the primary management strategies for the patients with significant CAD were primary PCI (96.3% of patients), deferred PCI (0.1%), CABG (1.8%), and medical therapy (1.8%). All patients with no-CAD were treated medically. The cardiac enzymes were elevated in 63.2% of patients with no-CAD compared to 98.7% of patients with CAD (p <0.001). Patients with no-CAD compared to those with significant CAD were less likely to be discharged with cardiac medications, including statins (55.6% vs 95.2%, p <0.001), β blockers (50.0% vs 90.2%, p <0.001), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (54.0% vs 81.8%, p <0.001), aspirin (73.0% vs 98.5%, p <0.001), and thienopyridines (24.6% vs 95.8%, p <0.001).
At 30 days ( Table 2 ), a trend was seen toward a lower incidence of death or reinfarction in patients with no-CAD compared to those with CAD (0.8% vs 4.3%, p = 0.06). Patients with no-CAD had lower 30-day rates of unplanned revascularization owing to less ischemia-driven target vessel revascularization and revascularization of a nontarget vessel.
| CAD | p Value | ||
|---|---|---|---|
| No (n = 127) | Yes (n = 3,475) | ||
| Net adverse clinical events (primary end point) | 6.4% (8) | 11.4% (395) | 0.09 |
| Major adverse cardiovascular events | 1.6% (2) | 5.7% (196) | 0.053 |
| Death | 0.8% (1) | 2.7% (92) | 0.20 |
| Cardiac death | 0.8% (1) | 2.4% (83) | 0.25 |
| Reinfarction | 0% (0) | 1.9% (66) | 0.12 |
| Death or reinfarction | 0.8% (1) | 4.3% (148) | 0.06 |
| Stroke | 0.8% (1) | 0.7% (25) | 0.92 |
| Target vessel revascularization for ischemia | 0% (0) | 2.5% (85) | 0.08 |
| Nontarget vessel revascularization for ischemia | 0% (0) | 1.8% (61) | 0.14 |
| Any revascularization | 0% (0) | 3.5% (119) | 0.04 |
| Major bleeding not related to coronary artery bypass grafting | 4.7% (6) | 7.3% (252) | 0.30 |
| Blood transfusion | 2.4% (3) | 3.1% (108) | 0.64 |
| Q wave | 22.5% | 66.8% | <0.001 |
Similar results were noted at 3 years ( Table 3 and Figure 1 ). At 3 years of follow-up, patients with no-CAD compared to those with significant CAD had lower rates of major adverse cardiovascular events, net adverse clinical events (major adverse cardiovascular events or major bleeding not related to CABG), and any revascularization subsequent to the index procedure. The numerical reductions in the rates of death or reinfarction, stroke, and major bleeding did not reach statistical significance. No significant differences were found in the 30-day and 3-year outcomes between patients with angiographically normal and mildly diseased coronaries ( Table 4 ).
| CAD | p Value | ||
|---|---|---|---|
| No (n = 127) | Yes (n = 3,475) | ||
| Net adverse clinical events (primary end point) | 12.5% (12) | 26.9% (915) | 0.005 |
| Major adverse cardiovascular events | 7.7% (6) | 22.2% (750) | 0.002 |
| Death | 3.8% (3) | 6.9% (235) | 0.20 |
| Cardiac death | 0.8% (1) | 4.0% (137) | 0.12 |
| Reinfarction | 4.4% (3) | 7.3% (237) | 0.22 |
| Death or reinfarction | 8.2% (6) | 13.1% (441) | 0.10 |
| Stroke | 0.8% (1) | 1.9% (62) | 0.59 |
| Target vessel revascularization for ischemia | 0% | 13.5% (439) | 0.001 |
| Nontarget target vessel revascularization for ischemia | 0% | 10.0% (326) | 0.004 |
| Any revascularization | 0% | 19.5% (639) | <0.001 |
| Major bleeding not related to coronary artery bypass grafting | 4.7% (6) | 8.8% (300) | 0.19 |
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