It is not known whether the extent and severity of nonculprit coronary lesions correlate with outcomes in patients with ST-segment elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI). We sought to quantify complex plaques in patients with STEMI referred for primary PCI and to determine their effect on short- and long-term clinical outcomes by examining the core laboratory database for plaque analysis from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction study. Baseline demographic, angiographic, and procedural details were compared between patients with single versus multiple complex plaques who underwent single-vessel PCI. Multivariable analysis was performed for predictors of long-term major adverse cardiac events (MACEs), a combined end point of death, reinfarction, ischemic target-vessel revascularization, or stroke, and for death alone. Single-vessel PCI was performed in 3,137 patients (87%): 2,174 (69%) had multiple complex plaques and 963 (31%) had a single complex plaque. Compared with those with a single complex plaque, patients with multiple complex plaques were older (p <0.0001) and had more co-morbidities. The presence of multiple complex plaques was an independent predictor of 3-year MACE (hazard ratio 1.58, 95% confidence interval 1.26 to 1.98, p <0.0001), and death alone (hazard ratio 1.68, 95% confidence interval 1.05 to 2.70, p = 0.03). In conclusion, multiple complex plaques are present in the majority of patients with STEMI who underwent primary PCI, and their presence is an independent predictor of short- and long-term MACE, including death (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; NCT00433966 ).
Acute plaque rupture or erosion with subsequent thrombotic occlusion is the hallmark of ST-segment elevation myocardial infarction (STEMI). Complex plaque morphology associated with the propensity for plaque disruption was believed to be present only in the infarct-related artery, but the identification of multiple complex plaques in patients with STEMI has been reported in a small, single-center study. Our aim was to assess the prevalence of culprit and nonculprit complex plaques in a large group of patients with STEMI who underwent primary percutaneous coronary intervention (PCI) in an era of contemporary medical therapy and interventional techniques and to determine their influence on short- and long-term clinical outcomes. To this end, we analyzed data from the large, prospective, randomized, multicenter Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, which included detailed plaque analysis of the entire coronary tree.
Methods
The HORIZONS-AMI trial evaluated bivalirudin (compared with heparin and glycoprotein receptor inhibitors) and, in a secondary randomization, drug-eluting stents (compared with bare metal stents) in patients with STEMI who underwent primary PCI. All patients were preloaded in the emergency department with a thienopyridine before the procedure. Of the 3,602 patients, randomized, quantitative, and qualitative coronary angiographic analysis of all major epicardial coronary arteries was performed in 3,467 (96%) patients, and of these, PCI of a single coronary artery was performed in 3,137 (87%) patients. These 3,137 patients form the basis of our study and were categorized as having single or multiple complex plaques. Patients with multivessel PCI were excluded to eliminate the confounding effect of treatment of multiple complex lesions beyond the infarct-related lesion. A single complex plaque was, by definition, the infarct-related lesion within the infarct-related artery. In patients who had multiple complex plaques, the additional plaques were located at different sites within the infarct-related artery (proximal or distal to the infarct-related lesion) or in a noninfarct-related artery. Noninfarct-related complex plaques were not treated at the time of the index procedure, even when located in the infarct-related artery.
Coronary angiograms were analyzed by a core angiographic laboratory (Cardiovascular Research Foundation, New York, New York), and detailed quantitative and qualitative coronary angiography was performed in all major epicardial coronary arteries. A prespecified definition for complex plaque defined as a lesion that had >50% diameter stenosis with at least 2 of the following conditions: presence of a filling defect or thrombus, ulceration, irregularity, thrombolysis in myocardial infarction <3 flow, moderate or severe calcification, or involvement of a bifurcation was used by the core angiographic laboratory. Multiple complex plaques within the same vessel were determined to be “multiple” when they were located in a different segment separated by ≥5 mm of a normal appearing vessel.
Outcomes including death, cardiac death, reinfarction, stroke, and major bleeding (HORIZONS-AMI definition, which includes intracranial, intraocular, or retroperitoneal bleeding, access site bleeding requiring intervention or surgery, hematoma >5 cm, any blood product transfusion, reoperation for bleeding, or decrease in hemoglobin of >3 g/dl with and ≥4 g/dl without overt source of bleeding) were independently adjudicated by a committee blinded to the study allocation. In addition, major adverse cardiac events (MACEs), a combined end point of death, reinfarction, ischemia/clinically driven target-vessel revascularization, or stroke, and net adverse clinical events, the combined end point of MACE or noncoronary artery bypass graft-related major bleeding, were analyzed for those with single versus multiple complex plaques. Clinical follow-up was obtained at hospital discharge, at 30 days, and at 1, 2, and 3 years.
Baseline categorical variables are summarized as counts and percentages and were compared using chi-square or Fisher’s exact test, as appropriate. Continuous variables are summarized as medians with interquartile range and were compared using Mann-Whitney U test. Multivariable analysis adjusting for age, gender, race, diabetes, hypertension, previous myocardial infarction, previous coronary artery bypass graft, history of congestive heart failure, baseline creatinine clearance, left ventricular ejection fraction <40%, treatment with balloon angioplasty only, and time to reperfusion as covariates was performed to determine the predictors of MACE and death alone. A 2-tailed p value of <0.05 was considered significant. All analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).
Results
Of the 3,137 subjects, 963 (31%) had a single complex plaque (the infarct-related lesion), and 2,174 (69%) had multiple complex plaques. Of the patients with multiple plaques, 809 (26%) had 2 complex plaques, 533 (17%) had 3 complex plaques, 358 (11%) had 4 complex plaques, and 474 (15%) had 5 complex plaques. The demographic and baseline characteristics of the 2 groups are listed in Table 1 . Patients with multiple complex plaques had more co-morbidities, had higher rates of baseline medication use, were less likely to undergo primary PCI (95.4% vs 97.6%, p = 0.003), and were more likely to be referred for coronary artery bypass graft (2.7% vs 0.3%, p <0.0001). Moreover, those with multiple complex plaques had longer symptom onset to presentation (118 [65.0, 210.0] minutes vs 107 [60.0, 190.0] minutes, p = 0.036) and longer door-to-balloon times (100 [73.0, 135.0] minutes vs 93 [69.0, 130.0] minutes, p = 0.007).
| Variable | Single Complex Plaque (n = 963) | Multiple Complex Plaques (n = 2,174) | p Value |
|---|---|---|---|
| Age (yrs) | 57.2 (49.4, 65.7) | 61.8 (54.1, 71.0) | <0.0001 |
| Men | 73.9 (712/963) | 78.1 (1,698/2,174) | 0.011 |
| Body mass index (kg/m 2 ) | 26.8 (24.3, 30.1) | 27.3 (24.7, 30.3) | 0.057 |
| Hypertension ∗ | 46.9 (452/963) | 55.7 (1,210/2,172) | <0.0001 |
| Hyperlipidemia † | 40.5 (390/963) | 43.8 (952/2,172) | 0.082 |
| Current smoker | 53.9 (516/958) | 43.9 (948/2,161) | <0.0001 |
| Diabetes mellitus | 11.8 (114/963) | 19.0 (413/2,172) | <0.0001 |
| Previous myocardial infarction | 6.6 (64/963) | 13.4 (290/2,172) | <0.0001 |
| Previous PCI | 8.7 (84/963) | 12.0 (261/2,171) | 0.007 |
| Previous coronary bypass | 0.5 (5/963) | 4.0 (86/2,172) | <0.0001 |
| Previous angina pectoris | 19.0 (183/963) | 22.4 (486/2,171) | 0.033 |
| Heart failure | 1.9 (18/963) | 3.2 (70/2,172) | 0.034 |
| Ventricular arrhythmias | 1.3 (13/963) | 0.6 (13/2,172) | 0.032 |
| Peripheral vascular disease | 3.4 (33/963) | 4.7 (103/2,171) | 0.095 |
| Renal insufficiency | 2.3 (22/963) | 3.2 (69/2,171) | 0.169 |
| Baseline medications | |||
| Aspirin | 19.4 (187/963) | 25.6 (554/2,168) | 0.0002 |
| Thienopyridines | 2.0 (19/963) | 3.4 (73/2,174) | 0.034 |
| β blocker | 17.4 (168/963) | 23.2 (503/2,168) | 0.0003 |
| Calcium channel blocker | 8.4 (81/963) | 11.5 (250/2,168) | 0.009 |
| ACE/ARB | 20.4 (196/963) | 25.6 (555/2,168) | 0.002 |
| Insulin | 3.4 (33/963) | 4.5 (97/2,168) | 0.175 |
| Oral hypoglycemic | 7.3 (70/963) | 11.7 (253/2,167) | 0.0002 |
| Diuretic | 9.4 (91/963) | 11.9 (258/2,168) | 0.044 |
| Symptom onset to presentation (minutes) | 107.0 (60.0, 190.0) | 118.0 (65.0, 210.0) | 0.036 |
| Door-to-balloon time (minutes) | 93.0 (69.0, 130.0) | 100.0 (73.0, 135.0) | 0.007 |
| Primary PCI | 97.6 (940/963) | 95.4 (2,073/2,174) | 0.003 |
| Coronary bypass without PCI | 0.3 (3/963) | 2.7 (59/2,174) | <0.0001 |
∗ Patients treated with antihypertensive medication and untreated patients with known systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg.
† Patients with total cholesterol level >200 mg/dl or currently using lipid-lowering drugs.
The angiographic and procedural details of the 2 groups are listed in Table 2 . Patients with multiple complex plaques had worse left ventricular ejection fraction, more extensive coronary artery disease, lower rates of thrombolysis in myocardial infarction 3 flow before PCI, and worse infarct artery reperfusion as demonstrated by higher final corrected thrombolysis in myocardial infarction frame counts and lower rates of final myocardial blush grade 3. In patients with multiple complex plaques, the majority of plaques (79%) were located in a nonculprit artery.
| Variable | Single Complex Plaque (n = 963) | Multiple Complex Plaques (n = 2,174) | p Value |
|---|---|---|---|
| Randomized to bivalirudin | 50.2 (484/964) | 49.3 (1,078/2,187) | 0.636 |
| Randomized to UFH + GP IIbIIIa | 49.8 (480/964) | 50.7 (1,109/2,187) | 0.636 |
| LVEF <40% | 11.6 (97/838) | 15.7 (286/1,818) | 0.005 |
| Extent of coronary artery disease | <0.0001 | ||
| 1-Vessel disease | 99.9 (962/963) | 20.9 (455/2,174) | |
| 2-Vessel disease | 0.0 (0/963) | 48.5 (1,054/2,174) | |
| 3-Vessel disease | 0.0 (0/963) | 30.4 (660/2,174) | |
| ≥1 Total occlusion | 57.9 (558/963) | 66.0 (1,434/2,174) | <0.0001 |
| Length of disease (mm)/patient | 26.42 ± 17.05 (880) | 52.47 ± 29.34 (2,171) | <0.0001 |
| Total number of stents/patient | 1.3 ± 0.6 (913) | 1.5 ± 0.8 (1,956) | <0.0001 |
| Total stent length (mm)/patient | 24.0 (16.0, 28.0) (895) | 24.0 (20.0–36.0) (1,916) | <0.0001 |
| Any aspiration device | 12.6 (117/932) | 11.4 (234/2,046) | 0.381 |
| Any thrombectomy device | 1.0 (9/925) | 1.1 (23/2,042) | 0.708 |
| Drug-eluting stent | 70.7 (622/880) | 76.3 (1,404/1,839) | 0.002 |
| Bare metal stent | 29.3 (258/880) | 23.7 (435/1,839) | 0.002 |
| Pre-PCI TIMI 3 flow in IRA | 25.5 (240/940) | 20.8 (426/2,051) | 0.004 |
| Final TIMI 3 flow in IRA | 87.1 (817/938) | 85.1 (1,743/2,047) | 0.166 |
| Pre-PCI cTFC in IRA | 26.0 (18.0, 38.0) | 30.0 (20.0, 44.0) | 0.001 |
| Final cTFC in IRA | 20.0 (14.0, 28.0) | 21.0 (15.0, 30.0) | 0.001 |
| Pre-PCI MBG 3 in IRA | 4.9 (46/939) | 3.8 (78/2,037) | 0.175 |
| Final MBG 3 in IRA | 55.5 (520/937) | 48.6 (989/2,033) | 0.0005 |
Clinical outcomes at 30 days and 3 years are listed in Table 3 . At 3-year follow-up, patients with multiple complex plaques had significantly higher rates of MACE, all-cause death, cardiac death, and bleeding. Rates of reinfarction alone, however, were not significantly different between patients with single and multiple complex plaques. On multivariable analysis, the presence of multiple complex plaques was a significant independent predictor of MACE at 3 years (hazard ratio 1.58, 95% confidence interval 1.26 to 1.98, p <0.0001), together with a history of congestive heart failure, diabetes mellitus, previous myocardial infarction, depressed ejection fraction, worse kidney function, non-Caucasian race, and balloon angioplasty without stenting ( Figure 1 ). The presence of multiple complex plaques was also a significant independent predictor of death alone at 3 years (hazard ratio 1.68, 95% confidence interval 1.05 to 2.70, p = 0.03), together with history of congestive heart failure, diabetes, previous myocardial infarction, low ejection fraction, and worse kidney function ( Figure 2 ). There was a stepwise increase in MACE and death alone with increasing numbers of complex plaques. At 3-year follow-up, MACE doubled from 14.4% in patients with a single complex plaque to 29.5% in patients with ≥5 complex plaques ( Figure 3 ). Similarly, death tripled from 3.6% in patients with a single complex plaque to 10.0% in patients with ≥5 complex plaques ( Figure 4 ).
| Variable | Single Complex Plaque (n = 963) | Multiple Complex Plaques (n = 2,174) | p Value |
|---|---|---|---|
| 30 Days | |||
| Net adverse clinical events ∗ | 9.8 (94/963) | 11.4 (247/2,174) | 0.190 |
| MACEs | 3.5 (34/963) | 5.8 (126/2,174) | 0.008 |
| Death | 1.2 (12/963) | 2.8 (61/2,174) | 0.008 |
| Cardiac death | 1.1 (11/963) | 2.5 (54/2,174) | 0.015 |
| Reinfarction | 1.4 (13/963) | 1.8 (38/2,174) | 0.407 |
| Death or reinfarction | 2.5 (24/963) | 4.3 (94/2,174) | 0.013 |
| Stroke | 0.4 (4/963) | 0.7 (16/2,174) | 0.295 |
| TVR | 1.9 (18/963) | 2.5 (54/2,174) | 0.282 |
| HORIZONS major bleeding † | 7.9 (76/963) | 10.3 (223/2,174) | 0.039 |
| TIMI major bleeding | 2.8 (27/963) | 5.1 (111/2,174) | 0.004 |
| GUSTO severe bleeding | 0.5 (5/963) | 0.6 (127/2,174) | 0.002 |
| 3 yrs | |||
| Net adverse clinical events ∗ | 20.7 (196/963) | 28.6 (609/2,174) | <0.0001 |
| MACEs | 14.4 (135/963) | 24.6 (520/2,174) | <0.0001 |
| Death | 3.6 (34/963) | 7.6 (161/2,174) | <0.0001 |
| Cardiac death | 1.8 (17/963) | 4.5 (95/2,174) | 0.0003 |
| Reinfarction | 5.6 (52/963) | 7.7 (156/2,174) | 0.051 |
| Death or reinfarction | 8.8 (83/963) | 14.2 (299/2,174) | <0.0001 |
| Stroke | 1.0 (9/963) | 2.2 (45/2,174) | 0.021 |
| TVR | 10.0 (92/963) | 15.4 (315/2,174) | <0.0001 |
| HORIZONS major bleeding † | 9.4 (90/963) | 11.7 (251/2,174) | 0.066 |
| TIMI major bleeding | 3.4 (32/963) | 5.9 (127/2,174) | 0.003 |
| GUSTO severe bleeding | 0.7 (7/963) | 1.0 (20/2,174) | 0.571 |
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