The present study sought to determine the extent to which adverse angiographic events encountered during percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI) are associated with adverse clinical outcomes. Patients with STEMI represent a cohort at particularly high risk of intraprocedural thrombotic events (IPTEs). The overall frequency and implications of IPTEs occurring in patients with STEMI have not been systematically quantified in previous studies. A total of 3,163 patients undergoing primary percutaneous coronary intervention with stent implantation for STEMI in the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial underwent detailed frame-by-frame core laboratory angiographic analysis to assess IPTEs. The clinical outcomes at 30 days were compared between the patients with and without IPTEs. IPTEs, defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow, slow reflow, and distal embolization at any point during the procedure, occurred in 386 patients (12.2%). The independent predictors of IPTE were thrombus at baseline, lesion length, and randomization to bivalirudin; the patients with IPTEs were also more likely to receive bailout glycoprotein IIb/IIIa inhibitors and unplanned thrombectomy. Compared with patients without IPTEs, the patients with IPTEs had higher 30-day rates of composite major adverse cardiovascular events (death, myocardial infarction, ischemic target vessel revascularization, and stroke; 7.8% vs 4.2%, p = 0.002), major bleeding not related to coronary artery bypass grafting (11.8% vs 6.5%, p <0.001), and all-cause death (4.2% vs 1.8%, p = 0.002). On multivariate analysis, IPTEs were independently associated with 30-day major adverse cardiovascular events, major bleeding, and death. In conclusion, the development of IPTEs in patients undergoing primary percutaneous coronary intervention for STEMI was associated with subsequent adverse outcomes, including major adverse cardiovascular events, major bleeding, and death. Additional studies of strategies to decrease the occurrence of IPTEs are warranted.
Rapid and complete restoration of coronary blood flow is the mechanism underlying the benefit of reperfusion therapy in patients with ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI) restores Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow in >90% of patients. Despite the generally excellent outcomes of primary PCI for STEMI, patients with STEMI represent a cohort at particularly high risk of intraprocedural thrombotic events (IPTEs) because of the elevated thrombotic burden and prothrombotic milieu in these patients. Thus, slow flow or no reflow, distal embolization, and abrupt vessel closure are not infrequent complications encountered during PCI for STEMI. These complications can be associated with adverse procedural results and, in small-to-moderate size studies, have been associated with a greater frequency of adverse outcomes. Nonetheless, previous studies have not systematically quantified the overall frequency and implications of IPTE in STEMI using an independently adjudicated and dedicated core laboratory-based angiographic analysis, in part because such analysis would be a laborious and time-intensive process. We, and others, have demonstrated that IPTEs are associated with adverse outcomes in patients with high-risk non–ST-segment elevation acute coronary syndromes. We therefore sought to extend these previous observations to a higher risk patient cohort, performing a detailed core laboratory–adjudicated analysis of IPTEs in the multicenter, randomized, Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial. The goal of the present analysis was threefold: (1) to determine the overall incidence of IPTEs in patients with STEMI, (2) to evaluate the patient, lesion, and procedural characteristics associated with their occurrence, and (3) to evaluate the effect of IPTEs on the clinical outcomes.
Methods
The study design, protocol, and primary results of the HORIZONS-AMI trial have been previously described in detail. In brief, the HORIZONS-AMI trial was a large-scale, prospective, dual-arm, open-label, multicenter, randomized study designed to determine the safety and efficacy of the direct thrombin inhibitor bivalirudin compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors, and the paclitaxel-eluting TAXUS stent (Boston Scientific, Natick, Massachusetts) compared with an otherwise identical bare metal EXPRESS stent (Boston Scientific) in patients with STEMI undergoing primary PCI. A total of 3,602 patients undergoing primary PCI were enrolled internationally at 123 medical centers and randomized in a 1:1 ratio before coronary arteriography to unfractionated heparin with a glycoprotein IIb/IIIa inhibitor or bivalirudin, with the provisional use of glycoprotein IIb/IIIa inhibitors for strictly defined refractory thrombotic complications in the cardiac catheterization laboratory. Aspirin was administered indefinitely, and clopidogrel was prescribed for ≥6 months (≥1 year was recommended).
Quantitative coronary angiographic analysis was performed in all patients undergoing PCI at an independent core laboratory (Cardiovascular Research Foundation, New York, New York) by technicians who were unaware of the treatment assignment and clinical outcomes. Lesion morphology and flow assessment were determined according to previously determined criteria. In addition to routine pre-and postprocedural quantitative and qualitative assessments, intraprocedural complications were independently assessed for each angiographic run, with additional analyses performed for every cineangiographic frame, including the thrombus area and thrombus grade. The present study was confined to the 3,163 patients with stent implantation for whom films were available and evaluable for quantitative coronary angiographic analysis (of the 3,280 patients [96.4%] in whom stents were implanted).
IPTEs were defined as the development of new or increasing thrombus, abrupt vessel closure, no reflow or slow reflow, and distal embolization occurring at any point during the procedure that was not present at baseline. Intraprocedural stent thrombosis—a subset of IPTEs—was defined as new or increased thrombus within the deployed stent during PCI. Each complication was assessed relative to the status of the previous frames. Thus, if thrombus was present at baseline but had then resolved, only to recur later, this was coded as an IPTE. Similarly, thrombus that was present at baseline that qualitatively “grew” in the subsequent frames was considered an IPTE. In contrast, baseline thrombus that persisted without diminishing in size was not considered an IPTE.
Definitions of the primary study end points have been described in detail and were adjudicated by an independent clinical events committee that was unaware of the treatment assignment. Stent thrombosis was adjudicated using the Academic Research Consortium criteria. For the present analysis, the rates of major adverse cardiovascular events ([MACE], including death from any cause, myocardial infarction, ischemic target vessel revascularization, or stroke), major bleeding (not related to coronary artery bypass grafting), and overall mortality were evaluated at 30 days.
Categorical variables were compared using the chi-square or Fisher’s exact test, as appropriate. Continuous variables are expressed as the mean ± standard deviation and median and interquartile range and were compared using the Wilcoxon rank sum test. Time-to-event curves were constructed, and Kaplan-Meier–estimated event rates were compared using the log-rank test. Univariate analyses were performed to identify the factors associated with IPTEs and to determine which IPTE components were associated with ischemic outcomes. Logistic regression analysis was used to determine the predictors of IPTEs using stepwise selection with an entry and stay criterion of p <0.1. Cox multivariate regression analysis was performed to determine whether the occurrence of an IPTE was an independent correlate of clinical outcomes at 30 days. In addition to IPTEs and randomization to bivalirudin (both forced into the final models), the candidate covariates for the multivariate models were selected using stepwise selection with the entry and stay criterion set at p <0.1. The number of covariates was carefully considered to avoid model overfitting. The covariates preselected because of their association in previous studies with MACE, mortality, and major bleeding included stent type, age, gender, diabetes, hypertension, hyperlipidemia, current smoking, previous myocardial infarction, previous PCI, previous coronary artery bypass grafting, renal insufficiency, baseline hematocrit, and baseline white blood cell count.
Results
Of the 3,163 patients who underwent primary PCI with stent implantation and had frame-by-frame core laboratory angiographic analysis, 386 (12.2%) had an IPTE, including 37 (1.2%) with intraprocedural stent thrombosis (9.6% of all IPTEs). The individual components of IPTEs are listed in Table 1 . IPTEs occurred in a main epicardial branch in 366 patients (94.8%) and involved a side branch in 67 (17.4%; events occurred in both branches in most patients with a side branch IPTE). The most common form of IPTE was a new or an increasing thrombus.
| IPTE Location and Type | n (%) |
|---|---|
| Main branch IPTE | 366 (94.8) |
| New or worsened thrombus | 158 (40.9) |
| Abrupt closure | 74 (19.2) |
| No reflow | 64 (16.6) |
| Slow reflow | 142 (36.8) |
| Distal embolization | 139 (36.0) |
| Side branch IPTE | 67 (17.4) |
| New or worsened thrombus | 28 (7.3) |
| Abrupt closure | 38 (9.8) |
| Distal embolization | 22 (5.7) |
| IPTE after stenting | 265 (68.7) |
| IPTE before stenting | 209 (54.1) |
| Intraprocedural stent thrombosis | 37 (9.6) |
No significant differences were found among the patients with an IPTE compared with those without an IPTE with respect to the baseline demographic features ( Table 2 ), including the use of various medications (i.e., aspirin, thienopyridine, and preprocedural heparin), preprocedural laboratory measures (i.e., hematocrit, creatinine clearance, and platelet count), and the interval to treatment. Patients with IPTEs compared with those without IPTEs were more likely to present with hypotension and a lower left ventricular ejection fraction. Patients with IPTEs were also slightly more frequently randomized to bivalirudin than to unfractionated heparin plus glycoprotein IIb/IIIa inhibitors (55.7% vs 44.3%, p = 0.03). The use of glycoprotein IIb/IIIa inhibition as bailout therapy in the bivalirudin arm was more frequent in patients with IPTEs than in those without IPTEs (28.5% [61 of 214] vs 10.2% [140 of 1,375], p <0.001; Table 3 ).
| IPTE (n = 386) | No IPTE (n = 2,777) | p Value | |
|---|---|---|---|
| Age (yrs) | 61.0 (52.8–70.9) | 59.7 (52.4–69.4) | 0.12 |
| Male gender | 303 (78.5) | 2,139 (77.0) | 0.52 |
| Body mass index (kg/m 2 ) | 27.0 (24.8–30.1) | 27.1 (24.5–30.1) | 0.96 |
| History of hypertension | 209 (54.1) | 1,434/2,775 (51.7) | 0.36 |
| History of hyperlipidemia | 158 (40.9) | 1,186/2,775 (42.7) | 0.50 |
| History of smoking | 239/384 (62.2) | 1,801/2,766 (65.1) | 0.27 |
| Current smoker | 165/384 (43.0) | 1,324/2,766 (47.9) | 0.07 |
| History of diabetes mellitus | 55 (14.2) | 459/2,775 (16.5) | 0.25 |
| Insulin-dependent diabetes | 20 (5.2) | 121/2,775 (4.4) | 0.46 |
| History of previous MI | 36 (9.3) | 288/2,775 (10.4) | 0.52 |
| History of previous PCI | 32 (8.3) | 283/2,775 (10.2) | 0.25 |
| History of previous CABG | 13 (3.4) | 65/2,775 (2.3) | 0.22 |
| History of congestive heart failure | 12 (3.1) | 70/2,775 (2.5) | 0.50 |
| History of peripheral vascular disease | 13 (3.4) | 126/2,774 (4.5) | 0.29 |
| History of renal insufficiency | 15 (3.9) | 73/2,774 (2.6) | 0.16 |
| Characteristic | IPTE (n = 386) | No IPTE (n = 2,777) | p Value |
|---|---|---|---|
| Door to balloon time (min) | 97.0 (77.0–133.0) | 98.0 (72.0–134.0) | 0.52 |
| Symptom onset to balloon (min) | 230.0 (165.0–345.0) | 221.0 (160.0–332.0) | 0.37 |
| Prerandomization heparin | 248 (64.2) | 1,835/2,775 (66.1) | 0.47 |
| Randomization to bivalirudin | 215 (55.7) | 1,378 (49.6) | 0.03 |
| Any use of glycoprotein IIb/IIIa inhibitor | 234/385 (60.8) | 1,530/2,772 (55.2) | 0.04 |
| Bailout glycoprotein IIb/IIIa inhibitor use (bivalirudin arm) | 61/214 (28.5) | 140/1,375 (10.2) | <0.001 |
| No. of stents implanted | 1.7 ± 0.9 | 1.5 ± 0.8 | <0.001 |
| Total stent length implanted | 28.0 (20.0–44.0) | 24.0 (20.0–36.0) | <0.001 |
| Post-stent dilatation balloon used | 159/359 (44.3) | 967/2,566 (37.7) | 0.02 |
| Total fluoroscopy time (min) | 14.0 (9.0–22.0) | 11.0 (7.0–16.0) | <0.001 |
| Total amount of contrast (ml) | 250.0 (200.0–320.0) | 220.0 (180.0–290.0) | <0.001 |
| Aspiration catheter use | 79/380 (20.8) | 279/2,762 (10.1) | <0.001 |
| Planned (prophylactic) | 66/79 (83.5) | 251/279 (90.0) | 0.11 |
| For complications | 23/79 (29.1) | 31/279 (11.1) | <0.001 |
| Index lesion | n = 410 | n = 3,027 | |
| Left anterior descending artery | 187 (45.6) | 1,217/3,027 (40.2) | 0.04 |
| Left circumflex artery | 41 (10.0) | 495/3,027 (16.4) | <0.001 |
| Right coronary artery | 173 (42.2) | 1,271/3,027 (42.0) | 0.94 |
| Left main artery | 1 (0.2) | 19/3,027 (0.6) | 0.50 |
| Saphenous vein graft | 8 (2.0) | 23/3,027 (0.8) | 0.03 |
| TIMI flow before PCI | |||
| TIMI 0-1 | 316 (77.1) | 1,910/3,020 (63.2) | <0.001 |
| TIMI 0 | 278 (67.8) | 1,641/3,020 (54.3) | <0.001 |
| TIMI 1 | 38 (9.3) | 269/3,020 (8.9) | 0.81 |
| TIMI 2 | 61 (14.9) | 491/3,020 (16.3) | 0.48 |
| TIMI 3 | 33 (8.0) | 619/3,020 (20.5) | <0.001 |
Patients with IPTEs were more likely to undergo PCI of the left anterior descending artery than other infarct vessels compared with the patients without IPTEs (45.6% vs 40.2%, p = 0.04). Also, the initial TIMI flow was worse for patients with IPTEs ( Table 3 ). The number of stents implanted per patient, the total stent length, and the use of post-stent balloon dilatation were significantly greater in the IPTE group. The total fluoroscopy time, amount of contrast used, and use of an aspiration catheter were all significantly greater in the IPTE group. Of the patients in whom aspiration thrombectomy was performed, the rate of planned or prophylactic aspiration was similar for the patients with and without IPTEs. However, aspiration for a procedural complication was more frequent in the group with IPTEs. Final TIMI 3 flow was restored in 238 of 385 patients (61.8%) with IPTEs versus 2,514 of 2,774 patients (90.6%) without IPTEs (p <0.001).
On multivariable analysis, the only independent predictors of IPTE were thrombus at baseline (odds ratio 3.21, 95% CI 2.00 to 5.15, p <0.001), total lesion length per millimeter (odds ratio 1.02, 95% CI 1.01 to 1.03, p <0.001), and randomization to bivalirudin (odds ratio 1.26, 95% CI 1.01 to 1.56, p = 0.04).
Patients experiencing IPTEs had significantly increased in-hospital and 30-day rates of MACE compared with the patients without IPTEs ( Table 4 and Figure 1 ). In addition, all-cause mortality was significantly increased in patients with IPTEs (4.2% vs 1.8% at 30 days, p = 0.002; Figure 1 ). In-hospital definite or probable stent thrombosis occurring outside of the catheterization laboratory (i.e., excluding Intraprocedural stent thrombosis) occurred more frequently in the IPTE group (3.4% vs 1.4%, p = 0.005); however, this difference was not significant at 30 days ( Figure 1 ). Finally, non–coronary artery bypass grafting major bleeding was significantly increased in patients with IPTEs in hospital and at 30 days ( Figure 1 ). The magnitude and direction of the associations between IPTEs and adverse events were consistent across the randomized treatment strata (all interaction terms with p >0.05) despite a lower rate of mortality, major bleeding, and MACE among patients treated with bivalirudin rather than unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor ( Figure 2 ).
| IPTE (n = 386) | No IPTE (n = 2,777) | p Value | |
|---|---|---|---|
| In-hospital | |||
| Major adverse cardiac event | 28 (7.3%) | 90 (3.2%) | <0.001 |
| Death | 15 (3.9%) | 43 (1.5%) | 0.001 |
| Reinfarction | 8 (2.1%) | 31 (1.1%) | 0.13 |
| Stroke | 3 (0.8%) | 7 (0.3%) | 0.11 |
| Major bleeding (non–CABG related) | 44 (11.4%) | 165 (5.9%) | <0.001 |
| Ischemic target vessel revascularization | 11 (2.8%) | 42 (1.5%) | 0.06 |
| Definite or probable stent thrombosis | 13 (3.4%) | 39 (1.4%) | 0.005 |
| At 30 days | |||
| Major adverse cardiac event | 7.8% (30) | 4.2% (117) | 0.002 |
| Death | 4.2% (16) | 1.8% (49) | 0.002 |
| Reinfarction | 2.4% (9) | 1.7% (48) | 0.38 |
| Stroke | 0.8% (3) | 0.4% (11) | 0.28 |
| Major bleeding (non–CABG related) | 11.8% (45) | 6.5% (179) | <0.001 |
| Ischemic target vessel revascularization | 2.9% (11) | 2.1% (59) | 0.34 |
| Definite or probable stent thrombosis | 3.7% (14) | 2.2% (60) | 0.07 |
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