Postprocedural anticoagulation (AC) after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) may be administered for a number of specific therapeutic indications (e.g. atrial fibrillation or left ventricular thrombus). However, the safety and effectiveness of such post-PCI AC for specific indications are not well defined. Thus, we sought to study outcomes after postprocedural AC for specific indications in patients undergoing primary PCI for STEMI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial. Patients who underwent primary PCI for STEMI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial were grouped according to whether they received specific indication AC. Adverse outcomes were assessed using propensity-adjusted multivariate analyses. After excluding patients who received post-PCI AC solely for routine prophylaxis, 410 patients (16.6%) received postprocedural AC for specific indications and 2,063 patients (83.4%) received no post-PCI AC. After propensity adjustment, use of postprocedural AC for specific indications was associated with higher rates of cardiac mortality, reinfarction, stent thrombosis, and major bleeding at 30 days compared with patients who received no AC post-PCI. In conclusion, in this large prospective study, use of postprocedural AC for specific indications after primary PCI for STEMI was independently associated with early rates of adverse ischemic and hemorrhagic outcomes. Post-PCI AC for specific indications was also associated with worse outcomes from 30 days to 3 years. Further studies are warranted to determine the optimal use of postprocedural AC after primary PCI in STEMI.
Patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) remain at risk for ischemic events in the postrevascularization setting. Although postprocedural anticoagulation (AC) to inhibit thrombin is frequently administered for a number of specific therapeutic indications, the few studies that have evaluated such AC use after primary PCI have demonstrated high rates of bleeding with uncertain benefits. The safety, effectiveness, and optimal regimens of postprocedural AC for specific indications in patients with STEMI has yet to be well defined, especially in the setting of primary PCI with drug-eluting stents (DES). Therefore, we sought to evaluate the practice of postprocedural AC for specific indications in patients undergoing primary PCI for STEMI in the large-scale prospective Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial.
Methods
The study design and primary results for HORIZONS-AMI have previously been reported. In brief, HORIZONS-AMI was a large-scale, multicenter, prospective study in which 3,602 patients presenting with STEMI who underwent a primary PCI strategy were randomized 1:1 to bivalirudin monotherapy or unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor. A total of 3,006 eligible patients were randomized again to receive TAXUS Express 2 (Boston Scientific, Natick, MA) paclitaxel-eluting stents or identical uncoated bare-metal stents in a 3:1 ratio. Patients ≥18 years of age presenting within 12 hours of symptom onset with ≥1 mm ST-segment elevation in ≥2 contiguous leads or new left-bundle branch block or true posterior myocardial infarction were eligible for enrollment. Major exclusion criteria included contraindications to study medications; previous administration of thrombolytic agents, bivalirudin, glycoprotein IIb/IIIa inhibitor, low–molecular-weight heparin, or fondaparinux during present hospitalization; current warfarin use, history of bleeding diathesis, coagulopathy, heparin-induced thrombocytopenia, intracerebral mass, aneurysm, arteriovenous malformation, or previous hemorrhagic stroke; stroke or transient ischemic attack in the past 6 months or any permanent neurologic deficits; blood transfusion refusal; gastrointestinal or genitourinary bleeding in the past 2 months; major surgery in the past 6 weeks; known thrombocytopenia (platelet count <100,000 cells/mm 3 ) or anemia (hemoglobin level <10 g/dl); planned elective surgery that would interrupt antiplatelet therapy within 6 months after enrollment; and noncardiac co-morbidities that would cause life expectancy to be <1 year or interfere with protocol compliance.
Aspirin (324 mg chewed or 250 to 500 mg intravenously) and clopidogrel (either 300 mg or 600 mg) were administered before catheterization. Postprocedural AC was defined as use of any AC therapy (whether unfractionated heparin, low-molecular-weight heparin, bivalirudin, or fondaparinux) administered per operator discretion after arterial sheath removal. The specific indications for post-PCI AC, its dose, and duration were prospectively collected in the electronic case report form.
Noncoronary artery bypass graft-related major bleeding was defined as intracranial or intraocular bleeding, access site hemorrhage requiring intervention, hematoma ≥5 cm in diameter, reduction in hemoglobin levels ≥4 g/dl without an overt bleeding source or ≥3 g/dl with an overt source, reoperation for bleeding, or any blood product transfusion at 30 days. Major adverse cardiovascular events (MACE [death, reinfarction, ischemia-driven target vessel revascularization, or stroke]) and net adverse clinical events (NACE [MACE or noncoronary artery bypass graft-related major bleeding]) were also assessed at 30 days. Post-PCI in-hospital acquired thrombocytopenia was defined as the development of an in-hospital nadir platelet count of <150,000/mm 3 in patients with baseline counts of ≥150,000/mm 3 . Acquired thrombocytopenia was classified as any (<150,000/mm 3 ), mild (100,000 to 150,000/mm 3 ), moderate (50,000 to 100,000/mm 3 ), and severe (<50,000/mm 3 ). All major adverse events, including bleeding, were adjudicated by an independent clinical events committee, blinded to treatment assignment.
Our primary objective was to assess the relation between the use of postprocedural AC for specific therapeutic indications and 30-day outcomes in patients in whom primary PCI was performed. Patients who received postprocedural AC solely for routine prophylaxis were excluded from the present analysis. Continuous data are presented as mean ± SD and were compared using the Student t test or analysis of variance, as appropriate. Binary variables were compared with the chi-square test. Thirty-day and 3-year event rates were estimated using Kaplan-Meier method and compared using the log-rank test. We constructed a propensity score for the use of postprocedural AC accounting for variables based on both clinical importance and those that differed significantly between groups: age, diabetes mellitus, hypertension, hyperlipidemia, previous myocardial infarction, previous PCI, baseline angina, renal insufficiency (defined as creatinine clearance <60 ml/min), Killip class, intervention in multiple vessels, aspirin on admission, history of atrial arrhythmia, baseline hematocrit, baseline platelet count, in-hospital warfarin administration, symptom to balloon time, post-PCI intra-aortic balloon pump use, and postprocedural Thrombolysis In Myocardial Infarction flow. Propensity-adjusted multivariate Cox regression with variable entry/stay criteria of 0.1/0.1 was performed to assess the association between postprocedural AC and 30-day outcomes, including death, cardiac death, myocardial infarction, noncoronary artery bypass graft-related major bleeding, stroke, MACE, and NACE. A p value <0.05 was considered to be statistically significant, and all p values are 2-sided. Statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, North Carolina).
Results
After excluding 1,279 patients who received postprocedural AC only for routine prophylaxis, the study population consisted of 2,473 patients. A total of 410 (16.6%) received post-PCI for specific indications and 2,063 (83.4%) received no post-PCI AC. The various therapeutic indications for which AC was administered are listed in Table 1 . The post-PCI AC agent administered was unfractionated heparin in 181 patients, low–molecular-weight heparin in 192 patients (162 of whom received enoxaparin), bivalirudin in 138 patients, and fondaparinux in 2 patients; some patients received >1 agent at different times.
| Indication ∗ | Post-PCI AC (N = 2,473) |
|---|---|
| For specific indications | 410 (16.6%) |
| Routine prophylaxis | 78 (3.2%) |
| Suboptimal results of PCI | 78 (3.2%) |
| Intra-aortic balloon pump | 70 (2.8%) |
| Atrial fibrillation | 67 (2.7%) |
| Post-index procedure revascularization (PCI or CABG) | 60 (2.4%) |
| Cardiomyopathy | 44 (1.8%) |
| Left ventricular aneurysm | 37 (1.5%) |
| High risk anatomy, multivessel or left main coronary disease | 35 (1.4%) |
| Left ventricular, mural, or giant coronary thrombus | 33 (1.3%) |
| Recurrent chest pain | 6/2472 (0.2%) |
| Stent thrombosis | 3/2469 (0.1%) |
| Bridge to warfarin | 2/2469 (0.1%) |
| Other | 26 (1.1%) |
∗ More than 1 indication was present in some patients, and some patients received >1 anticoagulant.
The differences in demographics and clinical characteristics between groups are listed in Table 2 , and angiographic and procedural characteristics are listed in Table 3 . Patients in the specific indication AC group were more likely to have had intervention attempted on the left anterior descending artery, and more often had baseline and post-PCI Thrombolysis In Myocardial Infarction 0/1 flow. The number of stents implanted and the rates of multivessel treatment were also higher in the group that received post-PCI AC for specific indications. There were no significant differences between groups, however, in terms of pharmacologic or stent randomization. Information on dosing and duration of therapy for postprocedural AC agents is also listed in Table 3 . Time from PCI to ambulation was significantly longer in the specific indication AC group than the no AC group (median 1.7 vs 1.0 days, p <0.0001).
| Variable | Post-PCI AC for Specific Indications | p Value | |
|---|---|---|---|
| Yes (N = 410) | No (N = 2,063) | ||
| Age (years) | 62.8 [54.0, 72.3] | 59.0 [52.1, 68.4] | <0.001 |
| Men | 303 (73.9%) | 1,602 (77.7%) | 0.10 |
| White | 382 (93.2%) | 1,922 (93.2%) | 1.00 |
| Body mass index (kg/m 2 ) | 27.0 [24.5, 29.8] | 27.2 [24.5, 30.5] | 0.36 |
| Treated outside United States | 295 (72.0%) | 1,491 (72.3%) | 0.89 |
| Hypertension ∗ | 217 (52.9%) | 1,049 (50.8%) | 0.44 |
| Hyperlipidemia † | 175 (42.7%) | 909 (44.1%) | 0.61 |
| Current or former smoker | 249/407 (61.2%) | 1,327/2,061 (64.4%) | 0.22 |
| Diabetes mellitus | 68 (16.1%) | 354 (17.2%) | 0.60 |
| Renal insufficiency ‡ | 21 (5.1%) | 49 (2.4%) | 0.002 |
| Prior myocardial infarction | 44 (10.7%) | 244 (11.8%) | 0.53 |
| Prior percutaneous coronary intervention | 47 (11.5%) | 229/2,062 (11.1%) | 0.84 |
| Prior coronary artery bypass grafting | 10 (2.4%) | 53 (2.6%) | 0.88 |
| History of atrial arrhythmia | 15 (3.7%) | 36 (1.7%) | |
| Killip class | |||
| 1 | 348 (84.9%) | 1,895/2,060 (92.0%) | <0.0001 |
| 2 | 44 (10.7%) | 136/2,060 (6.6%) | 0.003 |
| 3 | 7 (1.7%) | 17/2,060 (0.8%) | 0.10 |
| 4 | 11 (2.7%) | 12/2,060 (0.6%) | <0.0001 |
| Baseline laboratory values | |||
| Hematocrit (%) | 43.0 [40.0, 46.0] | 43.0 [40.0, 45.0] | 0.64 |
| Platelets (×10 3 /mm 3 ) | 248 [207, 292] | 250 [212, 296] | 0.49 |
∗ Hypertension is defined as history of and/or current high arterial blood pressure defined by local standard criteria.
† Hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) is defined as elevated lipids as diagnosed per local standard criteria.
‡ Renal insufficiency is defined as creatinine clearance rate <60 ml/min determined by the Cockcroft-Gault equation.
| Variable | Post-PCI AC for Specific Indications | p Value | |
|---|---|---|---|
| Yes (N = 410) | No (N = 2,063) | ||
| Antithrombotic randomization | |||
| Bivalirudin monotherapy | 217 (52.9%) | 1,018 (49.3%) | 0.19 |
| Heparin + glycoprotein IIb/IIIa inhibitor | 193 (47.1%) | 1,045 (50.7%) | 0.19 |
| Dose of post-PCI AC | |||
| Bivalirudin IV bolus (U) | 60.0 [52.5, 72.5] | — | |
| Bivalirudin infusion (U/hr) | 150.5 [129.0, 187.5] | — | |
| UFH IV bolus (U) | 4,568 [2,700, 6,800] | — | |
| UFH infusion (U/hr) | 1,200 [1,000, 2,150] | — | |
| Enoxaparin SQ (mg/kg) | 1.0 [0.7, 1.8] | — | |
| Duration of post-PCI AC (days) | 2.3 [0.9, 5.6] | — | |
| Time from PCI to ambulation (days) | 1.7 [1.0, 2.6] | 1.0 [0.7, 1.6] | <0.0001 |
| Index PCI vessel | |||
| Left main | 4/436 (0.9%) | 14/2,201 (0.6%) | 0.51 |
| Left anterior descending | 229/436 (52.5%) | 843/2,201 (38.3%) | <0.0001 |
| Left circumflex | 62/436 (14.2%) | 345/2,201 (15.7%) | 0.44 |
| Right | 136/436 (31.2%) | 975/2,201 (44.3%) | <0.0001 |
| Multiple vessels treated | 26/391 (6.6%) | 65/2020 (3.2%) | 0.001 |
| Number of stents implanted | 1.61 ± 0.87 | 1.49 ± 0.82 | 0.02 |
| Only drug-eluting stents implanted | 240/347 (69.2%) | 1,380/1,959 (70.4%) | 0.63 |
| Only bare-metal stents implanted | 98/347 (28.2%) | 546/1,959 (27.9%) | 0.89 |
| Baseline quantitative coronary angiography | |||
| Thrombus present in vessel | 347/432 (80.3%) | 1,669/2,147 (77.7%) | 0.69 |
| Lesion length (mm) | 14.4 [10.0, 21.2] | 14.5 [10.2, 20.0] | 1.00 |
| Reference vessel diameter (mm) | 2.83 [2.47, 3.20] | 2.88 [2.54, 3.22] | 0.43 |
| Minimum lumen diameter (mm) | 0.00 [0.00, 0.52] | 0.10 [0.00, 0.65] | 0.01 |
| Diameter stenosis (%) | 100.0 [79.9, 100.0] | 96.5 [76.2, 100.0] | 0.01 |
| TIMI flow of vessel | |||
| TIMI 0/1 | 289/432 (66.9%) | 1,303/2,148 (60.7%) | 0.04 |
| TIMI 2 | 55/432 (12.7%) | 286/2,148 (13.3%) | 1.00 |
| TIMI 3 | 88/432 (20.4%) | 559/2,148 (26.0%) | 0.04 |
| Final quantitative coronary angiography | |||
| Thrombus present in vessel | 35/431 (8.1%) | 54/2,149 (2.5%) | <0.0001 |
| Minimum lumen diameter (mm) | |||
| In-stent | 2.66 [2.35, 2.98] | 2.76 [2.46, 3.10] | 0.001 |
| In-segment | 2.19 [1.83, 2.62] | 2.33 [2.00, 2.70] | <0.0001 |
| Residual diameter stenosis (%) | |||
| In-stent | 6.1 [1.6, 13.2] | 5.8 [0.0, 11.5] | 0.13 |
| In-segment | 20.7 [13.4, 29.7] | 18.3 [12.5, 25.3] | <0.0001 |
| TIMI flow of vessel | |||
| TIMI 0/1 | 36/431 (8.4%) | 47/2,149 (2.2%) | <0.0001 |
| TIMI 2 | 63/431 (14.6%) | 193/2,149 (9.0%) | 0.001 |
| TIMI 3 | 332/431 (77.0%) | 1,909/2,149 (88.8%) | <0.0001 |
Antithrombotic agents administered at discharge are listed in Table 4 . Patients in the specific indication AC group were significantly less likely to receive dual antiplatelet therapy (aspirin, a thienopyridine or both), but were more likely to receive warfarin at discharge.
| Variable | Post-PCI AC for Specific Indications | p Value | |
|---|---|---|---|
| Yes (N = 410) | No (N = 2,063) | ||
| Dual antiplatelet therapy ∗ | 347/385 (90.1%) | 1,980/2,024 (97.8%) | <0.0001 |
| Aspirin | 365/385 (94.8%) | 2,009/2,024 (99.3%) | <0.0001 |
| Any thienopyridine | 363/387 (93.8%) | 1,994/2,024 (98.5%) | <0.0001 |
| Clopidogrel | 348/386 (90.2%) | 1,949/2,023 (96.3%) | <0.0001 |
| Ticlopidine | 15/387 (3.9%) | 45/2,022 (2.2%) | 0.06 |
| Warfarin | 66/388 (17.0%) | 39/2,023 (1.9%) | <0.0001 |
∗ Dual antiplatelet therapy is defined as both aspirin and a thienopyridine prescribed at discharge.
Thirty-day clinical outcomes stratified by post-PCI AC use according to the presence of a specific indication compared with no post-PCI AC are listed in Table 5 and Figure 1 . The propensity-adjusted rates of cardiac death, reinfarction, stent thrombosis, major bleeding, MACE, and NACE were all significantly greater in patients receiving post-PCI AC for a specific indication compared with no post-PCI AC at 30 days. No significant interactions were found among use of post-PCI AC for specific indications, baseline renal insufficiency, and 30-day major bleeding (p = 0.86) or MACE (p = 0.16).
| Variable | Post-PCI AC for Specific Indications | Adjusted HR [95% CI] | p Value | |
|---|---|---|---|---|
| Yes (N = 410) | No (N = 2,063) | |||
| All-cause death | 27 (6.6%) | 41 (2.0%) | 2.00 [0.99, 4.01] | 0.05 |
| Cardiac death | 25 (6.1%) | 39 (1.9%) | 2.13 [1.04, 4.37] | 0.04 |
| Reinfarction | 19 (4.7%) | 32 (1.6%) | 3.25 [1.67, 6.32] | 0.001 |
| Stent thrombosis ∗ | 22 (6.1%) | 38 (1.9%) | 3.17 [1.72, 5.84] | 0.0002 |
| Stroke | 4 (1.0%) | 10 (0.5%) | 1.14 [0.24, 5.38] | 0.86 |
| Non-CABG major bleeding | 70 (17.3%) | 123 (6.0%) | 2.24 [1.55, 3.24] | <0.0001 |
| Retroperitoneal | 6 (1.5%) | 8 (0.4%) | ||
| Access site | 3 (0.7%) | 3 (0.1%) | ||
| Hematoma ≥5 cm | 14 (3.4%) | 37 (1.8%) | ||
| Drop in Hgb ≥3 g/dL with overt source | 15 (3.7%) | 38 (1.9%) | ||
| Drop in Hgb ≥4 g/dL without overt source | 42 (10.4%) | 54 (2.6%) | ||
| Reoperation for bleeding | 3 (0.7%) | 1 (0.0%) | ||
| Blood product transfusions | 32 (7.9%) | 55 (2.7%) | ||
| Major adverse cardiovascular events | 57 (13.9%) | 90 (4.4%) | 2.65 [1.71, 4.11] | <0.0001 |
| Net adverse clinical events | 107 (26.1%) | 189 (9.2%) | 2.39 [1.77, 3.24] | <0.0001 |
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