Prasugrel is more potent than clopidogrel, but it is not known whether this translates into clinical benefit in patients undergoing primary percutaneous coronary intervention (PCI) with bivalirudin for ST elevation myocardial infarction. In the Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction trial, 452 patients with anterior STEMI undergoing primary PCI with bivalirudin were randomized to intralesional abciximab or placebo and to thrombus aspiration or no aspiration. Clopidogrel or prasugrel were administered at physician discretion. The primary end point was infarct size at 30 days by cardiac magnetic resonance imaging. Clinical events at 30 days and 1 year were independently adjudicated. Propensity score was used to adjust for nonrandom allocation of the drugs. Prasugrel and clopidogrel were administered to 155 patients (34.3%) and 297 patients (65.7%), respectively. Patients receiving prasugrel were younger with higher left ventricular ejection fraction and greater use of drug-eluting stents. Prasugrel-treated patients had higher rates of procedural success (94% vs 89%, p = 0.03), Thrombolysis In Myocardial Infarction (TIMI) 3 flow (95% vs 90%, p = 0.06), and lower corrected TIMI frame counts (21 ± 6 vs 23 ± 11, p = 0.008). At 30 days, infarct size was marginally lower in the prasugrel group (median [interquartile range] = 16.4% [6.5 to 20.0] vs 17.6% [8.1 to 25.7], p = 0.06). At 1 year, prasugrel group had significantly fewer deaths (1.3% vs 8.3%, p = 0.004) and fewer episodes of severe heart failure (2.0% vs 7.7%, p = 0.02). These findings persisted after propensity score adjustment. There were no significant differences in major bleeding. Stent thrombosis was 0% versus 2.5%, respectively, p = 0.054. We conclude that prasugrel was associated with improved efficacy and similar safety compared with clopidogrel in patients undergoing primary PCI with bivalirudin.
Antiplatelet therapy is central to achieving and maintaining reperfusion in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). When added to aspirin, prasugrel compared with clopidogrel was shown to reduce major adverse cardiac events (MACEs) by 20% in patients with acute coronary syndromes in the TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel (TRITON)–Thrombolysis In Myocardial Infarction (TIMI) 38 trial. One quarter of these patients had STEMI. This benefit was achieved predominantly on a background of heparin anticoagulation with or without glycoprotein IIb/IIIa inhibitors. Bivalirudin, which was used in only 3% of patients in TRITON-TIMI 38, has been shown to reduce mortality and major bleeding in patients with STEMI undergoing primary PCI, although at the cost of increased rates of stent thrombosis within 5 hours after procedure compared with heparin and glycoprotein IIb/IIIa inhibitors. The potential synergies between bivalirudin and prasugrel have not yet been studied. Toward this end, we examined the Intracoronary Abciximab and Aspiration Thrombectomy in Patients With Large Anterior Myocardial Infarction (INFUSE-AMI) randomized clinical trial database with respect to differences in outcomes between patients treated with clopidogrel versus prasugrel after bivalirudin-supported primary PCI.
Methods
In the INFUSE-AMI trial, 452 patients with anterior STEMI (culprit lesion in proximal or mid left anterior descending artery and TIMI flow grade 0 to 2) and anticipated symptom onset-to-reperfusion time of <5 hours underwent primary PCI with bivalirudin anticoagulation. All patients received aspirin and either clopidogrel or prasugrel at investigator discretion. They were randomized in a 2 × 2 factorial design to abciximab delivered locally at the site of the infarct lesion by means of the ClearWay Rx catheter (Atrium Medical, Hudson, New Hampshire) versus no abciximab and to thrombus aspiration using the Export catheter (Medtronic, Santa Rosa, California) versus no thrombus aspiration. The primary end point of the study was infarct size (IS), measured at 30 days by cardiac magnetic resonance imaging. Secondary end points included parameters of reperfusion (TIMI flow grade, myocardial blush grade, and ST-segment resolution after PCI) and MACE (composite of all-cause death, reinfarction, or new and/or severe heart failure) at 30 days and at 1 year. Bleeding was assessed using the Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction trial definition.
Continuous variables are presented as means with SD or medians with interquartile range, as appropriate, and were compared with the Wilcoxon rank sum test. Categorical variables are presented as frequencies and were compared with chi-square or Fisher’s exact test. We calculated a propensity score for choosing prasugrel from a logistic regression model incorporating the following variables: randomization arm, site, Killip class, age, gender, diabetes, body mass index, previous myocardial infarction, peripheral vascular disease, previous PCI, chronic kidney disease, symptom onset duration to PCI, baseline hemoglobin, platelet count, creatinine, and previous use of aspirin, thienopyridines, β blockers, and angiotensin-converting enzyme inhibitors. Propensity-adjusted Cox regression models for 1-year death, stent thrombosis, protocol-defined major bleeding, and MACE were derived using this score.
Results
Prasugrel and clopidogrel were administered to 155 patients (34.3%) and 297 patients (65.7%), respectively. Baseline characteristics between the groups were well matched ( Table 1 ), except prasugrel-treated patients were younger, had no previous stroke, had higher left ventricular ejection fraction, and greater use of drug-eluting stents. The results of primary PCI and 30-day IS are listed in Table 2 . Prasugrel-treated patients had higher rates of procedural success (94% vs 89%, p = 0.03), TIMI 3 flow (95% vs 90%, p = 0.06), and lower corrected TIMI frame counts (21 ± 6 vs 23 ± 11, p = 0.008). At 30 days, IS (percentage of left ventricular myocardium) was marginally lower in the prasugrel group (median [interquartile range] = 16.4% [6.5 to 20.0] vs 17.6% [8.1 to 25.7], p = 0.06). These differences did not retain statistical significance after controlling for the propensity to use prasugrel.
| Variable | Prasugrel (n = 155) | Clopidogrel (n = 297) | p Value |
|---|---|---|---|
| Randomization strata | |||
| Symptom onset to first angiogram | 0.67 | ||
| <3 h | 70.3 (109/155) | 68.4 (203/297) | |
| ≥3 h | 29.7 (46/155) | 31.6 (94/297) | |
| Left anterior descending segment | 0.70 | ||
| Proximal | 64.5 (100/155) | 66.3 (197/297) | |
| Mid | 35.5 (55/155) | 33.7 (100/297) | |
| Patient characteristics | |||
| Age (yrs) | 57.6 ± 10.4 (155) | 62.7 ± 12.7 (297) | <0.0001 |
| Men | 79.4 (123/155) | 71.0 (211/297) | 0.056 |
| Body mass index (kg/m 2 ) | 27.9 ± 4.8 (155) | 26.8 ± 4.4 (296) | 0.01 |
| Left ventricular ejection fraction, % (investigator estimate) | 47.4 ± 13.7 (147) | 40.5 ± 10.4 (274) | <0.0001 |
| Medically treated hypertension | 24.5 (38/155) | 35.0 (104/297) | 0.02 |
| Medically treated hyperlipidemia | 16.8 (26/155) | 15.2 (45/296) | 0.66 |
| Diabetes mellitus | 9.7 (15/154) | 12.1 (36/297) | 0.45 |
| Previous myocardial infarction | 1.9 (3/154) | 0.3 (1/296) | 0.12 |
| Previous PCI | 3.9 (6/154) | 1.3 (4/297) | 0.10 |
| Previous coronary bypass | 0.0 (0/155) | 0.0 (0/297) | N/A |
| Congestive heart failure | 1.3 (2/155) | 0.7 (2/295) | 0.61 |
| Smoking | 68.8 (106/154) | 56.3 (165/293) | 0.01 |
| Previous stroke or transient ischemic attack | 0.0 (0/155) | 2.4 (7/297) | 0.10 |
| Previous renal insufficiency | 0.0 (0/155) | 1.3 (4/297) | 0.30 |
| Variable | Prasugrel (n = 155) | Clopidogrel (n = 297) | p Value |
|---|---|---|---|
| Final TIMI flow grade | |||
| TIMI 0 or 1 | 1.3 (2/155) | 2.4 (7/297) | 0.72 |
| TIMI 3 | 94.8 (147/155) | 89.6 (266/297) | 0.06 |
| Final blush grade | 0.46 | ||
| Blush 0 or 1 | 16.8 (26/155) | 19.6 (58/296) | |
| Blush 2 or 3 | 83.2 (129/155) | 80.4 (238/296) | |
| Corrected TIMI frame count | 20.51 ± 6.26 (143) | 22.79 ± 10.94 (270) | 0.008 |
| Procedural success (%) | 94.2 (146/155) | 87.8 (258/294) | 0.03 |
| IS (% left ventricular mass), median (IQR) (total) | 16.4 (6.5–20.0) (114) | 17.6 (8.1–25.7) (239) | 0.06 |
| Left ventricular ejection fraction (%) | 51.1 (45.0–58.8) | 48.6 (41.1–55.7) | 0.004 |
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