The randomized TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38 trial compared prasugrel and clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). Patients treated with prasugrel had fewer ischemic events but more procedure-related bleeding. In the present study, we aimed to determine the effect of bivalirudin on bleeding in patients treated with prasugrel. A total of 692 patients with consecutive acute coronary syndrome underwent PCI with stent implantation and were anticoagulated with bivalirudin. The patients were divided into 2 groups according to the antiplatelet regimen (clopidogrel or prasugrel) chosen during or just after PCI. The bleeding complications during hospitalization were tabulated. Ischemic events were analyzed during hospitalization and at 30 days. Prasugrel was used in 96 patients (13.9%) and clopidogrel in 596 (86.1%). The clinical and procedural characteristics were similar, although the clopidogrel patients more often reported systemic hypertension (p = 0.01), previous PCI (p <0.001), and chronic renal insufficiency (p = 0.05). During hospitalization, the bleeding and ischemic complication rates were similar and low in both groups (major in-hospital complications 4.2% for clopidogrel vs 2.1% for prasugrel, p = 0.6; Thrombolysis In Myocardial Infarction major bleeding 2.5% vs 2.1%, p = 1.00; Thrombolysis In Myocardial Infarction minor bleeding 4.2% vs 5.2%, p = 0.6). At 30 days, no differences were found in ischemic events between both groups (target vessel revascularization/major adverse cardiac events 5.4% vs 2.1%, p = 0.2). In conclusion, prasugrel, when given after bivalirudin as the intraprocedural antithrombin agent for patients with acute coronary syndrome undergoing PCI, is as safe and effective as clopidogrel.
Large-scale, randomized trials have shown that the use of bivalirudin instead of heparin plus a glycoprotein IIb/IIIa inhibitor for intraprocedural anticoagulation during percutaneous coronary intervention (PCI) results in fewer major and minor bleeding complications and less thrombocytopenia. Moreover, this exchange does not increase the rate of adverse ischemic outcomes after PCI in patients with stable angina pectoris, unstable angina pectoris, non–ST-segment elevation myocardial infarction, or ST-segment elevation myocardial infarction. In these trials, platelet inhibition was attained with a standard therapy of aspirin and clopidogrel or ticlopidine.
In the TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction (TRITON-TIMI 38) clinical trial, prasugrel use was associated with fewer ischemic events than was clopidogrel. Prasugrel use was, however, associated with an increased risk of major bleeding. In that study, unfractionated heparin was administrated in about 2/3 of trial subjects undergoing PCI. Thus, the safety and efficacy of the addition of prasugrel in bivalirudin-treated patients is unknown. The present study was undertaken to compare prasugrel and clopidogrel antiplatelet therapy in patients with acute coronary syndrome undergoing PCI with bivalirudin, rather than heparin, anticoagulation.
Methods
We included 692 consecutive patients with acute coronary syndrome. From January 2010 to September 2011, all underwent PCI with stent implantation using intraprocedural bivalirudin anticoagulation. Patients were identified from an ongoing registry of coronary interventions kept at our institution. Patients with contraindications to, or cautions about, either clopidogrel or prasugrel were excluded.
We compared the clinical, procedural, and follow-up information for patients receiving prasugrel to the information of those receiving clopidogrel. Trained research personnel, who were unaware of the study’s objective, obtained the baseline clinical, laboratory, and procedural information and information about in-hospital events from chart review. These data were subsequently entered into the registry by dedicated data center personnel.
All patients had 30-day follow-up data available from a telephone interview or clinic visit. The basis for each clinical event was adjudicated by independent physicians not involved in the clinical procedure. All patients provided written informed consent for PCI, and the institutional review board at MedStar Washington Hospital Center approved the study.
PCI was performed according to standard clinical guidelines. Operator discretion dictated the type and number of stents deployed and the choice of pharmacologic therapy. All patients were pretreated with aspirin 325 mg and received a 300- or 600-mg dose of clopidogrel or 60 mg of prasugrel during the procedure (just after determination of the coronary anatomy and the decision to treat the lesion with a stent) or just after the intervention, during or just after the procedure. Anticoagulation during PCI was ensured using bivalirudin to achieve an activated clotting time of >250 seconds in all patients. Glycoprotein IIb/IIIa inhibitors were administered at the physician’s discretion and according to guidelines. The patients were discharged with aspirin 325 mg/day indefinitely and either clopidogrel 75 mg or prasugrel 10 mg for ≥3 months and ≥1 year, respectively, depending on the implanted stent.
The analyzed ischemic end points included all-cause mortality, cardiac death, Q-wave myocardial infarction (MI), non–Q-wave MI, target lesion revascularization, target vessel revascularization (TVR), cerebrovascular accident, transient ischemic attack, and stent thrombosis. Two composite end points were defined. Major in-hospital complications were defined as death, Q-wave MI, and coronary artery bypass grafting. In-hospital complications were defined as death, Q-wave MI, coronary artery bypass grafting, target lesion revascularization, and TVR. TVR major adverse cardiac events were defined as death, Q-wave MI, and TVR.
Death was defined as all-cause mortality. Q-wave MI and non–Q-wave MI were defined as an increment of creatine kinase-MB twice the upper limit of normal, associated, in the first case, with the development of a new Q wave, deeper than ≥1 mm, in ≥2 contiguous leads. TVR was defined as a clinically driven repeat percutaneous or surgical revascularization of the previously treated epicardial vessel. Cerebrovascular accident was defined as the loss of neurologic function caused by an ischemic or hemorrhagic event, with residual symptoms lasting ≥24 hours or leading to death. Transient ischemic attack was defined as a focal neurologic deficit that resolved spontaneously without evidence of a residual deficit at 24 hours. Stent thrombosis was determined using the Academic Research Consortium definitions and included both “definite” and “probable.” Early stent thrombosis was defined as thrombosis occurring within 30 days.
Bleeding complications included Thrombolysis In Myocardial Infarction major and minor bleeding. Individual events were also reported (e.g., blood transfusion, gastrointestinal bleeding, intracranial hemorrhage, and hematocrit decrease of ≥15% or a ≥5 g/dl decrease in the hemoglobin concentration), and transfusion.
A dedicated data-coordinating center (Data Center, MedStar Health Research Institute, Washington, DC) performed all data management and analyses. SAS, version 9.1 (SAS Institute, Cary, North Carolina) was used. Continuous variables are presented as mean ± SD and compared using Student’s t test. Categorical variables are expressed as absolute numbers and percentages and were compared using the chi-square test or the Fisher exact test, as appropriate. Statistical significance was set at a p <0.05.
Results
Before the availability of prasugrel, clopidogrel was the standard antiplatelet agent in our laboratory. Consequently, 596 patients (86.1%) in the present study cohort received clopidogrel and 96 patients (13.9%) received prasugrel during PCI. The baseline demographic and clinical characteristics were similar ( Table 1 ). Significantly fewer white patients were treated with clopidogrel (p = 0.01) and a greater proportion of patients had hypertension (p = 0.04) and renal insufficiency (p = 0.05) in the clopidogrel group. More patients in the clopidogrel group reported previous PCI (p <0.001).
| Characteristic | Clopidogrel (n = 596) | Prasugrel (n = 96) | p Value |
|---|---|---|---|
| Age (yrs) | 51.32 ± 15.4 | 59.66 ± 9.4 | 0.35 |
| Men | 342 (57.4%) | 73 (76.0%) | 0.13 |
| Body mass index (kg/m 2 ) | 31.20 ± 6.4 | 31.18 ± 5.9 | 0.98 |
| White race | 342 (57.4%) | 68 (70.8%) | 0.01 |
| Systemic hypertension ∗ | 513 (86.1%) | 75 (78.1%) | 0.04 |
| Hypercholesterolemia † | 477 (80.0%) | 81 (84.4%) | 0.32 |
| Diabetes mellitus | 277 (38.3%) | 31 (32.6%) | 0.29 |
| Current smoker | 201 (33.70) | 23 (24.0%) | 0.06 |
| Previous myocardial infarction | 146 (25.0%) | 15 (16.0%) | 0.06 |
| Previous coronary artery bypass surgery | 122 (20.50%) | 12 (12.5%) | 0.07 |
| Previous percutaneous coronary intervention | 236 (39.9%) | 21 (22.1%) | <0.001 |
| History of chronic renal insufficiency (creatine clearance <60 ml/min) | 95 (15.9%) | 8 (8.3%) | 0.05 |
| History of congestive heart failure | 53 (8.9%) | 6 (6.3%) | 0.39 |
| Left ventricular ejection fraction | 0.48 ± 0.1 | 0.50 ± 0.2 | 0.37 |
| Cardiogenic shock | 16 (2.7%) | 3 (3.1%) | 0.74 |
| Percutaneous coronary intervention indication | |||
| Unstable angina pectoris or non–ST-segment elevation myocardial infarction | 384 (64.6%) | 56 (58.3%) | 0.23 |
| ST-segment elevation myocardial infarction | 189 (31.8%) | 33 (34.4%) | 0.62 |
| Medication at discharge | |||
| Clopidogrel | 550 (92.3%) | 29 (4.9%) | <0.001 |
| Prasugrel | 39 (40.6%) | 54 (56.3%) | <0.001 |
| Angiotensin-converting enzyme inhibitor | 350 (59.5%) | 54 (56.8%) | 0.62 |
| Angiotensin-receptor blocker | 86 (14.6%) | 12 (12.5%) | 0.59 |
| β Blocker | 496 (84.2%) | 83 (86.5%) | 0.57 |
| Statin | 540 (90.9%) | 91 (94.8%) | 0.21 |
| Aspirin | 570 (96.8%) | 94 (97.9%) | 0.75 |
| Warfarin | 50 (8.5%) | 3 (3.1%) | 0.07 |
∗ History of systemic hypertension diagnosed and/or treated with medication or currently being treated with diet and/or medication by a physician.
† Included patients with a previously documented diagnosis of hypercholesterolemia; the patient might be treated with diet or medication; a new diagnosis can be made during this hospitalization with elevated total cholesterol >160 mg/dl; did not include elevated triglycerides.
Almost all patients were discharged with aspirin and a statin, with no differences between the 2 groups. In terms of thienopyridines, 92.3% of patients undergoing PCI with clopidogrel were discharged with the same medication, but only 56.4% of patients treated with prasugrel during hospitalization were discharged with that agent. The rest were discharged with clopidogrel ( Table 1 ).
The procedural characteristics are summarized in Table 2 . The target artery was successfully opened in nearly all patients (98.2% of those on clopidogrel and 96.1% of those on prasugrel); the target arteries were similar. Patients treated with clopidogrel during PCI somewhat more frequently had type C lesions treated (p = 0.03) and somewhat less frequently had type B lesions (p = 0.01). Intravascular ultrasonography was used more frequently in the prasugrel group (p = 0.003).
| Variable | Clopidogrel (n = 596) | Prasugrel (n = 96) | p Value |
|---|---|---|---|
| Target coronary vessel | |||
| Left main | 16 (1.9%) | 1 (0.8%) | 0.74 |
| Left anterior descending | 330 (38.9%) | 56 (43.4%) | 0.33 |
| Left circumflex | 261 (30.8%) | 37 (28.7%) | 0.63 |
| Right | 301 (35.5%) | 38 (29.5%) | 0.18 |
| Saphenous vein graft | 39 (4.6%) | 6 (4.7%) | 0.98 |
| Procedural characteristics (lesion based) | |||
| Angiographic success | 837 (98.2%) | 124 (96.1%) | 0.17 |
| Intravascular ultrasonography | 362 (42.5%) | 73 (56.6%) | 0.003 |
| Glycoprotein IIb/IIIa inhibitor | 30 (5.1%) | 4 (4.2%) | 1.00 |
| Intra-aortic balloon pump | 33 (5.5%) | 5 (5.2%) | 0.90 |
| Type A lesion | 101 (11.9%) | 9 (7.0%) | 0.10 |
| Type B1/B2 lesion | 427 (50.1%) | 81 (62.8%) | 0.01 |
| Type C lesion | 432 (50.7%) | 52 (40.3%) | 0.03 |
| Restenotic lesion | 42 (4.9%) | 6 (4.7%) | 0.89 |
| Treated lesions (n) | 1.40 ± 0.7 | 1.32 ± 0.7 | 0.32 |
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