Patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) commonly receive a loading dose of either clopidogrel or prasugrel, in addition to aspirin. The present study aimed to assess the safety of reloading prasugrel in patients who had initially received a loading dose of clopidogrel compared to prasugrel loading alone. The study included a cohort of 606 consecutive patients with acute coronary syndrome who had received a 60-mg loading dose of prasugrel before PCI. These patients were then categorized into clopidogrel preloading (300 or 600 mg) followed by prasugrel reloading (CP-load group, n = 90) and prasugrel loading only (P-load group, n = 516). Both groups received a 10-mg maintenance dose of prasugrel after PCI. The primary end point was in-hospital Thrombolysis In Myocardial Infarction-defined major bleeding. The secondary end points were other in-hospital bleeding complications and major cardiovascular events. Patients in the CP-load group compared to the P-load group were younger, with lower rates of cardiovascular risk factors. Significantly more patients in the CP-load group presented with biomarker-positive myocardial infarction (80.0% vs 30.6%, p ≤0.001) and cardiogenic shock (5.6% vs 1.4%, p = 0.022). No significant differences (p = NS) were seen in Thrombolysis In Myocardial Infarction major bleeding (2.6% vs 2.8%), Thrombolysis In Myocardial Infarction major or minor bleeding (12.2% vs 7.0%), the need for blood transfusion (2.6% vs 2.1%), and vascular complications (1.3% vs 2.0%) between groups. The CP-load group experienced more in-hospital major adverse cardiac events (5.6% vs 1.6%, p = 0.031), urgent coronary artery bypass grafting (3.3% vs 0.2%, p = 0.011), and longer hospital and intensive care unit stays. In conclusion, preloading with clopidogrel should not be prohibitive to reloading with prasugrel in patients presenting with acute coronary syndrome and undergoing PCI with respect to bleeding and vascular complications.
The current treatment guidelines recommend the use of a P2Y12 receptor inhibitor in combination with aspirin for patients who present with acute coronary syndromes (ACS) and/or those who are undergoing percutaneous coronary intervention (PCI). Dual antiplatelet therapy with aspirin and clopidogrel has become the treatment mainstay in the past decade. Clopidogrel, however, is a pro-drug requiring dual hepatic activation, which results in delayed onset of action and large interindividual response variability and, consequently, the link to recurrent thrombotic events in those with inadequate platelet inhibition. Newer and more potent P2Y12 receptor inhibitors, such as prasugrel and ticagrelor, have recently been developed to circumvent this problem and provide a viable alternative for patients with ACS who are undergoing PCI. These new agents have been shown to reduce the ischemic end points in clinical trials; however, they carry a greater bleeding risk. Both prasugrel and ticagrelor have received Food and Drug Administration approval and are indicated for use in the United States, for prasugrel, in patients with ACS who are undergoing PCI, and for ticagrelor, for patients with ACS. The present study aimed to compare the in-hospital bleeding complications and outcomes of patients with ACS who were undergoing PCI and received a reloading dose of prasugrel in addition to clopidogrel loading versus prasugrel loading alone.
Methods
The present single-center, retrospective, cohort study included 606 consecutive patients who presented with ACS and were undergoing PCI at the MedStar Washington Hospital Center (Washington, DC), who had received a 60-mg prasugrel loading dose before PCI. The patients were categorized into clopidogrel preloading (300 or 600 mg) followed by prasugrel reloading (CP-load group, n = 90) and prasugrel loading only (P-load group, n = 516) groups. A 10-mg maintenance dose of prasugrel was administered after PCI in both groups. All patients provided written informed consent, and the study complied with the Declaration of Helsinki. The institutional review board at MedStar Washington Hospital Center and the MedStar Health Research Institute (Washington, DC) approved the present study.
PCI was performed according to guidelines current at the procedure. In addition to clopidogrel or prasugrel loading, all patients received aspirin 325 mg before the procedure and were recommended to continue aspirin and prasugrel as maintenance therapy after PCI. The anticoagulation regimens were chosen at the operator’s discretion and included unfractionated heparin adjusted to a targeted activated clotting time or bivalirudin 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour for the duration of the procedure. The interventional strategy and the use of adjunct pharmacotherapy and devices were at the operator’s discretion.
The clinical, procedural, and follow-up data were prospectively collected and stored in a central database. A dedicated data coordinating center performed all data management and analyses. Prespecified clinical and procedural data and in-hospital complications were obtained from the hospital charts, which were reviewed by independent research personnel, who were unaware of the study objectives. Primary source documents were obtained for all events and were adjudicated by physicians not involved in the procedures and unaware of the study objectives.
The primary end point of the present study was in-hospital Thrombolysis In Myocardial Infarction (TIMI) major bleeding, consistent with the key safety end point in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38. The secondary end points were other key bleeding parameters and in-hospital major adverse cardiac events: death, Q-wave myocardial infarction (MI), urgent coronary artery bypass grafting (CABG), and urgent PCI. TIMI major bleeding was defined as any clinically overt bleeding with a hemoglobin decrease of ≥5 g/dl and/or intracranial hemorrhage. TIMI minor bleeding was defined as any clinically overt bleeding with a hemoglobin decrease of 3 to <5 g/dl. Gastrointestinal bleeding was defined as evidence of either upper (“coffee-ground” emesis or endoscopy demonstrating active bleeding) or lower (melena or endoscopy demonstrating active bleeding) gastrointestinal tract bleeding. The need for transfusion was defined as the need for ≥1 U of red blood cells. Major hematoma was defined as hematoma measuring ≥5 cm or requiring transfusions or necessitating prolonged hospitalization. A vascular complication was defined as any of the following at the access site: hematoma ≥5 cm in diameter, arteriovenous fistula, vascular perforation or laceration requiring surgery, pseudoaneurysm, retroperitoneal bleeding, and acute limb ischemia. In-hospital major adverse events were defined as death, Q-wave MI, urgent PCI, urgent CABG, or stroke. Death was defined as all-cause mortality. Q-wave MI was defined as evidence of new Q waves on the electrocardiogram with creatinine kinase-MB ≥3 times the upper limit of normal. Urgent PCI was defined as repeat intervention of the target lesion in the same hospitalization. Urgent CABG was defined as CABG performed in the same hospitalization. Definite stent thrombosis was defined according to the Academic Research Consortium. Angiographic success was defined as residual stenosis of <30% with TIMI grade III flow.
Statistical analysis was performed using SAS, version 9.1 (SAS Institute, Cary, North Carolina). Normally distributed continuous variables are presented as the mean ± SD. Variables not normally distributed are presented as the median ± interquartile range. Categorical variables are expressed as frequencies and percentages. The baseline characteristics were compared using Student’s t test for parametric variables or the Mann-Whitney U test for not normally distributed variables. Categorical variables were compared using chi-square test or Fisher’s exact test, as appropriate. A p value <0.05 is considered statistically significant.
Results
The patient baseline demographics are listed in Table 1 . The 2 groups were matched in terms of gender, race, body mass index, left ventricular ejection fraction, and the co-morbidities of hypertension, peripheral vascular disease, and chronic renal insufficiency. The P-load group was older and had more patients with diabetes, hypercholesterolemia, a history of coronary artery disease, and previous PCI than did the CP-load group. Presentation with biomarker-positive MI (including ST-segment elevation and non–ST-segment elevation MI) and cardiogenic shock were more frequent in the CP-load group.
| Variable | CP-load Group (n = 90) | P-load Group (n = 516) | p Value |
|---|---|---|---|
| Age (yrs) | 56 ± 10 | 59 ± 10 | 0.002 |
| Men | 67 (74.4%) | 373 (72.4%) | 0.69 |
| European American | 57 (63.3%) | 312 (60.5%) | 0.61 |
| African American | 28 (31.1%) | 164 (31.8%) | 0.90 |
| Body mass index (kg/m 2 ) | 30.5 ± 5.9 | 31.2 ± 6.8 | 0.37 |
| Left ventricular ejection fraction (%) | 46 ± 15 | 43 ± 22 | 0.11 |
| Systemic hypertension | 64 (71.1%) | 410 (79.5%) | 0.08 |
| Diabetes mellitus | 18 (20.0%) | 191 (37.0%) | 0.002 |
| Insulin-requiring diabetes mellitus | 2 (2.2%) | 65 (12.6%) | 0.004 |
| Hypercholesterolemia | 51 (56.7%) | 432 (83.7%) | <0.001 |
| Current smoker | 39 (43.3%) | 149 (28.9%) | 0.006 |
| Familial history | 33 (36.7%) | 236 (45.7%) | 0.11 |
| History of coronary artery disease | 15 (16.7%) | 129 (29.1%) | 0.041 |
| Previous myocardial infarction | 11 (12.2%) | 77 (15.0%) | 0.49 |
| Previous percutaneous coronary intervention | 8 (8.9%) | 95 (18.5%) | 0.026 |
| Previous coronary artery bypass grafting | 7 (7.8%) | 53 (10.3%) | 0.46 |
| History of congestive heart failure | 6 (6.7%) | 38 (7.4%) | 0.81 |
| Peripheral vascular disease | 4 (4.4%) | 35 (6.8%) | 0.40 |
| Chronic renal insufficiency | 6 (6.7%) | 53 (10.3%) | 0.29 |
| Clinical presentation | |||
| ST-segment elevation myocardial infarction | 58 (64.4%) | 111 (21.5%) | <0.001 |
| Biomarker-positive myocardial infarction | 72 (80.0%) | 158 (30.6%) | <0.001 |
| Cardiogenic shock | 5 (5.6%) | 7 (1.4%) | 0.022 |
| Medications | |||
| Aspirin | 87 (96.7%) | 496 (96.5%) | 1.00 |
| Warfarin | 6 (6.7%) | 23 (4.5%) | 0.42 |
| Statin | 87 (96.7%) | 439 (85.4%) | 0.003 |
| Angiotensin-converting enzyme inhibitor | 57 (63.3%) | 260 (50.6%) | 0.025 |
| Angiotensin 2 receptor blocker | 14 (15.6%) | 77 (14.9%) | 0.88 |
| β Blocker | 72 (80.0%) | 395 (76.6%) | 0.47 |
The angiographic and procedural characteristics are listed in Table 2 . The lesion characteristics were similar, except for more right coronary artery lesions in the CP-load group and more left anterior descending artery lesions in the P-load group. Intra-aortic balloon pump use showed a trend toward greater use in the CP-load group, and more drug-eluting stents were used in the P-load group. The CP-load group stayed in-hospital and in the intensive care unit significantly longer than did the P-load group. The primary end point of in-hospital TIMI major bleeding was similar in both the CP-load and the P-load group (2.6% vs 2.8%, respectively; Figure 1 ). Also, no significant differences were found in the combined TIMI major or minor bleeding, need for blood transfusion, major hematoma, and vascular complications between the 2 groups. Intracranial (0% vs 0.2%) and retroperitoneal bleeding (0% vs 0.6%) were similar between the 2 groups (p = NS), and no cases of gastrointestinal bleeding developed. The in-hospital clinical outcomes are shown in Figure 2 . All-cause and cardiac mortality were similar, but in-hospital major adverse cardiac events were greater in the CP-load group (5.6% vs 1.6%, p = 0.031), mainly driven by a greater rate of urgent CABG (3.3% vs 0.2%, p = 0.011). No cases of Q-wave MI or stent thrombosis developed. One patient in the P-load group experienced a stroke.
| Variable | CP-load Group (n = 90; n = 118 lesions ) | P-load Group (n = 516; n = 755 lesions) | p Value |
|---|---|---|---|
| Narrowed coronary vessels (n) | 1.61 ± 0.70 | 1.55 ± 0.75 | 0.44 |
| Lesions treated (n) | 1.29 ± 0.59 | 1.42 ± 0.71 | 0.06 |
| Target coronary vessel (n) | |||
| Left main | 0 | 8 (1.1%) | 0.61 |
| Left anterior descending | 35 (29.7%) | 308 (40.8%) | 0.021 |
| Left circumflex | 26 (22.0%) | 183 (24.2%) | 0.60 |
| Right | 56 (47.5%) | 243 (32.2%) | 0.001 |
| Saphenous vein graft | 1 (0.8%) | 13 (1.7%) | 0.71 |
| Lesion characteristics | |||
| American College of Cardiology/American Heart Association type | |||
| A | 12 (10.2%) | 78 (10.3%) | 0.96 |
| B | 47 (39.8%) | 348 (46.0%) | 0.21 |
| C | 59 (50.0%) | 330 (43.7%) | 0.20 |
| In-stent restenosis | 4 (3.4%) | 30 (4.0%) | 1.00 |
| Diameter stenosis (%) | 92 ± 9% | 87 ± 10% | <0.001 |
| Procedural characteristics | |||
| Bivalirudin | 82 (91.1%) | 455 (88.2%) | 0.42 |
| Unfractionated heparin | 14 (15.6%) | 81 (15.7%) | 0.97 |
| Glycoprotein IIb/IIa inhibitor | 11 (12.2%) | 40 (7.8%) | 0.16 |
| Intra-aortic balloon pump | 8 (8.9%) | 20 (3.9%) | 0.05 |
| Bare metal stent | 45 (38.1%) | 130 (17.5%) | <0.001 |
| Drug-eluting stent | 62 (52.5%) | 560 (74.1%) | <0.001 |
| Angiographic success | 116 (98.3%) | 740 (97.9%) | 1.00 |
| Procedure length (min) | 71 ± 48 | 71 ± 47 | 0.80 |
| Contrast amount (ml) | 175 ± 73 | 169 ± 70 | 0.40 |
| Length of hospital stay (days) | 3.2 ± 2.5 | 2.4 ± 2.7 | 0.014 |
| Length of intensive care unit stay (days) | 0.8 ± 1.2 | 0.3 ± 1.0 | <0.001 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
