The clinical safety and efficacy of clopidogrel reloading in patients receiving long-term clopidogrel therapy who present with acute coronary syndromes and undergo percutaneous coronary intervention have not yet been evaluated. The study cohort comprised 1,368 consecutive patients receiving long-term clopidogrel therapy (75 mg/day) who had presented with acute coronary syndromes and underwent coronary artery stent implantation. In total, 926 patients were given a 600-mg clopidogrel loading dose (reload cohort) before cardiac catheterization, while 442 patients were not reloaded (no-reload cohort). Patients who had presented with cardiogenic shock or stable angina were excluded. The 2 cohorts were well matched for the conventional risk factors for coronary artery disease. The analyzed clinical end points of death (1.1% vs 0.9%, p = 0.77), death or Q-wave myocardial infarction (0.9% vs 0.9%, p = 1.0), target lesion revascularization (0.2% vs 0.8%, p = 0.45), target vessel revascularization (1.1% vs 1.1%, p = 1.0), and major adverse cardiac events (2.0% vs 1.8%, p = 0.8) were similar between the no-reload and reload groups at 30 days. The in-hospital rates of major bleeding and gastrointestinal bleeding were also similar between the 2 cohorts. There were no cases of definite stent thrombosis. In conclusion, patients receiving long-term clopidogrel therapy who present with acute coronary syndromes do not gain any clinical benefit from additional reloading with clopidogrel.
Platelet activation and aggregation play critical roles in the pathogenesis of the entire spectrum of acute coronary syndromes. Activated platelets have been shown to mediate vessel inflammation and cause mechanical obstruction of the coronary lumen. This central role of platelets has served as the rationale for evaluation of dual-antiplatelet therapy in the landmark clinical trials Percutaneous Coronary Intervention–Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO), both of which demonstrated the beneficial effects of such adjunctive therapy in patients who undergo percutaneous coronary intervention (PCI).
In patients established on clopidogrel therapy, aggregometric studies have demonstrated that an additional 600-mg loading dose may lead to further reductions in residual platelet activity, although the relation between such laboratory measurements and clinical events remains to be determined. The aim of this study was therefore to evaluate whether clopidogrel reloading (600 mg) in patients who were receiving long-term clopidogrel therapy and presented with acute coronary syndromes provided any clinical benefits.
Methods
This single-center, retrospective study comprised 1,368 consecutive patients receiving long-term clopidogrel therapy (75 mg/day) who had presented with acute coronary syndromes and underwent coronary artery stent implantation at Washington Hospital Center from 2003 to 2009. In total, 926 patients were given a 600-mg clopidogrel loading dose (reload cohort) before cardiac catheterization, while 442 patients were not reloaded (no-reload cohort). Patients who had presented with cardiogenic shock or stable angina pectoris were excluded. All patients provided written informed consent. The study complied with the Declaration of Helsinki for investigation in human beings and was approved by the institutional ethics committee of Washington Hospital Center. The procedures were performed according to standard clinical guidelines. In all cases, the interventional strategy, as well as the use of adjunctive devices and pharmacotherapy, was at the discretion of the operating interventional cardiologist. All patients were advised to continue aspirin 325 mg/day indefinitely and clopidogrel 75 mg/day for ≥12 months. Follow-up data at 30 days were obtained by telephone contact, mailed questionnaire, or outpatient review.
Analyzed clinical end points were the 30-day rates of death, death or Q-wave myocardial infarction, target lesion revascularization, target vessel revascularization (TVR), definite stent thrombosis, and major adverse cardiac events, defined as the composite of death, Q-wave myocardial infarction, or TVR. Long-term clopidogrel therapy was defined as clopidogrel therapy at 75 mg/day for at least the preceding 5 days before hospital admission. Q-wave myocardial infarction was defined as evidence of new Q waves on electrocardiography at the time of myocardial infarction, the latter being defined as a total creatinine kinase increase ≥2 times the upper limit of normal and/or creatinine kinase-MB ≥20 ng/ml together with symptoms and/or ischemic electrocardiographic changes. Hypercholesterolemia was defined as fasting cholesterol >250 mg/dl or the use of lipid-lowering therapy. Systemic hypertension was defined as blood pressure >140/90 mm Hg or the use of antihypertensive therapy. Renal impairment was defined as serum creatinine >1.2 mg/dl. Congestive heart failure was defined as evidence of fluid retention due to cardiac causes before admission. Angiographic success was defined as postprocedural stenosis ≤30% and Thrombolysis In Myocardial Infarction (TIMI) flow grade 3. Gastrointestinal bleeding was defined as evidence of an upper (coffee ground emesis, endoscopy demonstrating active bleeding) or lower (melena, hematochezia, or endoscopy demonstrating an active bleeding site) gastrointestinal bleed. Target lesion revascularization was defined as ischemia-driven percutaneous or surgical repeat intervention in the stent or within 5 mm proximal or distal to the stent. Stent thrombosis was defined in accordance with the Academic Research Consortium definitions as definite, probable, or possible.
Statistical analysis was performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina). Continuous variables and categorical variables are expressed as mean ± SD and percentages, respectively. Student’s t tests were used to compare continuous variables, and chi-square or Fisher’s exact tests were used to compare categorical variables. A p value <0.05 was considered statistically significant.
Results
The baseline characteristics of the patients are listed in Table 1 . The 2 cohorts were well matched for age, gender, and the conventional risk factors for coronary artery disease. Presentation with acute myocardial infarction (9.3% vs 10.7%, p = 0.42) and unstable angina pectoris (90.7% vs 89.3%, p = 0.25) were also similar. The no-reload cohort had a higher proportion of patients with histories of myocardial infarction, coronary artery bypass surgery, and renal impairment. The angiographic and procedural characteristics are listed in Table 2 . The 2 cohorts differed in American College of Cardiology/American Heart Association lesion type, the use of intravascular ultrasound (58.8% vs 56.1%, p = 0.04), and bivalirudin (78.1% vs 83.9%, p = 0.008), as well as the number (1.4 ± 0.8 vs 1.5 ± 0.9, p = 0.03) and diameter (2.9 ± 0.4 vs 3.1 ± 1.3 mm, p = 0.002) of drug-eluting stents.
| Variable | No | Yes | p Value |
|---|---|---|---|
| (n = 442) | (n = 926) | ||
| Age (years) | 65.3 ± 11.5 | 64.6 ± 12.3 | 0.30 |
| Men | 270 (61.1%) | 560 (61.4%) | 0.90 |
| Systemic hypertension ⁎ | 392 (88.7%) | 846 (91.7%) | 0.08 |
| Diabetes mellitus | 179 (40.5%) | 386 (41.7%) | 0.70 |
| Hypercholesterolemia † | 412 (93.4%) | 870 (94%) | 0.66 |
| Current smoker | 82 (18.6%) | 188 (20.3%) | 0.45 |
| Acute myocardial infarction | 41 (9.3%) | 99 (10.7%) | 0.42 |
| Unstable angina pectoris | 401 (90.7%) | 827 (89.3%) | 0.25 |
| Body mass index (kg/m 2 ) | 29.5 ± 6.3 | 30.2 ± 6.4 | 0.06 |
| Previous myocardial infarction | 218 (49.4%) | 358 (38.7%) | <0.001 |
| Previous PCI | 302 (68.4%) | 590 (63.7%) | 0.10 |
| Previous coronary artery bypass grafting | 172 (39%) | 295 (32%) | 0.01 |
| Previous heart failure | 54 (12.3%) | 120 (13%) | 0.72 |
| Previous chronic renal impairment | 84 (19.3%) | 134 (14.5%) | 0.02 |
⁎ Blood pressure >140/90 mm Hg or the use of antihypertensive therapy.
† Fasting cholesterol >250 mg/dl or the use of lipid-lowering therapy.
| Variable | No | Yes | p Value |
|---|---|---|---|
| (n = 781) | (n = 1,604) | ||
| Angiographic | |||
| Coronary narrowing location | 0.19 | ||
| Right | 225 (28.8%) | 580 (36.2%) | |
| Left main stem | 22 (2.8%) | 34 (2.1%) | |
| Left anterior descending | 259 (33.2%) | 442 (27.6%) | |
| Left circumflex | 187 (23.9%) | 395 (24.6%) | |
| Saphenous vein graft | 76 (9.7%) | 143 (8.9%) | |
| American College of Cardiology/American Heart Association lesion type | 0.001 | ||
| A | 55 (7.5%) | 123 (7.9%) | |
| B1 and B2 | 474 (64.5%) | 945 (60.6%) | |
| C | 206 (28%) | 491 (31.5%) | |
| Angiographic success | 764 (97.8%) | 1,586 (98.9%) | 0.56 |
| No reflow | 2 (0.3%) | 1 (0.1%) | 0.23 |
| Intravascular ultrasound | 459 (58.8%) | 900 (56.1%) | 0.04 |
| Procedural | (n = 442) | (n = 926) | |
| Drug-eluting stents | |||
| Number implanted | 1.4 ± 0.8 | 1.5 ± 0.9 | 0.03 |
| Average length (mm) | 20.1 ± 6.5 | 19.7 ± 7.4 | 0.34 |
| Average diameter (mm) | 2.9 ± 0.4 | 3.1 ± 1.3 | 0.002 |
| Glycoprotein IIb/IIIa inhibitor | 29 (6.6%) | 49 (5.3%) | 0.35 |
| Bivalirudin | 345 (78.1%) | 777 (83.9%) | 0.008 |
In-hospital complications are listed in Table 3 . The in-hospital rates of major bleeding (1.4% vs 1.1%, p = 0.66) and gastrointestinal bleeding (0.9% vs 0.4%, p = 0.28) were also similar in the 2 cohorts, as were the rates of all other examined clinical parameters. The 30-day clinical outcomes are listed in Table 4 . The 2 cohorts had similar rates of death (1.1% vs 0.9%, p = 0.77), death or Q-wave myocardial infarction (0.9% vs 0.9%, p = 1.0), target lesion revascularization (0.2% vs 0.8%, p = 0.45), TVR (1.1% vs 1.1%, p = 1.0), and major adverse cardiac events (2.0% vs 1.8%, p = 0.8). There were no cases of definite stent thrombosis.
