In large clinical trials enrolling patients with acute coronary syndromes, a high loading dose of clopidogrel (600 mg) has been found to be more effective compared to a low loading dose (300 mg). However, the applicability of these data to stable patients who undergo elective percutaneous coronary intervention is still unclear. A total of 400 patients who underwent elective PCI were prospectively randomized to receive either 600 mg (n = 200) or 300 mg (n = 200) of clopidogrel, followed by a daily maintenance dose of 75 mg. The primary end point was the presence of major adverse cardiovascular events (combined death, myocardial infarction, acute neurologic event, stent thrombosis, and need for percutaneous or surgical revascularization of the target vessel) during hospitalization and at 30 days. The secondary end point was periprocedural vascular complications, major bleeding, and cardiac enzyme elevation. There were no differences in the primary end point among the groups immediately after the procedure (3.5% of patients in the 300-mg group vs 4.5% of those in the 600-mg group, p = 0.799) or at 30 days (6% vs 5%, respectively, p = 0.826). The rates of periprocedural vascular complications (2.5% vs 3%, respectively, p = 1.00), bleeding complications (9% vs 8.5%, respectively, p = 1.00), and cardiac enzyme elevation (11% vs 15.5%, respectively, p = 0.317) were similar between the 2 groups. In conclusion, adverse cardiovascular events and bleeding complications during the initial hospitalization and at 30-day follow-up were similar when a 600-mg loading dose of clopidogrel was used compared to the conventional dose of 300 mg.
Current guidelines, based on a single study, and conventional practice recommend a 600-mg loading dose of clopidogrel for patients who undergo percutaneous coronary intervention (PCI). However, although evidence seems to be clear for that particular clinical indication, the benefit of using of high doses of clopidogrel in more stable patients (elective PCI) is still unclear. The dosis de carga de Clopidogrel Adecuada Durante Intervencionismo Coronario Electivo (CADICE) study aimed to determine whether higher loading doses of clopidogrel are more beneficial than the conventional dose in stable elective patients who undergo primary PCI.
Methods
The CADICE study was a double-blind, randomized clinical trial conducted from January 2006 to May 2007 at the Corbic Research Institute (Envigado, Colombia). The study was approved by the local ethics committee, and an independent monitoring group carried out the performance of the study. There was no external financial support by any laboratory involved in the procurement of clopidogrel. We included all elective patients with typical effort angina, positive stress test results (conventional stress testing, myocardial perfusion imaging, or stress echocardiography) and indications for coronary angiography. Exclusion criteria were (1) unstable angina; (2) acute myocardial infarction with or without ST-segment elevation; (3) absence of symptoms, with elevated baseline levels of creatine kinase-MB (CK-MB) and troponins above the upper limit of normal; (4) contraindications to antithrombotic or antiplatelet therapy; (5) high baseline risk for bleeding (recent bleeding peptic ulcer); and (6) previous use of clopidogrel in the 10 days before the procedure.
A total of 400 patients who underwent elective coronary intervention were enrolled and randomized to receive an initial loading dose of clopidogrel of 600 mg (n = 200) or 300 mg (n = 200), followed by a daily maintenance dose of 75 mg for ≥6 weeks if treated with bare-metal stents (n = 266 [66.5%]) or 6 to 12 months if treated with drug-eluting stents (n=134 [33.5%]). Microsoft Excel (Microsoft Corporation, Redmond, Washington) was used to generate randomization. The interventional cardiologist who performed the procedure was blinded to the randomization group to which the patient had been assigned. All interventions were performed using femoral puncture access (standard Seldinger technique). All patients were treated with aspirin (300 mg/day) for ≥6 weeks after the intervention and then 100 mg/day at the physician’s discretion on the basis of the patient and the type of stent used. Anticoagulation of these patients before PCI was performed with an intravenous dose of low–molecular weight heparin (enoxaparin 0.5 mg/kg applied 5 minutes before angioplasty). The use of inhibitors of glycoprotein IIb/IIIa was allowed only during the coronary intervention at the discretion of the operator. The procedure was defined as successful if distal postintervention Thrombolysis In Myocardial Infarction (TIMI) flow grade was 3 (complete perfusion) and <30% residual stenosis at the site treated with coronary stenting was achieved. The femoral sheaths were removed without activated clotting time monitoring 4 hours after the intervention, and resumption of anticoagulation with unfractionated heparin or low–molecular weight heparin only was allowed at the discretion of the operator. Blood samples of all patients were collected from the peripheral vein at baseline and 12 to 24 hours after coronary intervention to assess total CK-MB levels. Additional samples were measured if symptoms suggestive of myocardial ischemia after intervention were noticed. Total CK-MB assessment was performed by immunoassay in which the upper limit of normal was defined as the 99th percentile of the normal population, with a total bias of 10%. The normal values for our laboratory was a limit of 18 IU/L for CK-MB. Electrocardiography was performed before the procedure, immediately afterward, the next day, and in the event of chest pain. Electrocardiograms were evaluated by 1 of the investigators to determine the presence of ST-segment elevation or the presence of other signs of ischemia. Patients underwent follow-up telephone interviews 30 days after PCI to evaluate primary and secondary end points.
The primary end point was combined death, myocardial infarction with or without ST-segment elevation, neurologic event, stent thrombosis, and need for percutaneous or surgical revascularization of the target vessel. The primary end point was assessed during hospitalization and at 30 days. We defined acute myocardial infarction with ST-segment elevation as the presence of chest pain lasting >30 minutes associated with ST-segment elevation >0.1 mV in ≥2 contiguous leads. Non–ST-segment elevation myocardial infarction was defined as chest pain accompanied by postprocedural enzyme elevation of CK-MB ≥3 times the normal reference value. We defined the presence of neurologic events as episodes of transient cerebral ischemia or embolic or hemorrhagic cerebrovascular disease (confirmed by a neurologist). To determine the presence of stent thrombosis, diagnostic coronary angiography was required. Secondary end points included (1) minimum elevation of cardiac markers 3 times the normal range, with or without associated chest pain; (2) bleeding complications, including major bleeding (defined as a decrease in hematocrit of >15% or intracranial bleeding), decrease in platelet count to <100,000, and minor bleeding not requiring transfusion; and (3) vascular complications, such as hematoma >5 cm at the puncture site, development of a postprocedural pseudoaneurysm, or arteriovenous fistula at the puncture site.
All information was collected in an Access database (Microsoft Corporation) and processed in Excel and SPSS version 13 (SPSS, Inc., Chicago, Illinois). Chi-square tests were used to compare categorical variables and unpaired Student’s t tests or Mann-Whitney U tests to compare continuous variables. Using Epi Info version 6.0 (Centers for Disease Control and Prevention, Atlanta, Georgia), sample power of 80% was calculated, and a confidence interval of 95% was calculated. For this calculation, a ratio of conventional-dose patients (clopidogrel 300 mg) to higher dose patients (clopidogrel 600 mg) of 1:1 was determined. According to a survey data from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty 2 (ARMYDA-2) study, the 600-mg dose of clopidogrel may reduce major adverse cardiovascular events by 67%, with reported results of 4% in the 600-mg group and 12% in the 300-mg group. Thus, the present sample size of 400 patients would provide >80% power to detect a difference, with an α value of 0.05.
Results
The baseline clinical variables of the 2 groups are listed in Tables 1 and 2 . Hypertension and dyslipidemia were the most common risk factors in the 2 groups. The most frequent angiographic lesions treated were type B2 (53% of patients in the 300-mg group and 61% of those in the 600-mg group). Most patients started the procedure with initial TIMI grade 3 flow (94.5% of patients in the 300-mg group and 97% of those in the 600-mg group), and almost all patients completed the procedure with TIMI grade 3 flow (100% of 300-mg patients and 99% of 600-mg patients). Table 2 lists the treatment characteristics and lesions distribution.
| Variable | Clopidogrel 300 mg (n = 200) | Clopidogrel 600 mg (n = 200) | p Value |
|---|---|---|---|
| Age (years) | 64.3 ± 10.7 | 64.5 ± 10.9 | 0.46 |
| Men | 112 (56%) | 107 (53.5%) | 0.62 |
| Hypertension | 179 (89.5%) | 177 (88.5%) | 0.75 |
| β blockers | 123 (61.5%) | 136 (68%) | 0.17 |
| ACE inhibitors | 107 (53.5%) | 114 (57%) | 0.48 |
| Calcium antagonists | 38 (19%) | 49 (24.5%) | 0.18 |
| Statins | 132 (66%) | 137 (68.5%) | 0.59 |
| Bypass at >3 months | 38 (19%) | 24 (12%) | 0.05 |
| Previous PCI | 63 (31.5%) | 59 (29.5%) | 0.66 |
| Diabetes mellitus | 46 (23%) | 41 (20.5%) | 0.55 |
| Active smokers | 31 (15.5%) | 20 (10%) | 0.01 |
| Dyslipidemia ⁎ | 165 (82.5%) | 166 (83%) | 0.90 |
| Previous myocardial infarction | 30 (15%) | 18 (9%) | 0.65 |
| Creatinine >1.5 mg | 6 (3%) | 6 (3%) | 1.00 |
⁎ Dyslipidemia was defined as abnormal plasma lipid status, includes elevation of total cholesterol, low-density lipoprotein cholesterol, or triglycerides, as well as low levels of high-density lipoprotein cholesterol.
| Variable | Clopidogrel 300 mg (n = 200) | Clopidogrel 600 mg (n = 200) | p Value |
|---|---|---|---|
| Left main coronary artery | 5 (2.5%) | 2 (1%) | 0.25 |
| Left anterior descending coronary artery | 109 (54.5%) | 111 (55.5%) | 0.84 |
| Left circumflex coronary artery | 64 (32%) | 72 (36%) | 0.40 |
| Right coronary artery | 102 (51%) | 77 (38.5%) | 0.01 |
| Mammary or saphenous graft | 5 (2.5%) | 2 (1%) | 0.25 |
| Restenotic lesions | 35 (17.5%) | 32 (16%) | 0.69 |
| Lesion type B2 | 106 (53%) | 122 (61%) | 0.28 |
| Number of vessels treated | 1.63 ± 2.1 | 1.38 ± 0.59 | 0.17 |
| Number of lesions treated | 1.97 ± 1.01 | 1.85 ± 0.98 | 0.18 |
| Number of stents used | 1.91 ± 1.02 | 1.83 ± 0.99 | 0.78 |
| Stent length (mm) | 26.0 ± 41.2 | 38.8 ± 24.8 | 0.36 |
| Stent diameter (mm) | 3.06 ± 0.51 | 2.30 ± 3.24 | 0.27 |
| Stent implantation pressure (atm) | 12.5 ± 3.7 | 12.9 ± 3.1 | 0.56 |
| Initial TIMI grade 3 flow | 189 (94.5%) | 194 (97%) | 0.53 |
| Final TIMI grade 3 flow | 200 (100%) | 198 (99%) | 0.52 |
| Coronary dissection | 3 (1.5%) | 7 (3.5%) | 0.20 |
| Branch compromise during PCI | 6 (3%) | 16 (8%) | 0.03 |
No difference was found between the 2 groups when the in-hospital primary end point was assessed. This was found in 3.5% of patients in the 300-mg group and 4.5% of patients in the 600-mg group (p = 0.80; Table 3 ). At 30 days after the intervention, the combined outcome was also similar (presenting in 6% of patients in the 300-mg group and 5% of patients in the 600-mg group, p = 0.83; Table 4 ).
