Current guidelines recommend pretreatment with a loading dose of clopidogrel before percutaneous coronary intervention (PCI) to reduce the incidence of periprocedural myocardial infarctions in patients undergoing PCI. However, because of concerns about postoperative bleeding, clopidogrel loading is frequently administered either immediately before or after PCI. Using the 2004/2005 Cornell Angioplasty Registry, we analyzed 1,041 consecutive patients undergoing urgent PCI for non–ST-elevation acute coronary syndrome. The patients were divided into 2 groups. The first group was the “preangiography clopidogrel therapy” group for those receiving chronic 75-mg clopidogrel therapy or receiving a clopidogrel loading dose (300 mg ≥12 hours or 600 mg ≥2 hours) before angiography according to the guidelines. The second group was the “in-laboratory 600-mg clopidogrel loading” group for the patients who received the clopidogrel loading dose <2 hours before PCI (immediately before or after PCI). The mean clinical follow-up was 23.8 ± 7.6 months. Of the 1,041 study patients, 467 (44.9%) received clopidogrel before angiography and 574 (55.1%) received in-laboratory loading. The incidence of in-hospital death (0.4% vs 0.5%, respectively; p = 1.000), myocardial infarction (7.7% vs 6.8%, respectively; p = 0.630), and major adverse cardiovascular events (8.4% vs 7.1%, respectively; p = 0.484) were similar between the 2 groups. The Kaplan-Meier long-term survival rates were similar in the 2 groups (93.4% vs 95.8%, p log-rank = 0.152). After multivariate Cox regression analysis, administration of a 600-mg clopidogrel loading dose <2 hours before PCI did not have a significant effect on long-term mortality (hazard ratio 0.97, 95% confidence interval 0.54 to 1.75, p = 0.927). In conclusion, treatment with a 600-mg loading dose <2 hours before PCI is associated with similar short-term ischemic outcomes and long-term mortality compared to the currently recommended clopidogrel pretreatment regimen.
Dual antiplatelet therapy with aspirin and a thienopyridine before percutaneous coronary intervention (PCI) has been found to decrease the occurrence of periprocedural thrombotic events. Patients with acute coronary syndromes (ACS) represent a high-risk population with a greater degree of platelet activation at baseline and lower platelet inhibition in response to antiplatelet therapy. Pretreatment with a 300-mg loading dose of clopidogrel, a P2Y12 adenosine diphosphate-receptor antagonist, has been consistently associated with a reduction in cardiovascular events after PCI. A high-loading dose with 600 mg of clopidogrel provides a greater degree of platelet inhibition than a 300-mg dose, and the maximum inhibition occurs after 2 hours of clopidogrel administration. The 2007 update of the American College of Cardiology/American Heart Association guidelines for PCI have recommended a periprocedural clopidogrel loading dose of 600 mg; however, the timing of clopidogrel treatment has not been clearly specified. A strategy of in-laboratory high-dose clopidogrel loading with 600 mg once the coronary anatomy has been defined allows the administration of clopidogrel only to patients requiring an “ad hoc” PCI and eliminates the need to wait for ≥5 to 7 days in those undergoing urgent surgery. The effectiveness of an in-laboratory 600-mg clopidogrel loading dose in higher risk patients with ACS has not been well established. Therefore, the goal of the present retrospective analysis was to evaluate the safety and efficacy of a high-dose (600-mg) clopidogrel load administered <2 hours before PCI (immediately before or after PCI) compared to “adequately pretreated” patients undergoing PCI for ACS.
Methods
All patients undergoing PCI at the New York Presbyterian Hospital, Weill Cornell Medical College are enrolled in the Cornell Angioplasty Registry. A standard case report form delineating comprehensive patient demographics, preintervention clinical status, procedural findings, and in-hospital complications is completed for each PCI performed. Immediate and in-hospital events are recorded. Patient follow-up data were obtained from publicly available mortality data through the Social Security Death Index and through regularly scheduled telephone interviews.
The present study included all consecutive patients undergoing PCI for non–ST-elevation (NSTE) ACS included in the database for January 1, 2004 through December 31, 2005. For patients who had undergone multiple PCIs during the defined study period, only the initial PCI was included in the present analysis. Patients presenting with stable coronary artery disease (stable angina or positive stress test results) for elective procedures were excluded. Patients presenting with ST-elevation myocardial infarction within 7 days or less or hemodynamic instability/shock, those who had been receiving thrombolytic therapy for ≤7 days, and those with severe renal insufficiency (serum creatinine ≥4 mg/dl) were excluded. The institutional review board of Cornell University Weill Medical College approved the study.
Aspirin (325 mg) was routinely administered before PCI. Clopidogrel treatment was categorized into 2 groups, each with 2 subgroups. The first group received clopidogrel before angiography; one subgroup consisted of patients who had been receiving chronic clopidogrel therapy (75 mg/day for ≥5 days), and the second subgroup consisted of clopidogrel-naive patients, who received pretreatment with clopidogrel 300 mg ≥12 hours or 600 mg ≥2 hours before PCI. The second group received an in-laboratory peri-PCI high-dose clopidogrel load with 600 mg after angiography. The first subgroup received 600 mg of clopidogrel after angiography and before PCI, and the second subgroup received a 600-mg clopidogrel loading dose immediately after PCI (within 30 minutes of PCI). We excluded patients with missing data regarding the dose or timing of clopidogrel administration. We also excluded patients who had received <600 mg of clopidogrel after angiography and immediately before or after PCI. Finally, patients who received ticlopidine were also excluded from the analysis.
After the clopidogrel loading dose, patients with a bare metal stent received 75 mg/day clopidogrel for ≥1 month and those with a drug-eluting stent for ≥3 to 6 months and ideally for ≥12 months according to the guidelines.
The administration of unfractionated heparin, bivalirudin, intravenous glycoprotein IIb/IIIa inhibitors, the choice of a bare metal or drug-eluting stent, and the dosage and timing of thienopyridine pretreatment were at the discretion of the physician. Bivalirudin was administered as a 0.75-mg/kg intravenous bolus dose, followed by an infusion of 1.75 mg/kg/hour for the duration of the PCI procedure. Upstream administration of bivalirudin before PCI was not practiced during the study period. We excluded patients who had received upstream glycoprotein IIb/IIIa inhibition within 12 hours of PCI. Provisional glycoprotein IIb/IIIa inhibition, in addition to unfractionated heparin or bivalirudin, was provided during PCI at any point for angiographic or procedural complications. Abciximab was administered as a 0.25-mg/kg bolus and a 0.125-μg/kg/min (maximum 10-μg/min) infusion for 12 hours. Eptifibatide was administered as two 180-μg/kg boluses, 10 minutes apart, followed by a 2.0-μg/kg/min infusion for 18 hours. Unfractionated heparin was administered as an initial bolus of 30 to 70 U/kg to reach a target activated clotting time of 200 to 250 seconds when used with glycoprotein IIb/IIIa inhibition and as a bolus of 50 to 100 U/kg to reach a target activated clotting time of 250 to 300 seconds when used without glycoprotein IIb/IIIa inhibitors.
The baseline patient clinical characteristics and angiographic data of patients undergoing the strategy of “preangiography clopidogrel treatment” were compared to those undergoing PCI with a strategy of “in-laboratory 600-mg clopidogrel loading.” The primary end points analyzed were the incidence of in-hospital myocardial infarctions and major adverse cardiovascular events (MACE). Long-term mortality data were obtained for 100% of the patients, with a mean follow-up period of 23.8 ± 7.6 months.
Myocardial infarction before PCI was defined as any elevation of creatine kinase-MB or troponin I level greater than the laboratory upper limits of normal. Myocardial infarction after PCI was defined as a creatine kinase-MB level of ≥3 times the upper limits of normal within 24 hours after PCI and ≥50% increase greater than the preprocedural levels. Multivessel disease was defined as the presence of >70% lesion in ≥2 major coronary arteries/branches or a left main coronary artery lesion. Multivessel PCI was defined as a coronary intervention in ≥2 major coronary arteries/branches or a left main coronary artery. Multilesion PCI was defined as a coronary intervention in ≥2 lesions of a single coronary artery or multiple coronary arteries. Congestive heart failure referred to patients with New York Heart Association class III or IV heart failure during admission. MACE was defined as post-PCI death, post-PCI myocardial infarction, emergency cardiac surgery, emergency PCI, or a cerebral vascular accident. Vascular injury referred to an access site complication requiring mechanical intervention. Peripheral vascular disease included carotid, aortofemoral, or lower extremity vascular disease documented by a radiologic study, a history of a vascular intervention or of a cerebral vascular accident. Major bleeding was defined as a decrease in hemoglobin ≥4 g/dl. Minor bleeding was defined as a decrease in hemoglobin of ≥2 and <4 g/dl. Angiographic success was defined as a final stenosis of ≤20% of the target vessel reference diameter.
Data management and analysis were performed using Statistical Package for Social Sciences, version 12.0 (SPSS, Chicago, Illinois). Data are presented as the mean ± SD for continuous variables or as proportions for dichotomous variables. Differences in prevalence between groups were compared using the chi-square test or Fisher’s exact test for dichotomous variables. Mean values for continuous variables were compared using the Student t test. Stepwise multivariate logistic regression analysis was performed to determine the independent effect of the “in-laboratory 600-mg clopidogrel loading” strategy on the incidence of in-hospital myocardial infarction, MACE, and bleeding complications after PCI. To test the independence of the “in-laboratory 600-mg clopidogrel loading” strategy as a predictor of long-term mortality, the “in-laboratory 600-mg clopidogrel loading” strategy was entered into the multivariate Cox proportional hazards model. Mortality rates were calculated and plotted according to the Kaplan-Meier methods, and comparisons between the groups were performed using the log-rank statistic. A subgroup of patients presenting with positive troponin I levels on admission and a subgroup treated with bivalirudin as a periprocedural anticoagulant were evaluated for in-hospital outcomes and long-term mortality. For all tests, a 2-tailed value of p <0.05 was required for statistical significance.
Results
A total of 3,611 PCIs were performed on 3,105 consecutive patients undergoing urgent or elective PCI during the study period. Of these patients, 601 presented with ST-segment elevation myocardial infarction within 7 days or less or hemodynamic instability/shock, had received thrombolytic therapy for ≤7 days, or had severe renal insufficiency (serum creatinine ≥4 mg/dl) and 846 patients presented with stable coronary artery disease (stable angina or positive stress test results) for elective procedures. These 1,447 patients were excluded from the analysis. Also, 406 patients had received <600 mg of the in-laboratory clopidogrel load after angiography and were excluded. The data for either the dose or timing of clopidogrel administration before PCI were missing for 211 patients. The remaining 1,041 patients were included in the final analysis ( Figure 1 ). In the “preangiography treatment” group, most patients (89.9%) had been receiving chronic clopidogrel therapy of 75 mg/day for ≥5 days. A number of patients taking chronic clopidogrel therapy received a repeat loading dose of clopidogrel either immediately before (14.3%) or after (29.8%) PCI. In the “in-laboratory 600-mg loading” group, most patients (83.1%) received the 600-mg clopidogrel loading dose immediately after PCI completion.
The baseline clinical characteristics of patients undergoing PCI with either the clopidogrel loading strategy are listed in Table 1 . Forty percent of patients had positive troponin I levels on admission. Most patients were undergoing angiography for either urgent or emergent indications (66.7%; Table 2 ). Patients receiving clopidogrel therapy before angiography had more adverse clinical characteristics. They were more likely to present with diabetes mellitus, previous heart failure, previous myocardial infarction, and previous PCI or bypass surgery and were more likely to have lower baseline hemoglobin levels and creatinine clearance. Femoral vascular access was used in >99% of the procedures.
| Variable | Clopidogrel Before Angiography (n = 467) | Clopidogrel In-Laboratory 600-mg Loading Dose (n = 574) | p Value |
|---|---|---|---|
| Age (years) | 67.1 ± 12.2 | 67.3 ± 11.7 | 0.801 |
| Men | 66.2% | 71.4% | 0.069 |
| White | 75.4% | 85.4% | <0.001 |
| Diabetes mellitus | 37.7% | 25.8% | <0.001 |
| Body mass index (kg/m 2 ) | 28.6 ± 5.3 | 28.2 ± 5.4 | 0.276 |
| Current congestive heart failure | 12.2% | 9.9% | 0.272 |
| Left ventricular ejection fraction (%) | 49.0 ± 10.6 | 50.6 ± 10.0 | 0.019 |
| Cardiac biomarker level elevation | 39.6% | 39.9% | 0.949 |
| Creatine kinase-MB elevation ⁎ | 11.6% | 11.8% | 0.923 |
| Troponin I elevation ⁎ | 39.0% | 38.3% | 0.848 |
| Canadian Cardiovascular Society Angina class III/IV | 72.2% | 69.2% | 0.306 |
| Chronic obstructive pulmonary disease | 6.9% | 3.8% | 0.035 |
| Peripheral vascular disease | 7.3% | 5.1% | 0.151 |
| Previous stroke | 9.0% | 7.3% | 0.360 |
| Previous congestive heart failure | 4.5% | 1.4% | 0.004 |
| Previous myocardial infarction | 56.1% | 41.5% | <0.001 |
| Previous percutaneous coronary intervention | 39.4% | 23.0% | <0.001 |
| Previous coronary bypass surgery | 19.9% | 12.0% | 0.001 |
| Hemoglobin level (g/dl) | 12.9 ± 1.8 | 13.3 ± 1.7 | 0.001 |
| Creatinine clearance (ml/min) | 74.2 ± 31.0 | 77.0 ± 33.1 | 0.165 |
| Chronic clopidogrel therapy | 89.9% | 0% | — |
| Preangiography clopidogrel therapy | 10.1% | 0% | — |
| 300 mg ≥12 hours | 85.1% | 0% | — |
| 600 mg ≥2 hours | 14.9% | 0% | — |
| Pre-percutaneous coronary intervention clopidogrel therapy | 14.3% | 16.9% | 0.268 |
| Post-percutaneous coronary intervention clopidogrel therapy | 29.8% | 83.1% | <0.001 |
| Pre-percutaneous coronary intervention aspirin therapy | 99.4% | 98.8% | 0.526 |
⁎ Elevations of creatine kinase-MB or troponin I levels were defined as creatine kinase-MB or troponin I levels of ≥1 times the upper limit of normal within 24 hours after PCI.
| Variable | Clopidogrel Before Angiography (n = 467) | Clopidogrel In-Laboratory 600-mg Loading Dose (n = 574) | p Value |
|---|---|---|---|
| Nature of procedure | |||
| Urgent | 68.1% | 62.0% | 0.043 |
| Emergent | 1.3% | 2.4% | 0.256 |
| No. of narrowed coronary arteries | |||
| 1 | 46.5% | 46.7% | 0.950 |
| 2 | 37.7% | 37.1% | 0.847 |
| 3 | 15.0% | 15.5% | 0.863 |
| Multivessel or left main disease | 53.5% | 53.3% | 0.950 |
| Target coronary artery percutaneous coronary intervention | |||
| Left anterior descending | 45.8% | 50.5% | 0.135 |
| Right | 28.5% | 29.1% | 0.837 |
| Left circumflex | 31.5% | 32.1% | 0.894 |
| Left main | 2.4% | 1.0% | 0.139 |
| Saphenous vein graft | 7.7% | 2.6% | <0.001 |
| Multivessel or left main percutaneous coronary intervention | 13.7% | 15.0% | 0.595 |
| Multilesion percutaneous coronary intervention | 46.7% | 49.0% | 0.493 |
| Device used | |||
| Stent | 94.6% | 97.2% | 0.038 |
| Drug-eluting stent | 85.7% | 90.6% | 0.015 |
| Sirolimus-eluting stent | 66.0% | 70.9% | 0.093 |
| Paclitaxel-eluting stent | 22.9% | 22.0% | 0.709 |
| Cutting balloon | 11.8% | 15.3% | 0.104 |
| Rotational atherectomy | 2.4% | 2.1% | 0.834 |
| Intravascular ultrasound | 15.8% | 17.9% | 0.407 |
| Glycoprotein IIb/IIIa | 46.7% | 52.6% | 0.062 |
| Abciximab | 8.8% | 5.6% | 0.051 |
| Eptifibatide or tirofiban | 37.9% | 47.0% | 0.003 |
| Bivalirudin administration | 58.2% | 53.5% | 0.132 |
| Stenosis severity before percutaneous coronary intervention (%) | 84.6 ± 11.1 | 84.2 ± 11.6 | 0.572 |
| Stenosis severity after percutaneous coronary intervention (%) | 3.2 ± 10.9 | 2.2 ± 8.1 | 0.118 |
The angiographic and procedural characteristics are summarized in Table 2 . The use of stents (96%) or drug-eluting stents (88%) was high in this population, with slightly greater stent use in the “in-laboratory 600-mg clopidogrel load” group. The incidence of multivessel or left main disease was similarly high in both groups (53%), with a similar incidence of multivessel or multilesion PCI performed. Bivalirudin was used in 56% of patients and glycoprotein IIb/IIIa inhibitors in 50% of patients, with a similar use of bivalirudin or glycoprotein IIb/IIIa inhibition in both groups.
Angiographic success was similarly high in both groups ( Table 3 ). The overall mortality for the entire study sample was low at 0.5%. The unadjusted incidence of in-hospital myocardial infarction (7.7% vs 6.8%, respectively; odds ratio [OR] 0.87, 95% confidence interval [CI] 0.55 to 1.40, p = 0.630) and MACE (8.4% vs 7.1%, respectively; OR 0.85, 95% CI 0.54 to 1.33, p = 0.484) was similar in the “preangiography clopidogrel treatment” and the “in-laboratory 600-mg clopidogrel loading” groups ( Figure 2 ). The incidence of major (0.9% vs 1.2%, respectively; OR 1.43, 95% CI 0.42 to 4.91, p = 0.763) or minor (15.0% vs 13.9%, respectively; OR 0.92, 95% CI 0.65 to 1.30, p = 0.658) bleeding complications was also similar in the “preangiography clopidogrel treatment” and the “in-laboratory 600-mg clopidogrel loading” groups. After adjustment for baseline differences with multivariate logistic modeling, the “in-laboratory 600-mg clopidogrel loading” strategy was not predictive of in-hospital myocardial infarction (OR 0.77, 95% CI 0.46 to 1.28, p = 0.312), MACE (OR 0.81, 95% CI 0.50 to 1.32, p = 0.398), or any bleeding complications (OR 0.90, 95% CI 0.60 to 1.34, p = 0.607).
| Variable | Clopidogrel Before Angiography (n = 467) | Clopidogrel In-Laboratory 600-mg Loading Dose (n = 574) | p Value |
|---|---|---|---|
| Angiographic success | 99.4% | 99.8% | 0.331 |
| Death | 0.4% | 0.5% | 1.000 |
| Emergent revascularization | 0% | 0.2% | 1.000 |
| Emergent percutaneous coronary intervention | 0% | 0.2% | 1.000 |
| Emergent coronary bypass surgery | 0% | 0% | — |
| Myocardial infarction | 7.7% | 6.8% | 0.630 |
| Creatine kinase-MB ≥3× and <5× upper limit of normal (%) | 3.0% | 3.3% | 0.860 |
| Creatine kinase-MB ≥5× and <10× upper limit of normal (%) | 2.1% | 2.3% | 1.000 |
| Creatine kinase-MB ≥10× upper limit of normal (%) | 2.6% | 1.2% | 0.161 |
| Troponin I ≥3× upper limit of normal (%) | 36.4% | 40.4% | 0.201 |
| Stroke | 0.2% | 0% | 0.449 |
| Major adverse cardiovascular events | 8.4% | 7.1% | 0.484 |
| Renal failure | 0% | 0% | — |
| Access site injury | 0.6% | 0.9% | 0.737 |
| Stent thrombosis | 0% | 0.5% | 0.257 |
| Any bleeding | 15.8% | 15.2% | 0.796 |
| Major bleeding | 0.9% | 1.2% | 0.763 |
| Minor bleeding | 15.0% | 13.9% | 0.658 |
| Length of stay (days) | |||
| Total | 3.3 ± 3.8 | 2.9 ± 3.4 | 0.055 |
| After percutaneous coronary intervention | 2.3 ± 3.2 | 2.0 ± 1.8 | 0.094 |
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