The optimal loading dose of clopidogrel in patients with chronic kidney disease who undergo primary percutaneous coronary intervention for ST-segment elevation myocardial infarction has not been investigated. The aim of this study was to assess the impact of clopidogrel loading dose on clinical outcomes in this setting. A total of 1,457 patients with CKD (estimated glomerular filtration rate <60 ml/min/1.73 m 2 ) were evaluated according to clopidogrel loading dose: 600 mg (n = 861) versus 300 mg (n = 596). In-hospital complications, including major bleeding and clinical outcomes at 1 and 12 months, were compared between the 2 groups. The in-hospital major bleeding rate was similar (0.8% vs 0.2%, p = 0.09). Also, there were no differences in major adverse cardiac event rates, including death, recurrent myocardial infarction, target lesion revascularization, and stent thrombosis, at 1 month (15.6% vs 16.4%, p = 0.70) and 12 months (19.0% vs 21.3%, p = 0.32). On multivariate analysis, a 600-mg loading dose of clopidogrel was not an independent predictor of 1-month (odds ratio 1.13, 95% confidence interval 0.49 to 2.57, p = 0.78) and 12-month (odds ratio 0.89, 95% confidence interval 0.52 to 1.51, p = 0.66) major adverse cardiac events. After propensity score–matched analysis, these results were unchanged. In conclusion, a 600-mg loading dose of clopidogrel was not effective in reducing 1- and 12-month major adverse cardiac events in patients with chronic kidney disease who underwent primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, but this dose did not increase the in-hospital major bleeding rate.
Patients with chronic kidney disease (CKD) have increased risk for adverse ischemic events, including stent thrombosis, after percutaneous coronary intervention (PCI) in the setting of stable angina and acute coronary syndromes. Two recent post hoc analyses of large randomized controlled trials showed that clopidogrel might have reduced efficacy in patients with CKD, and pharmacodynamic studies have suggested that CKD is associated with reduced clopidogrel-induced antiplatelet effects. In addition, recent clinical trials have reported that a 600-mg loading dose of clopidogrel reduces the 30-day ischemic adverse event rate, without increasing the bleeding rate, compared to a 300-mg loading dose in patients with acute coronary syndromes who undergo PCI. Considering that CKD is associated with reduced clopidogrel-induced antiplatelet effects and that platelet aggregation is increased during the first few days after myocardial infarction, patients with CKD may have benefited from high loading doses of clopidogrel 600 mg before primary PCI. In the present study, we evaluated the efficacy and safety of a 600-mg clopidogrel loading dose compared to a 300-mg dose in patients with CKD who underwent primary PCI for ST-segment elevation myocardial infarction (STEMI), using the Korea Acute Myocardial Infarction Registry (KAMIR) database.
Methods
The KAMIR is an on-line database of a Korean prospective multicenter registry ( http://www.kamir.or.kr ), which was launched in November 2005 with the support of the Korean Circulation Society. The purpose and methods used to register patients in the KAMIR have been described previously. The success of the KAMIR led to the establishment of the Korea Working Group on Myocardial Infarction, a subsequent study of the KAMIR, which is an ongoing open registry that captures data on the complete spectrum of patients with acute myocardial infarctions, including long-term clinical follow-up. Patients were diagnosed with STEMIs when they had new or presumed new ST-segment elevation ≥1 mm, seen in any location, or new left bundle branch block on the index or subsequent electrocardiogram, with ≥1 positive cardiac biochemical marker of necrosis (including creatine kinase-MB, troponin I, and troponin T).
A total of 20,708 patients were enrolled from December 2006 to August 2010. Of these, 18,770 patients were diagnosed with acute myocardial infarctions. In the present study, we retrospectively analyzed the patients with STEMIs and CKD, who underwent primary PCI (performed ≤24 hours after symptom onset). CKD was defined according to estimated glomerular filtration rate (eGFR), which was calculated using the Modification of Diet in Renal Disease (MDRD) equation, and patients with eGFRs <60 ml/min/1.73 m 2 were defined as having CKD. The main exclusion criteria were non-STEMI, STEMI with elective PCI, conservative treatment without PCI, contraindication to antithrombotic agents, known bleeding disorders, thrombocytopenia (<100 × 10 9 /L), administration of thrombolytic or fibrinolytic medications for STEMI, infarction related to the grafted vessel, and estimated life expectancy <12 months. Patients with resuscitation before arrival were also excluded because the prognosis of these patients depends mainly on their neurologic outcomes. Aspirin and clopidogrel loading doses were administered immediately after agreement by patients to undergo PCI. The loading dose of aspirin was 200 or 300 mg, and an indefinite maintenance dose of 100 mg/day was prescribed after discharge. The loading dose of clopidogrel was 300 or 600 mg, and a maintenance dose of 75 mg/day was recommended for 1 year. The clopidogrel loading dose was left to the decision of the individual physician. Patients were classified into 2 groups: those receiving the standard loading dose (300 mg; n = 596) and those receiving the high loading dose (600 mg; n = 861).
Diagnostic coronary angiography was performed using the femoral or radial approach. During primary PCI, an intravenous bolus of unfractionated heparin (2,000 to 3,000 U) was given to maintain an activated clotting time >250 seconds. The choice of the stent and the use of glycoprotein IIb/IIIa receptor blockers, thrombectomy devices, and thrombus aspiration devices were left to the physician’s discretion. A successful PCI procedure was defined as the achievement of Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow and residual stenosis <30% on final angiography. All patients were scheduled to be followed clinically at 1 month, 6 months, and 1 year after the index procedure or when angina-like symptoms occurred. Routine angiographic follow-up for asymptomatic patients was not mandatory. At 12 months after index PCI, follow-up data were collected and entered into a Web-based case report form.
All deaths were considered cardiac deaths unless noncardiac causes could be excluded. Cardiac death was defined as death from pump failure, arrhythmia, or mechanical complications, including ventricular septal rupture and free wall rupture. Recurrent myocardial infarction was defined as recurrent symptoms with new ST-segment elevation or reelevation of cardiac markers to ≥2 times the upper limit of normal. Target lesion revascularization was defined as ischemia-induced PCI of the target lesion, caused by restenosis or reocclusion within the stent or in the adjacent 5-mm area of the distal or proximal segment. Stent thrombosis was defined as angiographic proof of vessel occlusion, any recurrent myocardial infarction in the territory of the stent-implanted vessel, or any death from cardiac cause. Total major adverse cardiac events (MACEs) were defined as the composite of cardiac death, noncardiac death, nonfatal recurrent myocardial infarction, target lesion revascularization, and stent thrombosis. Major bleeding was defined as any intracranial bleeding, significant gastrointestinal bleeding, retroperitoneal bleeding, bleeding associated with the need for blood transfusion, or any other clinically relevant bleeding, as judged by the investigator. Stroke was defined as the presence of a new focal neurologic deficit thought to be vascular in origin, with signs or symptoms lasting >24 hours, and confirmed by means of computed tomography or magnetic resonance imaging of the brain.
Categorical variables were compared using chi-square or Fisher’s exact tests and are presented as percentages. Continuous variables were compared using Mann-Whitney rank-sum tests and are presented as medians with 25th and 75th percentiles. Patients in the 300-mg and the 600-mg clopidogrel loading dose groups were matched using a propensity score to attempt to make adjustments for potential selection biases and potential confounding. The propensity score was derived using a logistic regression model, and the included variables were age, gender, eGFR ≤30 ml/min/1.73 m 2 , time from symptom onset to admission ≤6 hours, history of diabetes mellitus, previous coronary heart disease, maximum creatinine kinase-MB fraction, TIMI flow grade before PCI, TIMI flow grade after PCI, stent type (drug-eluting stent or not), and anticoagulant use (glycoprotein IIb/IIIa inhibitors, unfractionated heparin, low-molecular-weight heparin). Multiple logistic regression analysis was used to identify independent predictors of 1- and 12-month MACEs. For 1-month MACEs, the following adjusted variables were included: age, female gender, body mass index, eGFR, time from symptom onset to admission ≤6 hours, diabetes mellitus, previous coronary heart disease, left ventricular ejection fraction ≤35%, high-sensitivity C-reactive protein, maximum troponin I, multivessel disease, TIMI grade 3 flow after PCI, and cardiogenic shock. For 12-month MACEs, the following adjusted variables were included: age, female gender, body mass index, eGFR, time from symptom onset to admission ≤6 hours, diabetes mellitus, previous coronary heart disease, left ventricular ejection fraction ≤35%, multivessel disease, TIMI grade 3 flow after PCI, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers use at discharge, and cardiogenic shock. Clopidogrel 600-mg loading dose was entered into both analyses, because it was the variable of interest for MACEs. Odds ratios and 95% confidence intervals were calculated, and all p values reported are 2 sided. A p value <0.05 was considered statistically significant. Statistical analysis was performed using SPSS version 19.0 (SPSS, Inc., Chicago, Illinois).
Results
A total of 1,457 patients with CKD who underwent primary PCI for STEMI <24 hours after symptom onset were enrolled in this study ( Figure 1 ). The median age was 71.6 years, and 834 patients (57.2%) were men. The median eGFR was 44.9 ml/min/1.73 m 2 , and 201 patients (13.8%) had eGFRs <30 ml/min/1.73 m 2 . The baseline clinical characteristics were generally well matched between the 2 groups, except for higher systolic blood pressure and a higher prevalence of current smokers and previous regular aspirin use in the 300-mg loading dose group compared to the 600-mg loading dose group ( Table 1 ). Procedural characteristics were also well matched between the 2 groups ( Table 2 ). The use of low-molecular-weight heparin during hospitalization was more prevalent in the 300-mg loading dose group compared to the 600-mg loading dose group, but prescription rates of in-hospital and discharge antiplatelet agents, β blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and statins were similar between the 2 groups ( Table 2 ).
| Variable | 300 mg | 600 mg | p Value |
|---|---|---|---|
| (n = 596) | (n = 861) | ||
| Age (years) | 73 (64–79) | 73 (64–80) | 0.441 |
| Women | 42.8% | 42.7% | 1.000 |
| Body mass index (kg/m 2 ) | 23.1 (20.7–25.7) | 23.1 (20.3–25.3) | 0.397 |
| eGFR (ml/min/1.73 m 2 ) | 48.5 (36.5–56.0) | 50.1 (39.1–55.9) | 0.182 |
| eGFR ≤30 ml/min/1.73 m 2 | 15.6% | 12.5% | 0.112 |
| Systolic blood pressure (mm Hg) | 118 (99–140) | 110 (90–130) | 0.026 |
| Heart rate (beats/min) | 74 (58–90) | 72 (60–88) | 0.850 |
| Time from symptom onset to admission ≤6 hours | 76% | 75% | 0.716 |
| Medical history | |||
| Hypertension ⁎ | 65.5% | 63.6% | 0.499 |
| Diabetes mellitus | 38.1% | 35.2% | 0.285 |
| Hyperlipidemia † | 10.6% | 9.5% | 0.563 |
| Current smoker | 33.9% | 26.6% | 0.004 |
| Coronary heart disease | 9.4% | 8.4% | 0.554 |
| Myocardial infarction | 2.7% | 4.1% | 0.206 |
| Coronary bypass | 0.3% | 0.7% | 0.296 |
| Heart failure | 2.0% | 2.3% | 0.830 |
| Stroke | 9.6% | 7.3% | 0.151 |
| Regular aspirin | 14.6% | 10.3% | 0.018 |
| Regular clopidogrel | 3.9% | 2.4% | 0.161 |
| Ejection fraction ≤35% | 20.0% | 15.5% | 0.090 |
| Killip class ≥2 | 45.5% | 48.8% | 0.253 |
| Glucose (mg/dl) | 180 (136–254) | 173 (135–248) | 0.614 |
| Low-density lipoprotein cholesterol (mg/dl) | 108 (84–132) | 108 (85–131) | 0.798 |
| High-sensitivity C-reactive protein (mg/dl) | 0.83 (0.20–5.27) | 0.87 (0.20–4.51) | 0.865 |
| Maximum creatine kinase-MB fraction (ng/ml) | 112 (27–234) | 117 (30–252) | 0.488 |
| Maximum troponin I (mg/ml) | 30.0 (6.1–70.6) | 30.0 (3.5–74.2) | 0.579 |
| N-terminal pro–B-type natriuretic peptide (pg/ml) | 686 (121–2186) | 468 (126–2,548) | 0.660 |
⁎ Previously diagnosed by a physician and/or receiving medication to lower blood pressure.
† Previously diagnosed by a physician and/or receiving lipid-lowering drugs.
| Variable | 300 mg | 600 mg | p Value |
|---|---|---|---|
| (n = 596) | (n = 861) | ||
| Target coronary artery | 0.922 | ||
| Left main | 2.6% | 2.5% | |
| Left anterior descending | 40.6% | 41.7% | |
| Left circumflex | 7.8% | 8.5% | |
| Right | 49.0% | 47.3% | |
| Multivessel disease | 62.8% | 61.2% | 0.555 |
| Left main coronary artery involvement | 3.4% | 2.8% | 0.631 |
| TIMI grade 0 or 1 flow before PCI | 75.4% | 74.6% | 0.761 |
| TIMI grade 3 flow after PCI | 86.4% | 87.8% | 0.479 |
| Drug-eluting stent | 89.0% | 90.6% | 0.404 |
| Stent diameter (mm) | 3.00 (2.75–3.50) | 3.00 (3.00–3.50) | 0.356 |
| Stent length (mm) | 24.0 (20.0–30.0) | 24.0 (19.0–30.0) | 0.904 |
| Number of stents per patient | 1.00 (1.00–2.00) | 1.00 (1.00–2.00) | 0.782 |
| Multivessel revascularization | 18.0% | 17.7% | 0.925 |
| In-hospital medications | |||
| Glycoprotein IIb/IIIa inhibitors | 24.6% | 22.8% | 0.464 |
| Unfractionated heparin | 59.2% | 61.3% | 0.453 |
| Low-molecular-weight heparin | 31.9% | 22.9% | <0.001 |
| Aspirin | 98.5% | 98.1% | 0.760 |
| Clopidogrel | 97.5% | 98.6% | 0.178 |
| Cilostazol | 29.5% | 27.1% | 0.348 |
| β blockers | 72.0% | 69.4% | 0.311 |
| ACE inhibitors or ARBs | 75.0% | 72.7% | 0.359 |
| Statins | 67.0% | 69.4% | 0.366 |
| Discharge medications | (n = 523) | (n = 745) | |
| Aspirin | 96.2% | 97.9% | 0.123 |
| Clopidogrel | 96.3% | 98.2% | 0.060 |
| Cilostazol | 29.9% | 27.8% | 0.459 |
| β blockers | 75.5% | 78.0% | 0.230 |
| ACE inhibitors or ARBs | 79.3% | 79.3% | 1.000 |
| Statins | 71.5% | 74.5% | 0.260 |
When compared between the 300-mg and the 600-mg loading dose groups, in-hospital complication rates were not different, including stroke (1.7% vs 0.7%, p = 0.131) and major bleeding (0.2% vs 0.8%, p = 0.097) ( Figure 2 ). Also, there were no differences in the 1- and 12-month clinical outcomes, including cardiac death, noncardiac death, recurrent myocardial infarction, target lesion revascularization, stent thrombosis, and total MACEs, between the 2 groups ( Figures 3 and 4 ).
On multivariate analysis, independent predictors of 1-month MACEs were cardiogenic shock, left ventricular ejection fraction ≤35%, body mass index, eGFR, and maximum troponin I level. Clopidogrel 600-mg loading dose was not an independent predictor of 1-month MACEs ( Table 3 ). Independent predictors of 12-month MACEs were left ventricular ejection fraction ≤35%, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use at discharge, cardiogenic shock, diabetes mellitus, and eGFR. Again, clopidogrel 600-mg loading dose was not an independent predictor of 12-month MACEs ( Table 4 ).
| Predictor | All Patients (n = 1,457) | Propensity-Matched Patients (n = 1,144) | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p Value | OR | 95% CI | p Value | |
| Clopidogrel 600-mg loading dose | 1.13 | 0.49–2.57 | 0.778 | 1.12 | 0.47–2.65 | 0.800 |
| Cardiogenic shock | 7.20 | 3.01–17.22 | <0.001 | 8.30 | 3.35–20.58 | <0.001 |
| Left ventricular ejection fraction ≤35% | 5.22 | 2.21–12.36 | <0.001 | 5.67 | 2.32–13.87 | <0.001 |
| Body mass index | 0.94 | 0.90–0.98 | 0.008 | 0.94 | 0.89–0.99 | 0.011 |
| eGFR | 0.97 | 0.94–0.99 | 0.019 | 0.97 | 0.95–1.00 | 0.048 |
| Maximum troponin I | 1.01 | 1.01–1.01 | 0.024 | 1.01 | 1.01–1.01 | 0.021 |
| Age | 1.03 | 0.99–1.07 | 0.078 | 1.03 | 0.99–1.07 | 0.124 |
| Female gender | 0.54 | 0.24–1.21 | 0.133 | 0.60 | 0.26–1.41 | 0.244 |
| Time from symptom onset to admission ≤6 hours | 0.63 | 0.26–1.55 | 0.314 | 0.85 | 0.31–2.29 | 0.748 |
| Previous coronary heart disease | 1.75 | 0.55–5.55 | 0.343 | 2.55 | 0.74–8.77 | 0.137 |
| Diabetes mellitus | 0.87 | 0.38–1.99 | 0.748 | 0.83 | 0.33–2.06 | 0.686 |
| High-sensitivity C-reactive protein | 1.00 | 0.99–1.03 | 0.778 | 0.99 | 0.97–1.03 | 0.935 |
| TIMI grade 3 flow after PCI | 1.14 | 0.36–3.68 | 0.824 | 0.81 | 0.24–2.69 | 0.731 |
| Multivessel disease | 0.92 | 0.41–2.07 | 0.834 | 0.77 | 0.32–1.86 | 0.556 |
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