Data are lacking on the efficacy and safety of a loading dose (LD) of clopidogrel in elderly patients with acute myocardial infarction (AMI). FAST-MI is a nationwide registry that was carried out over a 1-month period in 2005 and included consecutive patients with AMI admitted to intensive care units <48 hours from symptom onset in 223 participating centers. We assessed the impact of a clopidogrel LD (≥300 mg) compared to a conventional dose (<300 mg) on bleeding, need for blood transfusion, and 30-day and 12-month survivals in 791 elderly patients (≥75 years old, mean age 81 ± 4 years, 48% women, 35% with ST-segment elevation MI) included in this registry. Fifty-nine percent (466 patients) received a clopidogrel LD. Follow-up was >99% complete. Major bleeding and blood transfusions were not significantly different in patients who received a clopidogrel LD (3.2% vs 3.7%, p = 0.72; 5.4% vs 6.2%, p = 0.64, respectively). Early mortality was also not significantly different (10.1 vs 10.8, p = 0.76). Using multivariate analyses, clopidogrel LD did not significantly affect major bleeding or transfusion (odds ratio 1.03, 95% confidence interval 0.49 to 2.17, p = 0.94) and 12-month mortality (hazard ratio 1.00, 95% confidence interval 0.72 to 1.40, p = 0.98). In conclusion, the present data showed that in elderly patients admitted for AMI, use of a LD of clopidogrel compared to a conventional dose was not associated with increased in-hospital bleeding, need for transfusion, or mortality. Large-scale randomized trials are still needed to identify the optimal LD of clopidogrel for elderly patients admitted for AMI.
The objective of this study was to assess the impact of using a loading dose (LD) of clopidogrel (≥300 mg) compared to a conventional dose (<300 mg) on major bleeding, need for transfusion, and 12-month survival in elderly patients (≥75 years of age) with acute myocardial infarction (AMI) from the French Registry of Acute ST-Elevation or Non–ST-elevation Myocardial Infarction (FAST-MI) of the French Society of Cardiology.
Methods
Patients ≥75 years of age receiving a known dose of clopidogrel ≤48 hours of admission and participating in the FAST-MI were included. Methods of the FAST-MI have been described in detail elsewhere. Briefly, the primary objectives were to evaluate practices for MI management in “real-life” practice and to measure their impact on medium- and long-term prognoses of patients admitted to intensive care units (ICUs) for MI. This registry results from a prospective multicenter (223 centers) study including 3,059 patients. Patients were recruited consecutively from ICU departments over a period of 1 month (October 2005). Participation in the study was offered to all French institutions, university teaching hospitals, general and regional hospitals, and private clinics with ICUs authorized to receive acute coronary syndrome (ACS) emergencies. In each center, a physician was in charge of the registry and provided a full list of all patients admitted to the unit.
Inclusion criteria were (1) men or women >18 years old; (2) patients admitted within 48 hours after symptom onset in an ICU for an AMI characterized by increased troponin or creatine kinase-MB associated with ≥1 of the following elements: symptoms compatible with myocardial ischemia, appearance of pathologic Q waves, or ST-T changes compatible with myocardial ischemia (ST-segment elevation or depression, T-wave inversion); and (3) consent to take part in the study. Exclusion criteria were (1) refusal to participate, (2) MI admitted >48 hours after symptom onset, (3) iatrogenic MIs, defined as MIs occurring within 48 hours of a therapeutic procedure (bypass surgery, coronary angioplasty, or any other medical or surgical intervention), (4) ACS diagnosis invalidated in favor of another diagnosis, and (5) patients with unstable angina and no increase in cardiac biomarkers.
The study was conducted in compliance with good clinical practice, French law, and the French data protection law. The protocol was reviewed by the committee for the protection of human subjects in biomedical research of Saint-Antoine University Hospital. The data file of the FAST-MI was declared to and authorized by the French data protection committee (Commission Nationale Informatique et Liberté).
Although the diagnosis of AMI was independently made at each participating center, to avoid heterogeneous criteria, ST-segment elevation MI was diagnosed when ST-segment elevation ≥1 mm was seen in ≥2 contiguous leads in any location on the index or qualifying electrocardiogram, and non–ST-segment elevation MI (non–Q-wave MI) was diagnosed when no ST-segment elevation was seen on the index or qualifying electrocardiogram. Presence of a presumed new left bundle branch block on admission electrocardiogram was also recorded. Patients who died very soon after admission and for whom cardiac markers were not measured were included if they had compatible signs or symptoms associated with typical ST-segment changes. Participating in the protocol did not change the therapeutic approach of the cardiologist in any way.
Baseline characteristics data, namely demographics (age, gender, body mass index), risk factors (hypertension, body mass index ≥30 kg/m 2 , diabetes, current smoking, hyperlipidemia), and medical history (previous AMI, previous percutaneous coronary intervention [PCI], previous coronary artery bypass grafting, previous stroke, chronic renal failure, severe concomitant illness), were collected prospectively and stored electronically as previously described. For safety analyses, the decision was made to focus on in-hospital major bleeding (defined as a decrease in hemoglobin ≥5 g, decrease in hematocrit ≥15%, intracranial hemorrhage, retroperitoneal bleeding) and transfusion. In addition, patients discharged alive were followed for 12 months.
Statistical analysis was performed using SPSS 18.0 (SPSS, Inc., Chicago, Illinois). For quantitative variables, mean ± SD and minimum and maximum values were calculated. In addition, medians with interquartile ranges were calculated for some variables. Discrete variables are presented as percentage. Comparisons were performed with chi-square or Fisher’s exact test for discrete variables and by unpaired t test, Wilcoxon sign-rank test, or 1-way analysis of variance for continuous variables. Each relative risk value is presented with its 95% confidence interval (CI). In-hospital survival is described as percentages and comparisons were made by chi-square test. Multivariate analyses of predictors of short-term outcome (30 days) were performed using stepwise multiple logistic regression analysis. Survival curves over the 1-year follow-up period were estimated using Kaplan–Meier estimation and compared using log-rank test. Correlates of 1-year survival were determined using a multivariate stepwise Cox backward model. Variables included in the final multivariate models are those with a significance level <0.15 in univariate analyses.
Results
Of the 3,059 patients included in the registry, 791 were ≥75 years and received a known dose of clopidogrel in the first 48 hours of admission in the ICU. Follow-up was 99% complete.
Baseline characteristics are listed in Table 1 ; 466 patients (59%) received an LD (≥300 mg, 300 mg in 384 patients, 375 mg in 5 patients, 450 mg in 16 patients, 600 mg in 60 patients, 900 mg in 1 patient) and 325 patients (41%) a conventional dose (75 mg in 287 patients, 150 mg in 27 patients, 225 mg in 11 patients) of clopidogrel during the first 48 hours. The 2 groups (LD and no LD) were similar in many respects. However, patients treated without a clopidogrel LD were slightly but significantly older with more hypertension, more chronic kidney disease, and more myocardial revascularization than those treated with a clopidogrel LD.
| No LD (n = 325) | LD (n = 466) | p Value | |
|---|---|---|---|
| Age (years) | 82 ± 5 | 81 ± 4 | 0.02 |
| Women | 159 (49%) | 224 (48%) | 0.88 |
| Body mass index (kg/m 2 ) | 25.9 ± 4.4 | 26.1 ± 4.3 | 0.53 |
| Hypertension | 255 (78.5%) | 331 (71%) | 0.02 |
| Left ventricular ejection fraction | 50 ± 13 | 50 ± 14 | 0.79 |
| Global registry of acute coronary events score | 174 ± 32 | 171 ± 30 | 0.09 |
| Diabetes mellitus | 96 (29.5%) | 126 (27%) | 0.44 |
| Current smoking | 29 (9%) | 42 (9%) | 0.93 |
| Hyperlipidemia ⁎ | 163 (50%) | 214 (46%) | 0.33 |
| Previous myocardial infarction | 94 (29%) | 75 (16%) | 0.001 |
| Previous percutaneous intervention | 70 (21.5%) | 56 (12%) | 0.001 |
| Previous coronary artery bypass grafting | 31 (9.5%) | 23 (5%) | 0.02 |
| Previous stroke | 23 (7%) | 28 (6%) | 0.39 |
| Chronic kidney disease | 39 (12%) | 28 (6%) | 0.002 |
| Severe co-morbidity | 52 (16%) | 70 (15%) | 0.67 |
| Previous clopidogrel use | 117 (36%) | 39 (8.4%) | 0.001 |
⁎ Included patients with previously documented diagnosis of hypercholesterolemia treated with diet or medication or new diagnosis during this hospitalization with increased total cholesterol >160 mg/dl; did not include increased triglycerides.
Early complications according to clopidogrel LD are presented in Table 2 . No difference was found in in-hospital bleeding and 30-day mortality in patients treated with clopidogrel LD versus conventional dose. A subgroup analysis of early mortality and major bleeding as a function of clopidogrel LD according to type of management in patients with ST-segment elevation MI, use of glycoprotein IIb/IIIa receptor blockers, previous use of clopidogrel, and use of PCI during hospital stay is presented in Table 3 . No difference was found in the different subgroups of patients treated with clopidogrel LD versus conventional dose except in the subgroup of patients without reperfusion therapy.
| No LD (n = 325) | LD (n = 466) | p Value | |
|---|---|---|---|
| Minor bleeding | 4 (1.2%) | 8 (1.7%) | 0.58 |
| Major bleeding | 12 (3.7%) | 15 (3.2%) | 0.72 |
| Transfusions | 20 (6.2%) | 25 (5.4%) | 0.64 |
| Major bleeding or transfusions | 20 (6.2%) | 25 (5.4%) | 0.64 |
| In-hospital mortality | 33 (10.2%) | 37 (7.9%) | 0.28 |
| Death at 30 days | 35 (10.8%) | 47 (10.1%) | 0.76 |
| Subgroups | 30-Day Mortality | Major Bleeding or Transfusions | ||||
|---|---|---|---|---|---|---|
| No LD | LD | p Value | No LD | LD | p Value | |
| ST-segment elevation myocardial infarction | ||||||
| No reperfusion therapy (n = 165) | 63 | 102 | 63 | 102 | ||
| 10 (15.9%) | 14 (13.7%) | 0.70 | 5 (7.9%) | 0 (0%) | 0.01 | |
| Primary percutaneous coronary intervention (n = 108) | 26 | 82 | 26 | 82 | ||
| 3 (11.5%) | 8 (9.8%) | 0.80 | 1 (3.8%) | 5 (6.1%) | 0.66 | |
| Intravenous fibrinolysis (n = 66) | 24 | 42 | 24 | 42 | ||
| 4 (16.7%) | 6 (14.3%) | 0.79 | 1 (4.2%) | 1 (2.4%) | 0.68 | |
| Glycoprotein IIb/IIIa blockers | ||||||
| No (n = 572) | 245 | 327 | 245 | 327 | ||
| 24 (9.8%) | 36 (11.0%) | 0.64 | 16 (6.5%) | 15 (4.6%) | 0.31 | |
| Yes (n = 219) | 80 | 139 | 80 | 139 | ||
| 11 (13.8%) | 11 (7.9%) | 0.17 | 4 (5.0%) | 10 (7.2%) | 0.52 | |
| Previous clopidogrel use | ||||||
| No (n = 635) | 208 | 427 | 208 | 427 | ||
| 20 (9.6%) | 42 (9.8%) | 0.93 | 9 (4.3%) | 24 (5.6%) | 0.49 | |
| Yes (n = 156) | 117 | 39 | 117 | 39 | ||
| 15 (12.8%) | 5 (12.8%) | 1.00 | 11 (9.4%) | 1 (2.6%) | 0.17 | |
| Percutaneous coronary intervention during hospital stay | ||||||
| No (n = 355) | 179 | 176 | 179 | 176 | ||
| 25 (14.0%) | 30 (17.0%) | 0.42 | 10 (5.6%) | 13 (7.4%) | 0.49 | |
| Yes (n = 436) | 146 | 290 | 146 | 290 | ||
| 10 (6.8%) | 17 (5.9%) | 0.69 | 10 (6.8%) | 12 (4.1%) | 0.22 | |
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