Abstract
Background
In patients under oral anticoagulant requiring percutaneous coronary intervention (PCI) with stent implantation, the optimal association between aspirin, clopidogrel and oral anticoagulant (OAC) remains cumberstome. Triple therapy and dual therapy using aspirin and OAC have been evaluated and are associated with a high frequency of major bleedings. The combination of clopidogrel and OAC has never been evaluated.
Objective
We aimed to investigate the safety and efficacy of clopidogrel and OAC in patients requiring OAC undergoing PCI for acute coronary syndrome.
Methods
A monocenter retrospective study was undertaken between 2000 and 2006 and included all patients undergoing PCI with stent implantation on OAC. On discharge dual therapy with clopidogrel and OAC was prescribed. The primary end-point was the frequency of major TIMI bleedings. Secondary end-points were major cardiovascular event (MACE). Results are reported as rate of events with 95% confidence intervals (CI).
Results
Two hundreds and nine patients were followed for 71 ± 22 months. The indication for oral anticoagulation was atrial fibrillation in 80% of patients, a valvular prothesis in 18% and a history of pulmonary embolism in 5%. The rate (95%CI) of major bleeding was 2.4% (0.9%-5.8%) 2.87% (1.17%-6.44%) and 3.8% (1.79%-7.68%) at 1 month, 12 months and 71 months respectively, which represent 8 events among which 2 were fatal. The MACE rate (95%CI) was low: 0% at one month, 3.8% (1.79%-7.68%) at 12 months and 24.4% (19.07%-30.65%) at 71 months of follow up. Only one stent thrombosis was recorded at the ninth month. The overall rate of death was 9.5% (6.28%-14.32%) among which 2.87% (1.17%-6.44%) were of cardiovascular origin.
Conclusion
The use of clopidogrel and OAC combination in patients on OAC undergoing coronary stenting is safe and efficient at the short-term. At the long-term, this combination is probably not safe, with a relatively high incidence of fatal stroke.
1
Introduction
The gold standard treatment after acute coronary syndrome and percutaneous coronary intervention (PCI) is dual antiplatelet therapy (clopidogrel and aspirin) for at least 12 months ; such therapy is associated with increased risk of bleeding . The potential for developing bleeding is further enhanced for patients also requiring oral anticoagulants (OAC) . This combination of clopidogrel, aspirin, and OAC is the most used after PCI in patients on OAC for at least 1 month followed by aspirin and OAC combination indefinitely as recommended by the American College of Cardiology/American Heart Association (ACC/AHA) recommendation for the management of unstable angina and non-ST-elevation myocardial infarction (STEMI) . This last combination is associated with high rate of bleeding especially gastrointestinal bleeding; on the other hand, the incidence of gastrointestinal bleeding is very low under clopidogrel compared with aspirin. Currently, there is no sufficient report concerning the combined use of clopidogrel and OAC; one small recent study showed the high efficacy of this combination at the short-term. The aim of our study was to evaluate the safety and efficacy of clopidogrel and OAC combination at both the short- and long-term.
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Materials and methods
This was a prospective, single-centre study. The study protocol was in accordance with the Declaration of Helsinki and was approved by the local ethics committee of our institution. All patients gave written informed consent before inclusion. We included all patients on OAC indefinitely for mechanical heart prostheses, recurrent pulmonary embolism, deep venous thrombosis, atrial fibrillation, or embolic stroke; who were admitted to the cardiologic intensive care unit of Hospital Nord, Marseille, for acute coronary syndrome; and who had PCI with stent implantation.
Exclusion criteria were as follows: platelet count of <100 000/mm 3 , history of bleeding diathesis, concurrent severe illness with expected survival of <1 month, or contraindication of antiplatelet therapy. The indications and the technical PCI procedure were in accordance with the European guidelines for the management of ST-elevation myocardial infarction (STEMI) and NSTEMI. The PCI was performed under OAC without switching to heparin if the international normalized ratio (INR) was between 2 and 3; if the INR was >3, the PCI is delayed if it was not urgent. If the INR was <2, we performed PCI under nonfractionated heparin. All patients received 600 mg loading dose of clopidogrel and 500 mg intravenous aspirin before performing PCI.
Safety was evaluated by the incidence of bleeding, classified as major or minor according to TIMI bleeding classification . Efficacy was evaluated by the incidence of major adverse cardiovascular events (MACE); death of cardiovascular (CV) origin; need for revascularization of the target vessel; myocardial infarction (MI); and ischemic stroke. Death is considered as CV if no other origin is identified. Myocardial infarction is defined as new onset of Q wave in two concordant ECG leads or chest pain with troponin Ic elevation.
The CHADS 2 score, a validated model that calculates stroke risk based on readily discernible clinical characteristics including heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke , was used to approximate thrombotic risk in patients with atrial fibrillation.
On discharge, patients received clopidogrel 75 mg daily indefinitely and OAC with target INR of between 2 and 3, except for mitral mechanical prostheses in which the target INR was 3 to 4.
The patients were followed with medical visits at 1 month after discharge and annually by medical visits or by phone.
The primary end point was the rate of major bleeding according to TIMI bleeding classification. The secondary end point was incidence of MACE at 1 month, 12 months, and at the end of the study. Results were reported as rate of event with 95% confidence intervals (CI).
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Results
Two hundred and nine patients were included between March 2000 and December 2006, and followed until May 2008. The complete follow-up was done for 208 patients (one was lost to follow-up); the mean duration of follow-up was 71±22 months.
The majority of patients were admitted for high-risk acute coronary syndrome with MI (50.2%). The mean age was 73.2±7years, the rate of diabetes mellitus was 45%, and the most common cause for anticoagulation was atrial fibrillation (80.8%). The mean CHADS 2 score was 2.13 ( Table 1 ).
| Number | Percent | |
|---|---|---|
| Age Mean±SD | 73±7.5 | |
| Male sex | 147 | 70 |
| Hypertension | 147 | 70 |
| Diabetes | 93 | 44.5 |
| Dyslipidemia | 134 | 64.1 |
| Current smoking | 91 | 43.5 |
| Weight Mean±SD | 74.9±10.9 | |
| Heredity | 68 | 32.5 |
| Ejection fraction | ||
| >50% | 141 | 67.4 |
| 35–50% | 66 | 31.5 |
| <35% | 2 | 0.9 |
| Indication of anticoagulation | ||
| Mitral prostheses | 14 | 6.6 |
| Aortic prostheses | 24 | 11.4 |
| Atrial fibrillation | 169 | 80.8 |
| Pulmonary embolism | 6 | 2.8 |
| Ischemic stroke | 15 | 7.1 |
| others | 11 | 5.2 |
| Indication of angioplasty | ||
| Unstable angina | 104 | 49.7 |
| NSTEMI troponin + | 53 | 25.3 |
| STEMI | 52 | 24.8 |
| Access site | ||
| Femoral | 197 | 94.2 |
| Radial | 10 | 4.7 |
| Humeral | 2 | 0.9 |
| Anti-GPIIb-IIIa use | 17 | 8.1 |
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