The EFFect of hIgh-dose ClopIdogrel treatmENT in patients with clopidogrel resistance (The EFFICIENT Trial)

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Abstract

Objectives

The aim of this study was to evaluate the effect of high-dose clopidogrel continuation treatment on the development of MACCE after elective PCI in patients with clopidogrel resistance.

Methods

The study group consisted of 192 patients. Of these, 98 participants without resistance served as the control group (Group 1) and received 75 mg/day clopidogrel for 1 month. Ninety-four patients with resistance were randomly divided into two groups: 47 patients in the standard-dose group (Group 2) received 75 mg/day continuation therapy, whereas 47 patients in the high-dose group (Group 3) received 150 mg/day continuation therapy for 1 month. Clopidogrel resistance was evaluated with the VerifyNow P2Y12 test. Patients with a platelet inhibition value lower than 40% were classified as resistant.

Results

During the 6-month follow-up for MACCE, the event-rate in Group 2 was significantly higher than both Groups 1 and 3 (Group 1 vs Group 2; p = 0.019, Group 1 vs Group 3; p = 0.82, Group 2 vs Group 3; p = 0.045). Total bleeding rate in all groups were similar (Group 1 vs Group 2; p = 0.54, Group 1 vs Group 3; p = 0.27, Group 2 vs Group 3; p = 0.16). The rate of NACE was similar in all groups (Group 1 vs Group 2; p = 0.08, Group 1 vs Group 3; p = 0.50, Group 2 vs Group 3; p = 0.39).

Conclusion

In patients who underwent elective PCI and had clopidogrel resistance, high-dose clopidogrel continuation therapy was more efficient in preventing MACCE than the standard dose. High-dose continuation therapy did not increase the risk of bleeding complication (The EFFICIENT Trial; ClinicalTrials.gov number: NCT01032668).

Introduction

Inhibition of platelet activation by using aspirin and clopidogrel constitutes the basis for medical treatment of ischemic complications that may occur after percutaneous coronary intervention (PCI). Clopidogrel is an ADP receptor antagonist, is a pro-drug. It irreversibly inhibits platelet P2Y12 receptor. It transforms into its active metabolite after oxidation by hepatic cytochrome P450 3A4 (CYP3A4) [1]. Clopidogrel-dependent platelet inhibition level and inhibition rate are dose-dependent [2]. In addition to a strong antithrombotic effect, clopidogrel also has other effects, such as inhibition of erythrocyte aggregation [3] and reduction of fibrinogen levels [2].

Today, despite aspirin and clopidogrel treatment in patients undergoing PCI, atherothrombotic complications occur frequently. Some of the atherothrombotic complications are explained by resistance to the effects of antithrombotic drugs. Therefore, interest in recent years has focused on insufficient antithrombotic treatment and resistance. Insufficient treatment can be defined as the occurrence of cardiovascular events despite antithrombotic treatment, whereas drug resistance is insufficient platelet inhibition in laboratory tests. Individual differences, such as decreased bioavailability and genetic variations affecting clopidogrel metabolism, accelerated platelet turnover, enhanced platelet reactivity and drug interactions, may explain clopidogrel resistance.

Following the CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) study, daily, single-dose 75-mg clopidogrel usage was approved [4]. On the other hand, following the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) study, a 300-mg loading dose in acute coronary syndrome was approved [5]. In the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) study, a 600-mg clopidogrel loading dose achieved higher plasma concentration and more prominent platelet inhibition, but increasing the dose from 600 mg to 900 mg provided no additional inhibition [6]. In the light of the results from these studies, the loading-dose approach entered clinical usage. The beneficial effects of clopidogrel loading doses are limited to early periods of the treatment. Therefore, long-term prevention of unwanted events depends on daily-maintenance dose regimes. Recently, high-dose clopidogrel maintenance treatment was shown to increase platelet inhibition [7], [8], [9], [10], [11]. However, there are limited data on the clinical consequences of high-dose maintenance treatment. The aim of this study is to evaluate the effects of high-dose clopidogrel maintenance treatment on major adverse cardiovascular and cerebrovascular events (MACCE) in clopidogrel-resistant individuals who have undergone elective PCI.

Section snippets

Study groups

This prospective, randomized, active-control, two-center study included 192 elective PCI patients (mean age ± SD, 57 ± 10 years, range 34–80) who applied to cardiology clinics of the two hospitals between September 2008 and July 2009. The study protocol was approved by the local ethics committee. Written informed consent was obtained before enrollment.

Patients were taking 100 mg/day aspirin for at least 5 days and 75 mg/day clopidogrel for at least 3 days before intervention were included in the study.

Results

Two hundred ten patients who had undergone elective PCI and met our selection criteria were recruited to the study. Of these, 192 patients [male, 153 (79.6%); female, 39 (20.4%)] volunteered to participate and were evaluated for clopidogrel and aspirin resistance. The mean age of the study group was 57 years (range 34–80 years). The control group consisted of 98 (51%) patients with sufficient response to 75 mg/day clopidogrel treatment. The remaining 94 (49%) patients with clopidogrel resistance

Discussion

The major results of this study are 1) 150 mg/day clopidogrel treatment reduced major adverse events in clopidogrel resistant patients, 2) increased dose did not lead to increased bleeding, 3) the rate of NACE in 150 mg/day clopidogrel treatment in clopidogrel resistant patients was similar to control group and standard dose group, 4) although it was not statistically significant, aspirin resistance also increased the development of adverse events, and 5) the VerifyNow P2Y12 laboratory test is a

Study limitations

The small number of patients is an important limitation. Nevertheless, we used a randomized approach and objective criteria. Our results are similar to those of recently published articles and may serve as a guide for larger-scale studies.

Clinical recommendations

One of the main treatment methods in coronary artery disease is PCI. One of the factors that limit the success of intervention is clopidogrel resistance-dependent complications. To prevent such complications, clopidogrel resistance should be defined. There are easy and simple laboratory tests for determining resistance. In resistant patients with high risk for MACCE and low risk for bleeding, increased clopidogrel dose may be the optimal treatment.

Conclusion

High-dose clopidogrel maintenance treatment in elective PCI patients with clopidogrel resistance was more effective in preventing MACCE when compared to the standard dose. This effect was independent of bleeding risk. Larger studies are needed to verify these findings.

Acknowledgements

We thank Giuseppe Biondi-Zoccai, assistant professor, and Dirk Belmans, PhD, for their valuable assistance for the statistical analyses.

The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology [42].

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