Thromb Haemost 2019; 119(02): 264-273
DOI: 10.1055/s-0038-1676795
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

Influence of Amlodipine on Haemostatic Measurements during Clopidogrel Treatment in Patients with Coronary Artery Disease

Jin-Sin Koh
1  Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Yongwhi Park
2  Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Jong-Hwa Ahn
2  Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Min Gyu Kang
1  Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Kye-Hwan Kim
1  Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Jae Seok Bae
2  Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Hyun Woong Park
1  Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Jeong Yoon Jang
2  Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Jeong Rang Park
1  Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Seok-Jae Hwang
1  Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Choong Hwan Kwak
2  Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
,
Jin-Yong Hwang
1  Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
,
Udaya S. Tantry
3  Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, United States
,
Paul A. Gurbel
3  Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, United States
,
Young-Hoon Jeong
2  Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
4  Institute of the Health Sciences, Gyeongsang National University, Jinju, Republic of Korea
› Author Affiliations
Funding This study was partly supported by research grants from the Daewoong Pharm., and the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A5A2008833).
Further Information

Publication History

09 June 2018

10 November 2018

Publication Date:
04 January 2019 (eFirst)

Abstract

Amlodipine has a potential to reduce clopidogrel bioactivation through the cytochrome P450 3A4 enzyme in vivo, but the clinical impact of this interaction remains controversial. This randomized, open-label, two-period, crossover study was performed to evaluate the influence of amlodipine on the haemostatic profiles of high-risk patients during clopidogrel treatment. We recruited 40 Asian patients (Male/Female: n = 36/4) receiving clopidogrel (75 mg/day), aspirin (100 mg/day) and rosuvastatin for at least 6 months following percutaneous coronary intervention. Patients were randomly assigned to receive either 5 mg daily amlodipine or not for 2 weeks, and then were crossed over to the other treatment for 2 weeks. Haemostatic measurements were conducted with the VerifyNow assay and thromboelastography (TEG). Primary endpoint was P2Y12 Reaction Units (PRU) during on- versus off-amlodipine treatment. The on-amlodipine strategy showed higher level of PRU compared with the off-amlodipine strategy (176.8 ± 75.4 vs. 150.7 ± 65.5 PRU; ∆mean: 26.1 PRU; ∆95% confidence interval [CI]: 4.5–47.7 PRU; p = 0.019). Platelet-fibrin clot strength measured by TEG was lower during on- versus off-amlodipine treatment (7,712 ± 1,889 vs. 8,559 ± 2,174 dyne/cm2; ∆mean: –847 dyne/cm2; ∆95% CI: –1,632 to –62 dyne/cm2; p = 0.035). After amlodipine discontinuation, 27 patients (67.5%) showed a decrease in PRU, which was associated with ‘PRU ≥ 160 on-amlodipine’ in multivariate analysis (odds ratio: 62.014; 95% CI: 2.302–1670.328; p = 0.014). In conclusion, amlodipine increases platelet reactivity and decreases platelet-fibrin clot strength during clopidogrel treatment. In addition, the effect of amlodipine discontinuation on clopidogrel responsiveness is associated with on-amlodipine platelet reactivity.

Note

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript and its final contents.