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

Jin-Sin Koh; Yongwhi Park; Jong-Hwa Ahn; Min Gyu Kang; Kye-Hwan Kim; Jae Seok Bae; Hyun Woong Park; Jeong Yoon Jang; Jeong Rang Park; Seok-Jae Hwang; Choong Hwan Kwak; Jin-Yong Hwang; Udaya S. Tantry; Paul A. Gurbel; Young-Hoon Jeong

doi:10.1055/s-0038-1676795

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

Authors

Jin-Sin Koh

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
Yongwhi Park

²Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
Jong-Hwa Ahn

²Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
Min Gyu Kang

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
Kye-Hwan Kim

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
Jae Seok Bae

²Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
Hyun Woong Park

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
Jeong Yoon Jang

²Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
Jeong Rang Park

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
Seok-Jae Hwang

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
Choong Hwan Kwak

²Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
Jin-Yong Hwang

¹Department of Internal Medicine, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea
Udaya S. Tantry

³Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, United States
Paul A. Gurbel

³Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Fairfax, Virginia, United States
Young-Hoon Jeong

²Department of Internal Medicine, Gyeongsang National University School of Medicine and Cardiovascular Center, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea

⁴Institute of the Health Sciences, Gyeongsang National University, Jinju, Republic of Korea

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.

Keywords

amlodipine - clopidogrel - platelet - clot

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References
1 Amsterdam EA, Wenger NK, Brindis RG. , et al; ACC/AHA Task Force Members. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 130 (25) e344-e426
2 Fihn SD, Blankenship JC, Alexander KP. , et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2014; 130 (19) 1749-1767
3 Levine GN, Bates ER, Blankenship JC. , et al. 2015 ACC/AHA/SCAI focused update on primary percutaneous coronary intervention for patients with ST-elevation myocardial infarction: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention and the 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2016; 133 (11) 1135-1147
4 Tantry US, Bonello L, Aradi D. , et al; Working Group on On-Treatment Platelet Reactivity. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013; 62 (24) 2261-2273
5 Kazui M, Nishiya Y, Ishizuka T. , et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 2010; 38 (01) 92-99
6 Beltrame JF, Sasayama S, Maseri A. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients. J Am Coll Cardiol 1999; 33 (06) 1442-1452
7 Pristipino C, Beltrame JF, Finocchiaro ML. , et al. Major racial differences in coronary constrictor response between Japanese and Caucasians with recent myocardial infarction. Circulation 2000; 101 (10) 1102-1108
8 Zhou SF, Xue CC, Yu XQ, Li C, Wang G. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 2007; 29 (06) 687-710
9 Bliden KP, DiChiara J, Tantry US, Bassi AK, Chaganti SK, Gurbel PA. Increased risk in patients with high platelet aggregation receiving chronic clopidogrel therapy undergoing percutaneous coronary intervention: is the current antiplatelet therapy adequate?. J Am Coll Cardiol 2007; 49 (06) 657-666
10 Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52 (19) 1557-1563
11 Aggarwal S, Loomba RS, Arora RR. Effects of concurrent calcium channel blocker on antiplatelet efficacy of clopidogrel therapy: a systematic review. Am J Ther 2016; 23 (01) e29-e36
12 Park Y, Jeong YH, Tantry US. , et al. Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study. Eur Heart J 2012; 33 (17) 2151-2162
13 Harmsze AM, Robijns K, van Werkum JW. , et al. The use of amlodipine, but not of P-glycoprotein inhibiting calcium channel blockers is associated with clopidogrel poor-response. Thromb Haemost 2010; 103 (05) 920-925
14 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310 (20) 2191-2194
15 Jeong YH, Bliden KP, Antonino MJ, Park KS, Tantry US, Gurbel PA. Usefulness of the VerifyNow P2Y12 assay to evaluate the antiplatelet effects of ticagrelor and clopidogrel therapies. Am Heart J 2012; 164 (01) 35-42
16 Jeong YH, Bliden KP, Shuldiner AR, Tantry US, Gurbel PA. Thrombin-induced platelet-fibrin clot strength: relation to high on-clopidogrel platelet reactivity, genotype, and post-percutaneous coronary intervention outcomes. Thromb Haemost 2014; 111 (04) 713-724
17 Hobson AR, Agarwala RA, Swallow RA, Dawkins KD, Curzen NP. Thrombelastography: current clinical applications and its potential role in interventional cardiology. Platelets 2006; 17 (08) 509-518
18 Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition. Heart 2010; 96 (03) 186-189
19 Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med 2003; 348 (06) 538-549
20 Park KW, Kang J, Park JJ. , et al. Amlodipine, clopidogrel and CYP3A5 genetic variability: effects on platelet reactivity and clinical outcomes after percutaneous coronary intervention. Heart 2012; 98 (18) 1366-1372
21 Sarafoff N, Neumann L, Morath T. , et al. Lack of impact of calcium-channel blockers on the pharmacodynamic effect and the clinical efficacy of clopidogrel after drug-eluting stenting. Am Heart J 2011; 161 (03) 605-610
22 Li AYW, Ng FH, Chan FKL, Tunggal P, Chan K, Lau YK. Effect of amlodipine on platelet inhibition by clopidogrel in patients with ischaemic heart disease: a randomised, controlled trial. Heart 2013; 99 (07) 468-473
23 Pelliccia F, Greco C, Gaudio C. , et al. Comparison of the pharmacodynamic effects of ranolazine versus amlodipine on platelet reactivity in stable patients with coronary artery disease treated with dual antiplatelet therapy: the ROMAN (RanOlazine vs. aMlodipine on platelet reactivity in stable patients with CAD treated with dual ANtiplatelet therapy) study. J Thromb Thrombolysis 2015; 40 (03) 331-339
24 Lee SP, Bae JW, Park KW. , et al. Inhibitory interaction between calcium channel blocker and clopidogrel. Efficacy of cilostazol to overcome it. Circ J 2011; 75 (11) 2581-2589
25 Olesen JB, Gislason GH, Charlot MG. , et al. Calcium-channel blockers do not alter the clinical efficacy of clopidogrel after myocardial infarction: a nationwide cohort study. J Am Coll Cardiol 2011; 57 (04) 409-417
26 Good CW, Steinhubl SR, Brennan DM, Lincoff AM, Topol EJ, Berger PB. Is there a clinically significant interaction between calcium channel antagonists and clopidogrel?: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Circ Cardiovasc Interv 2012; 5 (01) 77-81
27 Nagano M, Hokimoto S, Nakao K, Kaikita K, Akasaka T, Ogawa H. ; Kumamoto Intervention Conference Study (KICS) Investigators. Relation between stent thrombosis and calcium channel blocker after drug-eluting stent implantation: Kumamoto Intervention Conference Study (KICS) registry. J Cardiol 2015; 66 (04) 333-340
28 Wang CY, Lin ZF, Lee CM. , et al. Concomitant use of calcium channel blockers with dual antiplatelet therapy and re-hospitalization for acute coronary syndrome. Pharmacoepidemiol Drug Saf 2017; 26 (03) 229-238
29 Gurbel PA, Bliden KP, Saucedo JF. , et al. Bivalirudin and clopidogrel with and without eptifibatide for elective stenting: effects on platelet function, thrombelastographic indexes, and their relation to periprocedural infarction results of the CLEAR PLATELETS-2 (Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets) study. J Am Coll Cardiol 2009; 53 (08) 648-657
30 Lev EI, Bliden KP, Jeong YH. , et al. Influence of race and sex on thrombogenicity in a large cohort of coronary artery disease patients. J Am Heart Assoc 2014; 3 (05) e001167
31 Fogari R, Zoppi A. Antihypertensive drugs and fibrinolytic function. Am J Hypertens 2006; 19 (12) 1293-1299
32 Rajzer M, Wojciechowska W, Kawecka-Jaszcz K, Undas A. Plasma fibrin clot properties in arterial hypertension and their modification by antihypertensive medication. Thromb Res 2012; 130 (01) 99-103
33 Ozkan G, Ulusoy S, Sönmez M. , et al. Thrombin activatable fibrinolysis inhibitor (TAFI) levels in hypertensive patients and a comparison of the effects of amlodipine and ramipril on TAFI levels. Clin Exp Hypertens 2013; 35 (02) 134-140
34 Spencer CG, Felmeden DC, Blann AD, Lip GY. Effects of “newer” and “older” antihypertensive drugs on hemorrheological, platelet, and endothelial factors. A substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. Am J Hypertens 2007; 20 (06) 699-704