Download PDF
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 (online)

    Permissions and Reprints

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

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.


 

  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310 (20) 2191-2194
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 19 Evans WE, McLeod HL. Pharmacogenomics--drug disposition, drug targets, and side effects. N Engl J Med 2003; 348 (06) 538-549
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 31 Fogari R, Zoppi A. Antihypertensive drugs and fibrinolytic function. Am J Hypertens 2006; 19 (12) 1293-1299
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar