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Thromb Haemost 2014; 111(02): 258-265
DOI: 10.1160/TH13-07-0529
Platelets and Blood Cells
Schattauer GmbH

Pharmacodynamic effects of standard dose prasugrel versus high dose clopidogrel in non-diabetic obese patients with coronary artery disease

Andrew Darlington
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Antonio Tello-Montoliu
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Fabiana Rollini
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Masafumi Ueno
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
José Luis Ferreiro
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Ronakkumar Patel
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Bhaloo Desai
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Luis A. Guzman
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Theodore A. Bass
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
,
Dominick Angiolillo
1   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA
› Author Affiliations Financial support: The present investigation was funded in part by a Dean’s Award from the University of Florida College of Medicine-Jacksonville and by Institutional Research Funds from the Division of Cardiology of the University of Florida College of Medicine-Jacksonville.
Further Information

Publication History

Received: 01 July 2013

Accepted after minor revision: 17 September 2013

Publication Date:
27 November 2017 (online)

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Summary

Increased body weight is independently associated with impaired clopidogrel pharmacodynamic (PD) response. Prasugrel has more potent PD effects compared with clopidogrel, although its PD effects in obese patients are unknown. The aim of this prospective, randomised, study was to compare the PD effects of standard-dose prasugrel [60 mg loading dose (LD)/10 mg daily maintenance dose (MD)] with highdose clopidogrel (900 mg LD/150 mg daily MD) in non-diabetic obese [body mass index (BMI) ≥30 kg/m2] patients, with coronary artery disease (CAD) on aspirin therapy. PD assessments (baseline, 2 hours post-LD and 6 ± 2 days after MD) were conducted using four platelet function assays, and the platelet reactivity index (PRI) assessed by VASP was used for sample size estimation. A total of 42 patients with a BMI of 36.42 ± 5.6 kg/m2 completed the study. There were no differences in baseline PD measures between groups. At 2 hours post-LD, prasugrel was associated with lower PRI compared with clopidogrel (24.3 ± 5.5 vs 58.7 ± 5.7, p≤0.001), with consistent findings for all assays. At one-week, PRI values on prasugrel MD were lower than clopidogrel MD without reaching statistical significance (34.7 ± 5.8 vs 42.9 ± 5.8, p=0.32), with consistent findings for all assays. Accordingly, rates of high on-treatment platelet reactivity were markedly reduced after prasugrel LD, but not after MD. In conclusion, in non-diabetic obese patients with CAD, standard prasugrel dosing achieved more potent PD effects than high-dose clopidogrel in the acute phase of treatment, but this was not sustained during maintenance phase treatment. Whether an intensified prasugrel regimen is required in obese patients warrants investigation.

Keywords

Platelet function - obesity - coronary artery disease - prasugrel - clopidogrel
 

  • References

  • 1 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives.. J Am Coll Cardiol 2007; 49: 1505-1516.
    CrossrefPubMedGoogle Scholar
  • 2 Ferreiro JL, Angiolillo DJ. Clopidogrel response variability: current status and future directions.. Thromb Haemost 2009; 102: 7-14.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Bonello L, Tantry US, Marcucci R. et al. for the Working Group on High On-Treatment Platelet Reactivity.. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919-933.
    PubMedGoogle Scholar
  • 4 Gaglia Jr MA, Torguson R, Pakala R. et al. Relation of body mass index to on-treatment (clopidogrel + aspirin) platelet reactivity.. Am J Cardiol 2011; 108: 766-771.
    CrossrefPubMedGoogle Scholar
  • 5 Breet NJ, van Donkersgoed HE, van Werkum JW. et al. Is platelet inhibition due to thienopyridines increased in elderly patients, in patients with previous stroke and patients with low body weight as a possible explanation of an increased bleeding risk?. Neth Heart J 2011; 19: 279-284.
    CrossrefPubMedGoogle Scholar
  • 6 Zhu B, Effron MB, Kulkarni MP. et al. The onset of inhibition of platelet aggregation with prasugrel compared with clopidogrel loading doses using gatekeeping analysis of integrated clinical pharmacology data.. J Cardiovasc Pharmacol 2011; 57: 317-324.
    CrossrefPubMedGoogle Scholar
  • 7 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted?. J Invasive Cardiol 2004; 16: 169-174.
    PubMedGoogle Scholar
  • 8 Bonello-Palot N, Armero S, Paganelli F. et al. Relation of body mass index to high on-treatment platelet reactivity and of failed clopidogrel dose adjustment according to platelet reactivity monitoring in patients undergoing percutaneous coronary intervention.. Am J Cardiol 2009; 104: 1511-1515.
    CrossrefPubMedGoogle Scholar
  • 9 Sibbing D, von Beckerath O, Schomig A. et al. Impact of body mass index on platelet aggregation after administration of a high loading dose of 600 mg of clopidogrel before percutaneous coronary intervention.. Am J Cardiol 2007; 100: 203-205.
    CrossrefPubMedGoogle Scholar
  • 10 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.. J Am Coll Cardiol 2006; 48: 1742-1750.
    CrossrefPubMedGoogle Scholar
  • 11 Bonello L, Berbis J, Laine M. et al. Biological efficacy of a 600 mg loading dose of clopidogrel in ST-elevation myocardial infarction.. Thromb Haemost 2012; 108: 101-106.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Cayla G, Cuisset T, Silvain J. et al. Prasugrel monitoring and bleeding in real world patients.. Am J Cardiol 2013; 111: 38-44.
    CrossrefPubMedGoogle Scholar
  • 13 Alexopoulos D, Xanthopoulou I, Perperis A. et al. Factors Affecting Residual Platelet Aggregation in Prasugrel Treated Patients.. Curr Pharm Des 2013; 19: 5121-5126.
    CrossrefPubMedGoogle Scholar
  • 14 Cuisset T, Quilici J, Morange PE. et al. Predictors of long-term high on-treatment platelet reactivity in clopidogrel-treated patients undergoing coronary stenting for acute coronary syndrome.. Int J Cardiol 2013; 168: 1565-1566.
    CrossrefPubMedGoogle Scholar
  • 15 Gremmel T, Steiner S, Seidinger D. et al. Obesity is associated with poor response to clopidogrel and an increased susceptibility to protease activated receptor-1 mediated platelet activation.. Transl Res 2013; 161: 421-429.
    CrossrefPubMedGoogle Scholar
  • 16 Zürn CS, Geisler T, Gawaz M. ADP-receptor blockade: A case for personalised pharmacotherapy?. Thromb Haemost 2010; 103: 496-506.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Mokdad AH, Ford ES, Bowman BA. et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.. J Am Med Assoc 2003; 289: 76-79.
    CrossrefPubMedGoogle Scholar
  • 18 Angiolillo DJ, Badimon JJ, Saucedo J. et al. A Pharmacodynamic comparison of prasugrel vs.. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimising anti-Platelet Therapy in diabetes MellitUS (OPTIMUS)-3 Trial. Eur Heart J 2011; 32: 838-846.
    PubMedGoogle Scholar
  • 19 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment.. Diabetes 2005; 54: 2430-2435.
    CrossrefPubMedGoogle Scholar
  • 20 Ueno M, Ferreiro JL, Tomasello SD. et al. Functional profile of the platelet P2Y12 receptor signalling pathway in patients with type 2 diabetes mellitus and coronary artery disease.. Thromb Haemost 2011; 105: 730-732.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Erlinge D, Varenhorst C, Braun O. et al. Patients with poor responsiveness to thienopyridine treatment and those with diabetes have lower levels of circulating active metabolites but their platelets respond normally to the active meta-bolite added ex-vivo.. J Am Coll Cardiol 2008; 52: 1968-1977.
    CrossrefPubMedGoogle Scholar
  • 22 Sibbing D, Braun S, Morath T. et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis.. J Am Coll Cardiol 2009; 53: 849-856.
    CrossrefPubMedGoogle Scholar
  • 23 Brar SS, ten Berg J, Marcucci R. et al. Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data.. J Am Coll Cardiol. 2011; 58: 1945-1954.
    CrossrefPubMedGoogle Scholar
  • 24 Price MJ, Angiolillo DJ, Teirstein PS. et al. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial.. Circulation 2011; 124: 1132-1137.
    CrossrefPubMedGoogle Scholar
  • 25 Wiviott SD, Trenk D, Frelinger AL. et al. Prasugrel compared with high loading and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial.. Circulation 2007; 116: 2923-2932.
    CrossrefPubMedGoogle Scholar
  • 26 Jernberg T, Payne C, Winters K. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin- treated patients with stable coronary artery disease.. Eur Heart J 2006; 27: 1166-1173.
    CrossrefPubMedGoogle Scholar
  • 27 Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome.. Circulation 2011; 123: 798-813.
    CrossrefPubMedGoogle Scholar
  • 28 Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans.. Clin Pharmacokinet. 2010; 49: 71-87.
    CrossrefPubMedGoogle Scholar
  • 29 Santilli F, Vazzana N, Liani R. et al. Platelet activation in obesity and metabolic syndrome.. Obes Rev 2012; 13: 27-42.
    CrossrefPubMedGoogle Scholar
  • 30 Gandhi A, Moorthy B, Ghose R. Drug disposition in pathophysiological conditions.. Curr Drug Metab 2012; 9: 1327-1344.
    CrossrefPubMedGoogle Scholar
  • 31 Kotlyar M, Carson SW. Effects of obesity of the cytochrome p450 system.. Int J Clin Pharmacol Ther 1999; 1: 8-19.
    PubMedGoogle Scholar
  • 32 Rocca B, Santilli F, Pitocco D. et al. The recovery of platelet cyclooxygenase activity explains inter-individual variability in responsiveness to low-dose aspirin in patients with and without diabetes.. J Thromb Haemost 2012; 7: 1220-1230.
    CrossrefPubMedGoogle Scholar
  • 33 Takaya J, Iwamoto Y, Higashino H. et al. Altered intracellular calcium and phorbol 12,13-dibutyrate binding to intact platelets in young obese subject.. J Lab Clin Med 1997; 129: 245-250.
    CrossrefPubMedGoogle Scholar
  • 34 Scherrer U, Nussberger J, Torriani S. et al. Effect of weight reduction in moderately overweight patients on recorded ambulatory blood pressure and free cytostolic platelet calcium.. Circulation 1991; 83: 552-558.
    CrossrefPubMedGoogle Scholar
  • 35 Anfossi G, Russo I, Trovati M. Platelet resistance to the anti-aggregating agents in the insulin resistant states.. Curr Diabetes Rev 2006; 4: 409-430.
    PubMedGoogle Scholar
  • 36 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease.. Eur Heart J 2008; 29: 21-30.
    CrossrefPubMedGoogle Scholar
  • 37 Wrishko RE, Ernest CS, Small DS. et al. Population pharmacokinetic analyses to evaluate the influence of intrinsic and extrinsic factors on exposure of prasugrel active metabolite in TRITON-TIMI 38.. J Clin Pharmacol 2009; 49: 984-998.
    CrossrefPubMedGoogle Scholar
  • 38 Erlinge D, Ten Berg J, Foley D. et al. Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial.. J Am Coll Cardiol 2012; 60: 2032-2040.
    CrossrefPubMedGoogle Scholar
  • 39 Ernest CS, Small DS, Rohatagi S. et al. Population pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel in aspirin-treated patients with stable coronary artery disease.. J Pharmacokinet Pharmacodyn 2008; 35: 593-618.
    CrossrefPubMedGoogle Scholar
  • 40 Payne CD, Li YG, Small DS. et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel.. J Cardiovasc Pharmacol 2007; 50: 555-562.
    CrossrefPubMedGoogle Scholar
  • 41 Wiviott S, Antman E, Winters K. et al. Randomized Comparison of Prasugrel (CS-747, LY640315), a Novel Thienopyridine P2Y 12 Antagonist, With Clopidogrel in Percutaneous Coronary Intervention: Results of the Joint Utilisation of Medications to Block Platelets Optimally (JUMBO)–TIMI 26 Trial.. Circulation 2005; 111: 3366-3373.
    CrossrefPubMedGoogle Scholar
  • 42 Angiolillo DJ, Gibson CM, Cheng S. et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies.. Clin Pharmacol Ther 2011; 1: 65-74.
    CrossrefPubMedGoogle Scholar
  • 43 Linden M, Furman M, Frelinger A. et al. Indices of platelet activation and the stability of coronary artery disease.. J Thromb Haemost 2007; 4: 761-765.
    CrossrefPubMedGoogle Scholar
  • 44 Hochholzer W, Trenk D, Frundi D. et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention.. Circulation 2005; 111: 2560-2564.
    CrossrefPubMedGoogle Scholar
  • 45 Zhu B, Effron MB, Kulkarni MP. et al. The onset of inhibition of platelet aggregation with prasugrel compared with clopidogrel loading doses using gatekeeping analysis of integrated clinical pharmacology data.. J Cardiovasc Pharmacol 2011; 57: 317-324.
    CrossrefPubMedGoogle Scholar
  • 46 Jakubowski JA, Li YG, Small DS. et al. A comparison of the VerifyNow P2Y12 point-of-care device and light transmission aggregometry to monitor platelet function with prasugrel and clopidogrel: an integrated analysis.. J Cardiovasc Pharmacol 2010; 56: 29-37.
    CrossrefPubMedGoogle Scholar
  • 47 Montalescot G, Sideris G, Meuleman C. et al. ALBION Trial Investigators.. A randomized comparison of high clopidogrel loading doses in patients with nonST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial.. J Am Coll Cardiol 2006; 48: 931-938.
    CrossrefPubMedGoogle Scholar