Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease

Summary

Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6–8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin–antithrombin complex values at 2 h post-PCI were 3.90 [6.8] μg/l and 3.90 [10.1] μg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin–antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting.

Clinical trial registration: Clinical Trials.gov Identifier: NCT01442792 URL: EudraCT. Unique identifier: No: 2011–001094–58.

Keywords

Anticoagulation - coronary artery disease - rivaroxaban - thrombosis

• References

• 1 Leon MB, Baim DS, Popma JJ. et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339: 1665-1671.
• 2 Mann KG. Thrombin formation. Chest 2003; 124 (Suppl. 03) 4S-10S.
• 3 Silber S, Albertsson P, Aviles FF. et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005; 26: 804-847.
• 4 King III SB, Smith Jr. SC, Hirshfeld Jr. JW. et al. 2007 Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 writing group to review new evidence and update the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention, writing on behalf of the 2005 writing committee. Circulation 2008; 117: 261-295.
• 5 Ndrepepa G, Berger PB, Mehilli J. et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008; 51: 690-697.
• 6 Perzborn E, Strassburger J, Wilmen A. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939 □– an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005; 03: 514-521.
• 7 Kubitza D, Becka M, Wensing G. et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005; 61: 873-880.
• 8 Kubitza D, Becka M, Roth A. et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin 2008; 24: 2757-2765.
• 9 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
• 10 Thygesen K, Alpert JS, White HD. et al. Universal definition of myocardial infarction. Circulation 2007; 116: 2634-2653.
• 11 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123: 2736-2747.
• 12 Rao AK, Pratt C, Berke A. et al. Thrombolysis in Myocardial Infarction (TIMI) trial-phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol 1988; 11: 1-11.
• 13 Lip GYH, Windecker S, Huber K. et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014; 35: 3155-3179.
• 14 Mueck W, Stampfuss J, Kubitza D. et al. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53: 1-16.
• 15 Bayer Pharma AG. Xarelto^® (rivaroxaban) Summary of Product Characteristics. 2014 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf Accessed January 6, 2015.
• 16 Mueck W, Eriksson BI, Bauer KA. et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct Factor Xa inhibitor – in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47: 203-216.
• 17 Mueck W, Lensing AWA, Agnelli G. et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50: 675-686.
• 18 Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J 2013; 11: 10.
• 19 Samama MM, Contant G, Spiro TE. et al. Laboratory assessment of rivaroxaban: a review. Thromb J 2013; 11: 11.
• 20 Xu XS, Moore K, Burton P. et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol 2012; 74: 86-97.
• 21 Samama MM, Martinoli JL, Le Flem L. et al. Assessment of laboratory assays to measure rivaroxaban – an oral, direct Factor Xa inhibitor. Thromb Haemost 2010; 103: 815-825.
• 22 Theroux P, Waters D, Lam J. et al. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 1992; 327: 141-145.
• 23 Vranckx P, Verheugt FW, de Maat MP. et al. A randomised study of dabigatran in elective percutaneous coronary intervention in stable coronary artery disease patients. EuroIntervention 2013; 08: 1052-1060.
• 24 Mauri L, Kereiakes DJ, Yeh RW. et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155-2166.
• 25 Stone GW, Maehara A, Lansky AJ. et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011; 364: 226-235.
• 26 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
• 27 Merlini PA, Bauer KA, Oltrona L. et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-68.
• 28 Mega JL, Braunwald E, Wiviott SD. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.