Exploring unmet needs in venous and arterial thromboembolism with rivaroxaban

Summary

The vast clinical research programme for the direct, oral factor Xa inhibitor rivaroxaban has generated a wealth of data since the first rivaroxaban approval in 2008 for the prevention of venous thrombo embolism (VTE) in patients undergoing elective hip or knee replacement surgery. While rivaroxaban is widely used across a spectrum of seven indications, there is continuous commitment to investigating its wider benefits in new indications and attempts to refine current evidence. Key data from recently completed randomised controlled trials (RCTs) have shown that rivaroxaban is a feasible anticoagulation option for patients with non-valvular atrial fibrillation (NVAF) undergoing cardioversion or catheter ablation. Now, a number of Phase II and III RCTs are underway that seek to uncover further roles for rivaroxaban in patients at risk of thrombosis and aim to improve quality of life. This article will introduce and provide context for these RCTs in the contemporary management of arterial and venous thromboembolism in the following underserved areas: Patients with both NVAF and acute coronary syndrome (ACS) requiring percutaneous coronary intervention (PCI); patients with embolic stroke of undetermined source (ESUS); patients who require transcatheter aortic valve replacement (TAVR); patients with acute or chronic coronary artery disease (CAD; including those with heart failure [HF]); those at risk of or suffering from cancer-associated thrombosis (CAT) and those requiring long-term anticoagulation. It is hoped that this collection of studies provides clarity around the use of rivaroxaban as a fundamental component of antithrombotic therapy in an array of clinical situations.

Keywords

Rivaroxaban - acute coronary syndrome - atrial fibrillation - venous thromboembolism - transcatheter aortic valve replacement

• References

• 1 Bayer AGPharma. Xarelto Summary of Product Characteristics. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/docu ment_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf Accessed May 18, 2016.
• 2 FierceBiotech. Bayer’s Xarelto Approved in Canada. Available at: http://www.fiercebiotech com/biotech/bayer-s-xarelto-approved-canada Accessed May 23, 2016.
• 3 Patel MR. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
• 4 EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 5 EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
• 6 Mega JL. ATLAS ACS 2-TIMI 51 Investigators. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-12.
• 7 Cappato R. et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J 2014; 35: 3346-3355.
• 8 Cappato R. et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J 2015; 36: 1805-1811.
• 9 Stellbrink C. et al. Safety and efficacy of enoxaparin compared with unfractionated heparin and oral anticoagulants for prevention of thromboembolic complications in cardioversion of nonvalvular atrial fibrillation: the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial. Circulation 2004; 109: 997-1003.
• 10 Camm AJ. et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33: 2719-2747.
• 11 Piccini JP. et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013; 61: 1998-2006.
• 12 Ezekowitz MD. et al. Rationale and design of the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prEvention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion trial: A comparison of oral rivaroxaban once daily with dose-adjusted vitamin K antagonists in patients with nonvalvular atrial fibrillation undergoing elective cardioversion. Am Heart J 2014; 167: 646-652.
• 13 Bayer AGPharma. European label update of Bayer’s Xarelto^® now including guidance for use in patients with atrial fibrillation undergoing cardioversion (Press Release). Available at: https://www.xarelto.com/en/resources/newsfeed/european-label-update-of-bayers-xarelto-now-including-guidance-for-use-in-patients-with-atrial-fibrillation-undergoing-cardioversion Accessed June 20, 2016.
• 14 Naccarelli GV. et al. Rationale and design of VENTURE-AF: a randomized, open-label, active-controlled multicenter study to evaluate the safety of rivaroxaban and vitamin K antagonists in subjects undergoing catheter ablation for atrial fibrillation. J Interv Card Electrophysiol 2014; 41: 107-116.
• 15 A Study Exploring Two Treatment Strategies in Patients With Atrial Fibrillation Who Undergo Catheter Ablation Therapy. https://ClinicalTrials.gov/show/ NCT01729871
• 16 Connolly S. et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903-1912.
• 17 Leon MB. 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.
• 18 Camm AJ. et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369-2429.
• 19 Dewilde WJ. et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381: 1107-1115.
• 20 A Study Exploring Two Strategies of Rivaroxaban (JNJ39039039; BAY-59-7939) and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention. https://ClinicalTrials.gov/show/ NCT01830543
• 21 Gibson CM. et al. An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J 2015; 169: 472-478.
• 22 Fang MC. et al. Long-term survival after ischemic stroke in patients with atrial fibrillation. Neurology 2014; 82: 1033-1037.
• 23 Hart RG. et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429-438.
• 24 Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS). https://ClinicalTrials.gov/show/NCT02313909
• 25 Eggebrecht H, Mehta RH. Transcatheter aortic valve implantation (TAVI) in Germany 2008-2014: on its way to standard therapy for aortic valve stenosis in the elderly?. EuroIntervention 2016; 11: 1029-1033.
• 26 Reardon MJ. et al. 2-Year Outcomes in Patients Undergoing Surgical or Self-Expanding Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2015; 66: 113-121.
• 27 Eggebrecht H. et al. Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients. EuroIntervention 2012; 08: 129-138.
• 28 Merie C. et al. Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding. J Am Med Assoc 2012; 308: 2118-2125.
• 29 Latib A. et al. Treatment and clinical outcomes of transcatheter heart valve thrombosis. Circ Cardiovasc Interv 2015; 08: e001779.
• 30 Makkar RR. et al. Possible Subclinical Leaflet Thrombosis in Bioprosthetic Aortic Valves. N Engl J Med 2015; 373: 2015-2024.
• 31 Global Study Comparing a rivAroxaban-based Antithrombotic Strategy to an antipLatelet-based Strategy After Transcatheter aortIc vaLve rEplacement to Optimize Clinical Outcomes. ttps://ClinicalTrials.gov/show/NCT02556203
• 32 Grech ED, Ramsdale DR. Acute coronary syndrome: unstable angina and non-ST segment elevation myocardial infarction. Br Med J 2003; 326: 1259-1261.
• 33 Fox KA. et al. Underestimated and under-recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study). Eur Heart J 2010; 31: 2755-2764.
• 34 Steg PG. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-2619.
• 35 Roffi M. et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267-315.
• 36 Yusuf S. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
• 37 Wallentin L, et al., PLATO Investigators. Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 10: 1045-1057.
• 38 Povsic TJ. et al. A Randomized Trial to Compare the Safety of Rivaroxaban versus Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome: The Design of the GEMINI-ACS-1 Phase II. Am Heart J 2016; 174: 120-128.
• 39 A Study to Compare the Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome. https://ClinicalTrials.gov/show/NCT02293395
• 40 Steg PG. et al. One-year cardiovascular event rates in outpatients with atherothrombosis. J Am Med Assoc 2007; 297: 1197-1206.
• 41 Montalescot G. et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34: 2949-3003.
• 42 Tendera M. et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2851-2906.
• 43 Mauri L. et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155-2166.
• 44 Bonaca MP. et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791-1800.
• 45 Morrow DA. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404-1413.
• 46 Norgren L. et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45 Suppl: S5-67.
• 47 Hur DJ. et al. Frequency of coronary artery disease in patients undergoing peripheral artery disease surgery. Am J Cardiol 2012; 110: 736-740.
• 48 Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease. https://ClinicalTrials.gov/show/NCT01776424
• 49 Sarac TP. et al. Warfarin improves the outcome of infrainguinal vein bypass grafting at high risk for failure. J Vasc Surg 1998; 28: 446-457.
• 50 Ullery BW. et al. Safety and efficacy of antiplatelet/anticoagulation regimens after Viabahn stent graft treatment for femoropopliteal occlusive disease. J Vasc Surg 2015; 61: 1479-1488.
• 51 Geraghty AJ, Welch K. Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery. Cochrane Database Syst Rev 2011; 06: CD000536.
• 52 Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities. https://Clinical-Trials.gov/show/NCT02504216
• 53 McMurray JJ. et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787-1847.
• 54 Zannad F. et al. Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges. Int J Cardiol 2013; 167: 1772-1782.
• 55 Cleland JG. et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004; 148: 157-164.
• 56 Homma S. et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012; 366: 1859-1869.
• 57 Cokkinos DV. et al. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail 2006; 08: 428-432.
• 58 Janssen Research & Development, LLC. Advisory Committee Briefing Document. Rivaroxaban for Reducing the Risk of Cardiovascular Events (Cardiovascular Death, Myocardial Infarction and Stroke) After Acute Coronary Syndrome (ACS). Document No.: EDMS-ERI-38428183:2.0 (April 2012). Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ UCM304757.pdf
• 59 Zannad F. et al. Rationale and design of a randomized, double-blind, eventdriven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and significant coronary artery disease following an exacerbation of heart failure: the COMMANDER HF trial. Eur J Heart Fail 2015; 17: 735-742.
• 60 A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure. https://ClinicalTrials.gov/show/NCT01877915
• 61 Prandoni P. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92: 199-205.
• 62 Becattini C. et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366: 1959-1967.
• 63 Brighton TA. et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367: 1979-1987.
• 64 Weitz JI. EINSTEIN CHOICE Investigators. et al. Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study. Thromb Haemost 2015; 114: 645-650.
• 65 Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic VTE(Venous Thromboembolism). https://ClinicalTrials.gov/show/NCT02064439
• 66 Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer 2011; 117: 1334-1349.
• 67 Gould MK. et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e227S-e277S.
• 68 Lyman GH. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31: 2189-2204.
• 69 Watson HG. et al. Guideline on aspects of cancer-related venous thrombosis. Br J Haematol 2015; 170: 640-648.
• 70 Mandala M. et al. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22 (Suppl. 06) 85-: 92.
• 71 Konstantinides SV. et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35: 3033-3069k.
• 72 Kearon C. et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149: 315-352.
• 73 Seaman S. et al. Cancer-associated thrombosis, low-molecular-weight heparin, and the patient experience: a qualitative study. Patient Prefer Adherence 2014; 08: 453-461.
• 74 Linkins LA. et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 141. 2 suppl e495S-e530S.
• 75 AWMF-Leitlinien-Register Nr. 065/002. Available at: http://www.awmf.org/ uploads/tx_szleitlinien/065-002l_S2k_VTE_2016-01.pdf Accessed February 16, 2016.
• 76 Prins MH. et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014; 01: e37-46.
• 77 Johnson and Johnson. New clinical research program initiated for the prevention and treatment of life-threatening blood clots in patients with cancer. Available at: http://www.jnj.com/news/all/New-Clinical-Research-Program-Initi ated-for-the-Prevention-and-Treatment-of-Life-Threatening-Blood-Clots-in-Patients-with-Cancer Accessed May 23, 2016.