Advertisement

Rivaroxaban plus aspirin versus acenocoumarol to manage recurrent venous thromboembolic events despite systemic anticoagulation with rivaroxaban

Published:December 20, 2022DOI:https://doi.org/10.1016/j.thromres.2022.12.008

      Abstract

      Introduction

      The evaluation and management of patients who sustain recurrent thromboembolic events while taking therapeutic anticoagulation have not been well characterized; moreover, there has been no systematic review or randomized trial focused on treating patients with recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) during anticoagulant treatment. Therefore, we developed a pilot trial to compare rivaroxaban plus aspirin versus acenocoumarol in patients with recurrent venous thromboembolism despite ongoing anticoagulation with rivaroxaban.

      Materials and methods

      The study was a multicenter, randomized clinical trial. We randomly assigned patients with objectively documented recurrent venous thromboembolism to receive rivaroxaban (20 mg once a day) plus aspirin (300 mg once a day) or an adjusted dose of acenocoumarol. The study was designed to evaluate the incidence of recurrent thromboembolic events (recurrent ipsilateral or contralateral DVT, PE, ischemic stroke, and myocardial infarction) and hemorrhagic events.

      Results

      A total of 58 patients were randomized: 28 were allocated to the rivaroxaban plus aspirin group and 30 to the acenocoumarol group. After 90 days of follow-up, three recurrent thromboembolic events (primary outcome) occurred in the acenocoumarol group – two DVTs and one ischemic stroke – and zero events in the rivaroxaban plus aspirin group (risk ratio [RR] 0.15; 95 % confidence interval [CI] 0.008–2.83; P = 0.20). Minor bleeding occurred in five patients in the acenocoumarol group and zero in the rivaroxaban plus aspirin group (RR 0.09; 95 % CI 0.005–1.68; p = 0.10). There was one non-fatal gastrointestinal major bleed in the rivaroxaban plus aspirin group.

      Conclusions

      In this pilot study, there were no significant differences in any outcome assessed; however, recurrent thromboembolic events and minor bleeding events occurred numerically less frequently in the rivaroxaban plus aspirin group. These data suggest the need to carry out more extensive randomized studies with sufficient statistical power to clarify these results.

      Graphical abstract

      Abbreviations:

      DVT (deep vein thrombosis), PE (pulmonary embolism), PC (protein C), PS (protein S), AT (antithrombin), Plg (plasminogen), APS (antiphospholipid syndrome), ASH (American Society of Hematology), DOACs (direct oral anticoagulants), VKAs (vitamin K antagonists), LMWH (low-molecular-weight heparin)

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Thrombosis Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Raskob G.E.
        • Angchaisuksiri P.
        • Blanco A.N.
        • et al.
        Thrombosis: a major contributor to global disease burden.
        Thromb. Res. 2014; 134: 931-938
        • Heit J.A.
        Epidemiology of venous thromboembolism.
        Nat. Rev. Cardiol. 2015; 12: 464-474
        • Tagalakis V.
        • Patenaude V.
        • Kahn S.R.
        • Suissa S.
        Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort.
        Am. J. Med. 2013 Sep; 126 (Epub 2013 Jul 3 PMID: 23830539): 832.e13-832.e21https://doi.org/10.1016/j.amjmed.2013.02.024
        • Kearon C.
        • Ageno W.
        • Cannegieter S.C.
        • et al.
        Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH.
        J. Thromb. Haemost. 2016; 14: 1480-1483
        • Lindstrom S.
        • Wang L.
        • Smith E.N.
        • et al.
        Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.
        Blood. 2019; 134: 1645-1657
        • Ortel T.L.
        • Neumann I.
        • Ageno W.
        • Beyth R.
        • Clark N.P.
        • Cuker A.
        • Hutten B.A.
        • Jaff M.R.
        • Manja V.
        • Schulman S.
        • Thurston C.
        • Vedantham S.
        • Verhamme P.
        • Witt D.M.
        • D Florez I.
        • Izcovich A.
        • Nieuwlaat R.
        • Ross S.
        • J Schünemann H.
        • Wiercioch W.
        • Zhang Y.
        • Zhang Y.
        American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
        Blood Adv. 2020 Oct 13; 4 (PMID: 33007077; PMCID: PMC7556153): 4693-4738https://doi.org/10.1182/bloodadvances.2020001830
        • Tahir F.
        • Riaz H.
        • Riaz T.
        • et al.
        The new oral anti-coagulants and the phase 3 clinical trials - a systematic review of the literature.
        Thromb. J. 2013; 11: 18
        • Gómez-Outes A.
        • Terleira-Fernández A.I.
        • Lecumberri R.
        • Suárez-Gea M.L.
        • Vargas-Castrillón E.
        Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis.
        Thromb. Res. 2014 Oct; 134 (Epub 2014 Jul 6 PMID: 25037495): 774-782https://doi.org/10.1016/j.thromres.2014.06.020
        • Hirschl M.
        • Kundi M.
        New oral anticoagulants in the treatment of acute venous thromboembolism - a systematic review with indirect comparisons [published correction appears in Vasa. 2014;43(6):477].
        Vasa. 2014; 43: 353-364
        • Kakkos S.K.
        • Kirkilesis G.I.
        • Tsolakis I.A.
        Editor's Choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials.
        Eur. J. Vasc. Endovasc. Surg. 2014; 48: 565-575
        • Kang N.
        • Sobieraj D.M.
        Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism.
        Thromb. Res. 2014; 133: 1145-1151
        • Loffredo L.
        • Perri L.
        • Del Ben M.
        • Angelico F.
        • Violi F.
        New oral anticoagulants for the treatment of acute venous thromboembolism: are they safer than vitamin K antagonists? A meta-analysis of the interventional trials.
        Intern. Emerg. Med. 2015; 10: 499-506
        • Dentali F.
        • Di Minno M.N.
        • Gianni M.
        • Ambrosino P.
        • Squizzato A.
        • Ageno W.
        Non-vitamin K oral anticoagulants in patients with pulmonary embolism: a systematic review and meta-analysis of the literature.
        Intern. Emerg. Med. 2015; 10: 507-514
        • Di Minno M.N.
        • Ambrosino P.
        • Lupoli R.
        • Di Minno A.
        • Dentali F.
        Direct oral anticoagulants for the treatment of unprovoked venous thromboembolism: a meta-analysis of randomised controlled trials.
        Blood Transfus. 2015; 13: 391-395
        • Fox B.D.
        • Kahn S.R.
        • Langleben D.
        • Eisenberg M.J.
        • Shimony A.
        Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials.
        BMJ. 2012; 345e7498
        • Ganji R.
        • Ala S.
        • Aarabi M.
        • Baghery B.
        • Salehifar E.
        Comparison of dabigatran vs. warfarin in acute venous thromboembolism: systematic review.
        Iran.J. Pharm. Res. 2016; 15: 611-617
        • Gómez-Outes A.
        • Suárez-Gea M.L.
        • Lecumberri R.
        • Terleira-Fernández A.
        • Vargas-Castrillón E.
        Direct oral anticoagulants in the treatment of venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review.
        Vasc. Health Risk Manag. 2014; 10: 627-639https://doi.org/10.2147/VHRM.S50543
        • van der Hulle T.
        • Kooiman J.
        • den Exter P.L.
        • Dekkers O.M.
        • Klok F.A.
        • Huisman M.V.
        Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis.
        J. Thromb. Haemost. 2014; 12: 320-328
        • van Es N.
        • Coppens M.
        • Schulman S.
        • Middeldorp S.
        • Büller H.R.
        Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials.
        Blood. 2014 Sep 18; 124 (Epub 2014 Jun 24 PMID: 24963045): 1968-1975https://doi.org/10.1182/blood-2014-04-571232
        • Vedovati M.C.
        • Becattini C.
        • Germini F.
        • Agnelli G.
        Efficacy and safety of direct oral anticoagulants after pulmonary embolism: a meta-analysis.
        Int. J. Cardiol. 2014; 177: 601-603
        • Mumoli N.
        • Cei M.
        • Pesavento R.
        • Campanini M.
        • Dentali F.
        Are direct oral anticoagulants equally effective in reducing deep vein thrombosis and pulmonary embolism?.
        Int. J. Cardiol. 2015; 187: 645-647
        • Petrov V.I.
        • Shatalova O.V.
        • Gorbatenko V.S.
        • Smuseva O.N.
        • Maslakov A.S.
        Efficacy and safety of the new oral anticoagulants in the treatment of venous thromboembolic complications: meta-analysis.
        Ration.Pharmacother.Cardiol. 2016; 12: 31-39
        • Robertson L.
        • Kesteven P.
        • McCaslin J.E.
        Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.
        Cochrane Database Syst. Rev. 2015; CD010956
        • Robertson L.
        • Kesteven P.
        • McCaslin J.E.
        Oral direct thrombin inhibitors or oral factor xa inhibitors for the treatment of pulmonary embolism.
        Cochrane Database Syst. Rev. 2015; CD010957
        • Senoo K.
        • Kondo Y.
        • Miyazawa K.
        • Isogai T.
        • Chun Y.H.
        • Kobayashi Y.
        Safety and efficacy of direct oral anticoagulants over warfarin in Japanese patients with acute venous thromboembolism: a meta-analysis.
        J. Cardiol. 2017; 69: 763-768
        • Adam S.S.
        • McDuffie J.R.
        • Ortel T.L.
        • Williams Jr., J.W.
        Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review.
        Ann. Intern. Med. 2012; 157: 796-807
        • Almutairi A.R.
        • Zhou L.
        • Gellad W.F.
        • et al.
        Effectiveness and safety of non-vitamin K antagonist oral anticoagulants for atrial fibrillation and venous thromboembolism: a systematic review and meta-analyses.
        Clin. Ther. 2017; 39: 1456-1478.e36
        • Castellucci L.A.
        • Cameron C.
        • Le Gal G.
        • et al.
        Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis.
        JAMA. 2014; 312: 1122-1135
        • Cohen A.T.
        • Hamilton M.
        • Mitchell S.A.
        • et al.
        Comparison of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the initial and long-term treatment and prevention of venous thromboembolism: systematic review and network meta-analysis.
        PLoS One. 2015; 10e0144856
        • Goy J.
        • Lee J.
        • Levine O.
        • et al.
        Sub-segmental pulmonary embolism in three academic teaching hospitals: a review of management and outcomes.
        J. Thromb. Haemost. 2015; 13: 214
        • Schmitz-Rode T.
        • Günther R.W.
        • Pfeffer J.G.
        • et al.
        Acute massive pulmonary embolism: use of a rotatable pigtail catheter for diagnosis and fragmentation therapy.
        Radiology. 1995; 197: 157
        • Schmitz-Rode T.
        • Janssens U.
        • Schild H.H.
        • et al.
        Fragmentation of massive pulmonary embolism using a pigtail rotation catheter.
        Chest. 1998; 114: 1427
        • Kuo W.T.
        • Gould M.K.
        • Louie J.D.
        • et al.
        Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.
        J. Vasc. Interv. Radiol. 2009; 20: 1431
        • Nakazawa K.
        • Tajima H.
        • Murata S.
        • et al.
        Catheter fragmentation of acute massive pulmonary thromboembolism: distal embolisation and pulmonary arterial pressure elevation.
        Br. J. Radiol. 2008; 81: 848
        • Kuo W.T.
        • van den Bosch M.A.A.J.
        • Hofmann L.V.
        • et al.
        Catheter-directed embolectomy, fragmentation, and thrombolysis for the treatment of massive pulmonary embolism after failure of systemic thrombolysis.
        Chest. 2008; 134: 250
        • Kumar N.
        • Janjigian Y.
        • Schwartz D.R.
        Paradoxical worsening of shock after using a percutaneous mechanical thrombectomy device in a postpartum patient with a massive pulmonary embolism.
        Chest. 2007; 132: 677
        • Buller H.R.
        • Agnelli G.
        • Hull R.D.
        • Hyers T.M.
        • Prins M.H.
        • Raskob G.E.
        Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
        Chest. 2004; 126: 401S-428S
        • Elting L.S.
        • Escalante C.P.
        • Cooksley C.
        • Avritscher E.B.
        • Kurtin D.
        • Hamblin L.
        • Khosla S.G.
        • Rivera E.
        Outcomes and cost of deep venous thrombosis among patients with cancer.
        Arch. Intern. Med. 2004; 164: 1653-1661
        • PREPIC Study Group
        Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study.
        Circulation. 2005; 112: 416-422
        • Hann C.L.
        • Streiff M.B.
        The role of vena caval filters in the management of venous thromboembolism.
        Blood Rev. 2005; 19: 179-202
        • Mismetti P.
        • Rivron-Guillot K.
        • Moulin N.
        Vena cava filters and treatment of venous thromboembolism in cancer patients.
        Pathol. Biol. 2008; 56 (Paris): 229-232
        • Jarrett B.P.
        • Dougherty M.J.
        • Calligaro K.D.
        Inferior vena cava filters in malignant disease.
        J. Vasc. Surg. 2002; 36: 704-707
        • Carrier M.
        • Le Gal G.
        • Cho R.
        • et al.
        Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients.
        J. Thromb. Haemost. 2009; 7: 760
        • Luk C.
        • Wells P.S.
        • Anderson D.
        • Kovacs M.J.
        Extended outpatient therapy with low molecular weight heparin for the treatment of recurrent venous thromboembolism despite warfarin therapy.
        Am. J. Med. 2001; 111: 270-273
        • Ansell J.
        • Hirsh J.
        • Hylek E.
        • et al.
        Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines.
        Chest. 2008; 133: 160S
        • Holbrook A.
        • Schulman S.
        • Witt D.M.
        • et al.
        Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
        Chest. 2012; 141: e152S
        • Ageno W.
        • Gallus A.S.
        • Wittkowsky A.
        • et al.
        Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
        Chest. 2012; 141: e44S
        • Garcia P.
        • Ruiz W.
        • Loza Munárriz C.
        Warfarin initiation nomograms for venous thromboembolism.
        Cochrane Database Syst. Rev. 2016 Jan 29; 2016 (PMID: 26822633; PMCID: PMC8078391): CD007699https://doi.org/10.1002/14651858.CD007699.pub3
        • Ortel T.L.
        • Neumann I.
        • Ageno W.
        • Beyth R.
        • Clark N.P.
        • Cuker A.
        • Hutten B.A.
        • Jaff M.R.
        • Manja V.
        • Schulman S.
        • Thurston C.
        • Vedantham S.
        • Verhamme P.
        • Witt D.M.
        • D Florez I.
        • Izcovich A.
        • Nieuwlaat R.
        • Ross S.
        • J Schünemann H.
        • Wiercioch W.
        • Zhang Y.
        • Zhang Y.
        American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.
        Blood Adv. 2020 Oct 13; 4 (PMID: 33007077; PMCID: PMC7556153): 4693-4738https://doi.org/10.1182/bloodadvances.2020001830
        • Perera K.S.
        • Ng K.K.H.
        • Nayar S.
        • Catanese L.
        • Dyal L.
        • Sharma M.
        • Connolly S.J.
        • Yusuf S.
        • Bosch J.
        • Eikelboom J.W.
        • Hart R.G.
        Association between low-dose rivaroxaban with or without aspirin and ischemic stroke subtypes: a secondary analysis of the COMPASS trial.
        JAMA Neurol. 2020 Jan 1; 77 (PMID: 31524941; PMCID: PMC6749537): 43-48https://doi.org/10.1001/jamaneurol.2019.2984
        • Tomkowski W.Z.
        • Davidson B.L.
        Thromboprophylaxis by rivaroxaban, aspirin, both, or placebo after hospitalization for medical illness.
        Thromb. Res. 2019 Aug; 180 (Epub 2019 Jun 11 PMID: 31226663): 62-63https://doi.org/10.1016/j.thromres.2019.06.002
        • Sim J.
        • Lewis M.
        The size of a pilot study for a clinical trial should be calculated in relation to considerations of precision and efficiency.
        J. Clin. Epidemiol. 2012; 65: 301-308
        • Cervera R.
        • Piette J.C.
        • Font J.
        • et al.
        Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.
        Arthritis Rheum. 2002; 46: 1019
        • Flemming K.D.
        • Brown Jr., R.D.
        • Petty G.W.
        • et al.
        Evaluation and management of transient ischemic attack and minor cerebral infarction.
        Mayo Clin. Proc. 2004; 79: 1071
        • Niccoli G.
        • Scalone G.
        • Crea F.
        Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management.
        Eur. Heart J. 2015; 36: 475
        • Goodnough L.T.
        • Saito H.
        • Ratnoff O.D.
        Thrombosis or myocardial infarction in congenital clotting factor abnormalities and chronic thrombocytopenias: a report of 21 patients and a review of 50 previously reported cases.
        Medicine. 1983; 62 (Baltimore): 248
        • Ratnoff O.D.
        • Busse R.J.
        • Sheon R.P.
        The demise of John Hageman.
        N. Engl. J. Med. 1968; 279: 760
        • Lodi S.
        • Isa L.
        • Pollini E.
        • et al.
        Defective intrinsic fibrinolytic activity in a patient with severe factor XII-deficiency and myocardial infarction.
        Scand. J. Haematol. 1984; 33: 80
        • Bergmark B.A.
        • Kamphuisen P.W.
        • Wiviott S.D.
        • Ruff C.T.
        • Antman E.M.
        • Nordio F.
        • Kuder J.F.
        • Mercuri M.F.
        • Lanz H.J.
        • Braunwald E.
        • Giugliano R.P.
        Comparison of events across bleeding scales in the ENGAGE AF-TIMI 48 trial.
        Circulation. 2019 Nov 26; 140 (Epub 2019 Oct 10 PMID: 31597460): 1792-1801https://doi.org/10.1161/CIRCULATIONAHA.119.041346