Thromb Haemost 2022; 122(08): 1279-1287
DOI: 10.1055/a-1778-1083
Invited Mini Series: Novel Clinical Concepts in Thrombosis

State-of-the-Art Mini Review: Dual-Pathway Inhibition to Reduce Arterial and Venous Thromboembolism

Mark Goldin
1   Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Ioannis Koulas
1   Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
,
Jeffrey I. Weitz
3   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
4   Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
5   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Alex C. Spyropoulos
1   Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
6   Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
› Author Affiliations
Funding This study was supported by Broxmeyer Fellowship in Clinical Thrombosis.

Abstract

Venous thromboembolism (VTE) and arterial thromboembolism (ATE) are linked by the common mechanism of thrombin generation. Historically these entities have been treated as separate pathophysiologic processes requiring different treatments: VTE, as the formation of fibrin-/coagulation-factor-derived thrombus in low-flow vasculature, requiring anticoagulants; versus ATE, as largely platelet-derived thrombus in high-flow vasculature, requiring antiplatelet agents. Observational studies have elucidated shared risk factors and comorbidities predisposing individuals with VTE to ATE, and vice versa, and have bolstered the strategy of dual-pathway inhibition (DPI)—the combination of low-dose anticoagulants with antiplatelet agents—to reduce thrombotic outcomes on both sides of the vasculature. Randomized clinical trials have evaluated the efficacy and safety of such regimens—mostly rivaroxaban and aspirin—in high-risk groups of patients, including those with recent acute or chronic coronary syndrome, as well as those with peripheral artery disease with or without revascularization. Studies of extended VTE prophylaxis in acutely ill medical patients have also contributed to the evidence evaluating DPI. The totality of available data supports the concept that DPI can reduce major and fatal thromboembolic outcomes, including stroke, myocardial infarction, VTE, and cardiovascular death in key patient cohorts, with acceptable risk of bleeding. Further data are needed to refine which patients derive the best net clinical benefit from such an approach. At the same time, other novel agents such as contact pathway inhibitors that reduce thrombin generation without affecting hemostasis—and thus maximize safety—should be assessed in appropriate populations.



Publication History

Received: 23 November 2021

Accepted: 19 February 2022

Accepted Manuscript online:
21 February 2022

Article published online:
27 May 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost 2002; 28 (Suppl. 02) 3-13
  • 2 Goldhaber SZ, Grodstein F, Stampfer MJ. et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277 (08) 642-645
  • 3 Hansson PO, Eriksson H, Welin L, Svärdsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: “the study of men born in 1913”. Arch Intern Med 1999; 159 (16) 1886-1890
  • 4 Ageno W, Prandoni P, Romualdi E. et al. The metabolic syndrome and the risk of venous thrombosis: a case-control study. J Thromb Haemost 2006; 4 (09) 1914-1918
  • 5 Anderson Jr FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151 (05) 933-938
  • 6 Nordström M, Lindblad B, Bergqvist D, Kjellström T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232 (02) 155-160
  • 7 Cogo A, Bernardi E, Prandoni P. et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994; 154 (02) 164-168
  • 8 Libertiny G, Hands L. Deep venous thrombosis in peripheral vascular disease. Br J Surg 1999; 86 (07) 907-910
  • 9 Vayá A, Mira Y, Ferrando F. et al. Hyperlipidaemia and venous thromboembolism in patients lacking thrombophilic risk factors. Br J Haematol 2002; 118 (01) 255-259
  • 10 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117 (01) 93-102
  • 11 Prandoni P, Bilora F, Marchiori A. et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348 (15) 1435-1441
  • 12 Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Age and sex differences in the distribution and ultrasound morphology of carotid atherosclerosis: the Tromsø Study. Arterioscler Thromb Vasc Biol 1999; 19 (12) 3007-3013
  • 13 Ebrahim S, Papacosta O, Whincup P. et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999; 30 (04) 841-850
  • 14 Hollander M, Bots ML, Del Sol AI. et al. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study. Circulation 2002; 105 (24) 2872-2877
  • 15 Becattini C, Agnelli G, Prandoni P. et al. A prospective study on cardiovascular events after acute pulmonary embolism. Eur Heart J 2005; 26 (01) 77-83
  • 16 Schulman S, Lindmarker P, Holmström M. et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006; 4 (04) 734-742
  • 17 Prandoni P, Ghirarduzzi A, Prins MH. et al. Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis. J Thromb Haemost 2006; 4 (09) 1891-1896
  • 18 Sørensen HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet 2007; 370 (9601): 1773-1779
  • 19 Bhatt DL, Steg PG, Ohman EM. et al; REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006; 295 (02) 180-189
  • 20 Steg PG, Bhatt DL, Wilson PW. et al; REACH Registry Investigators. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007; 297 (11) 1197-1206
  • 21 Alberts MJ, Bhatt DL, Mas JL. et al; REduction of Atherothrombosis for Continued Health Registry Investigators. Three-year follow-up and event rates in the international REduction of Atherothrombosis for Continued Health Registry. Eur Heart J 2009; 30 (19) 2318-2326
  • 22 Aboyans V, Ricco JB, Bartelink MEL. et al; ESC Scientific Document Group. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J 2018; 39 (09) 763-816
  • 23 Perzborn E, Heitmeier S, Laux V. Effects of rivaroxaban on platelet activation and platelet-coagulation pathway interaction: in vitro and in vivo studies. J Cardiovasc Pharmacol Ther 2015; 20 (06) 554-562
  • 24 Anderson DR, Dunbar M, Murnaghan J. et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med 2018; 378 (08) 699-707
  • 25 Weitz JI, Lensing AWA, Prins MH. et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
  • 26 Simes J, Becattini C, Agnelli G. et al; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation 2014; 130 (13) 1062-1071
  • 27 Mega JL, Braunwald E, Wiviott SD. et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366 (01) 9-19
  • 28 Spyropoulos AC, Ageno W, Albers GW. et al. Post-discharge prophylaxis with rivaroxaban reduces fatal and major thromboembolic events in medically ill patients. J Am Coll Cardiol 2020; 75 (25) 3140-3147
  • 29 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
  • 30 Bonaca MP, Bauersachs RM, Anand SS. et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020; 382 (21) 1994-2004
  • 31 Morrow DA, Braunwald E, Bonaca MP. et al; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366 (15) 1404-1413
  • 32 Parascandolo E, Eisen A. Aspirin and low-dose rivaroxaban - the dual pathway concept in patients with stable atherosclerotic disease: a comprehensive review. Expert Rev Cardiovasc Ther 2020; 18 (09) 577-585
  • 33 Hanjaya-Putra D, Haller C, Wang X. et al. Platelet-targeted dual pathway antithrombotic inhibits thrombosis with preserved hemostasis. JCI Insight 2018; 3 (15) 99329
  • 34 Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114 (08) 774-782
  • 35 Mega JL, Braunwald E, Mohanavelu S. et al; ATLAS ACS-TIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374 (9683): 29-38
  • 36 Steg PG, Mehta SR, Jukema JW. et al; RUBY-1 Investigators. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 2011; 32 (20) 2541-2554
  • 37 Alexander JH, Becker RC, Bhatt DL. et al; APPRAISE Steering Committee and Investigators. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009; 119 (22) 2877-2885
  • 38 Eikelboom JW, Bosch JJ, Connolly SJ. et al. Major bleeding in patients with coronary or peripheral artery disease treated with rivaroxaban plus aspirin. J Am Coll Cardiol 2019; 74 (12) 1519-1528
  • 39 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
  • 40 Cohen AT, Harrington RA, Goldhaber SZ. et al; APEX Investigators. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375 (06) 534-544
  • 41 Gibson CM, Chi G, Halaby R. et al; APEX Investigators. Extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: an APEX Trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation 2017; 135 (07) 648-655
  • 42 Gibson CM, Korjian S, Chi G. et al; APEX Investigators. Comparison of fatal or irreversible events with extended-duration betrixaban versus standard dose enoxaparin in acutely ill medical patients: an APEX trial substudy. J Am Heart Assoc 2017; 6 (07) e006015
  • 43 Spyropoulos AC, Ageno W, Albers GW. et al; MARINER Investigators. Rivaroxaban for thromboprophylaxis after hospitalization for medical illness. N Engl J Med 2018; 379 (12) 1118-1127
  • 44 Spyropoulos AC, Lipardi C, Xu J. et al. Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN Study. Clin Appl Thromb Hemost 2019; 25: 1076029619886022
  • 45 Spyropoulos AC, Barnathan ES, Ageno W. et al. Rivaroxaban plus ASA as extended thromboprophylaxis in acutely ill medical patients: insights from the Mariner trial. Paper presented at: American Society of Hematology Annual Meeting, December 7–10, O 2019; Florida, United States
  • 46 Raskob GE, Spyropoulos AC, Spiro TE. et al. Benefit-risk of rivaroxaban for extended thromboprophylaxis after hospitalization for medical illness: pooled analysis from MAGELLAN and MARINER. J Am Heart Assoc 2021; 10 (22) e021579
  • 47 Anand SS, Bosch J, Eikelboom JW. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 219-229
  • 48 Anand SS, Eikelboom JW, Dyal L. et al; COMPASS Trial Investigators. Rivaroxaban plus aspirin versus aspirin in relation to vascular risk in the COMPASS trial. J Am Coll Cardiol 2019; 73 (25) 3271-3280
  • 49 Gibson CM, Spyropoulos AC, Cohen AT. et al. The IMPROVEDD VTE risk score: incorporation of D-dimer into the IMPROVE score to improve venous thromboembolism risk stratification. TH Open 2017; 1 (01) e56-e65
  • 50 Spyropoulos AC, Raskob GE. New paradigms in venous thromboprophylaxis of medically ill patients. Thromb Haemost 2017; 117 (09) 1662-1670
  • 51 Demoulin S, Godfroid E, Hermans C. Dual inhibition of factor XIIa and factor XIa as a therapeutic approach for safe thromboprotection. J Thromb Haemost 2021; 19 (02) 323-329