Abstract
Recent years have witnessed an onslaught of large, multicenter, randomized controlled trials evaluating the prevention and management of thrombotic vascular diseases. While these trials have applied rigorous methodology to pragmatic and clinically relevant questions, several important gaps in knowledge remain. In this review, we critically appraise landmark studies in thrombosis published between 2016 and 2017 that address several ongoing areas of clinical uncertainty. Specifically, we review the role of endovascular therapy in the prevention of post-thrombotic syndrome following acute lower limb deep vein thrombosis (DVT) (ATTRACT trial), the efficacy of edoxaban as the first direct oral anticoagulant used for the treatment of cancer-associated thrombosis (HOKUSAI VTE-Cancer study), whether aspirin can be considered for thromboprophylaxis post-major orthopedic surgery (EPCAT-2 trial), and the need for anticoagulant therapy for treatment of isolated distal DVT (CACTUS trial). Using illustrative cases, we highlight the applicability of these trials to current practice and emphasize the unanswered questions that remain.
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References
Vedantham S, Goldhaber SZ, Julian JA et al (2017) Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 377(23):2240–2252
Raskob GE, van Es N, Verhamme P et al (2018) Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 378(7):615–624
Anderson DR, Dunbar M, Murnaghan J et al (2018) Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med 378:699–707
Righini M, Galanaud JP, Guenneguez H et al (2016) Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised double-blind, placebo-controlled trial. Lancet Haematol 3(12):e556–e562
Kahn SR, Shrier I, Julian JA et al (2008) Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 149(10):698–707
Prandoni P, Lensing AW, Prins MH et al (2002) Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 137(12):955–960
Jenkins JS (2011) Endovascular therapies to treat iliofemoral deep venous thrombosis. Prog Cardiovasc Disease 54(1):70–76
Sudheendra D, Vedantham S (2018) Catheter-directed therapy options for iliofemoral venous thrombosis. Surg Clin N Am 98(2):255–265
Kearon C, Akl EA, Ornelas J et al (2016) Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 149(2):315–352
Enden T, Haig Y, Klow N et al (2012) Long-term outcomes after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomized controlled trial. Lancet 379(9810):31–38
Haig Y, Enden T, Grotta O et al (2016) Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Hematol 3:e64–e71
Bashir R, Zack CJ, Zhao H et al (2014) Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med 174(9):1494–1501
Watson L, Broderick C, Armon MP (2016) Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev 11:CD002783
Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA (2000) Prognosis of cancers associated with venous thromboembolism. N Engl J Med 343(25):1846–1850
Horsted F, West J, Grainge MJ (2012) Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med 9(7):e1001275
Lee AYY (2018) Overview of VTE treatment in cancer according to clinical guidelines. Thromb Res. https://doi.org/10.1016/j.thromres.2018.01.002
Lee AY, Peterson EA, Wu C (2016) Clinical practice guidelines on cancer-associated thrombosis: a review on scope and methodology. Thromb Res 140(Suppl 1):S119–S127
Smrke A, Gross PL (2017) Cancer-associated venous thromboembolism: a practical review beyond low-molecular-weight heparins. Front Med (Lausanne) 4:142
van Es N, Di Nisio M, Bleker SM et al (2015) Edoxaban for treatment of venous thromboembolism in patients with cancer. Rationale and design of the Hokusai VTE-cancer study. Thromb Haemost 114(6):1268–1276
Young A, Marshall A, Thirlwall J et al (2017) Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism: results of the Select-D pilot trial. Blood 130:625 (Abstract #625)
Bach M, Bauersachs R (2016) Spotlight on advances in VTE management: CALLISTO and EINSTEIN CHOICE. Thromb Haemost 116(Suppl 2):S24–S32
Prins MH, Lensing AW, Brighton TA et al (2014) 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 1(1):e37–e46
Agnelli G, Buller HR, Cohen A et al (2015) Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 13(12):2187–2191
Annibali O, Napolitano M, Avvisati G, Siragusa S (2018) Incidence of venous thromboembolism and use of anticoagulation in hematological malignancies: critical review of the literature. Critc Rev Oncol Hematol 124:41–50
Bjornara BT, Gudmundsen TE, Dahl OE (2006) Frequency and timing of clinical venous thromboembolism after major joint surgery. J Bone Jt Surg Br 88(3):386–391
Arcelus JI, Monreal M, Caprini JA et al (2008) Clinical presentation and time-course of postoperative venous thromboembolism: results from the RIETE registry. Thromb Haemost 99(3):546–551
White RH, Zhou H, Romano PS (2003) Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost 90(3):446–455
Falck-Ytter Y, Francis CW, Johanson NA et al (2012) Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 141(2 Suppl):e278S–e325S
Dahl OE, Quinlan DJ, Bergqvist D, Eikelbloom JW (2010) A critical appraisal of bleeding events reported in venous thromboembolism prevention trials of patients undergoing hip and knee arthroplasty. J Thromb Haemost 8(9):1966–1975
Eriksson BI, Borris LC, Friedman RJ et al (2008) Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 358(26):2765–2775
Neumann I, Rada G, Claro JC et al (2012) Oral direct factor Xa inhibitors versus low-molecular weight heparin to prevent venous thromboembolism in patients undergoing total hip or knee replacement: a systematic review and meta-analysis. Ann Intern Med 156(10):710–719
Anderson DR, Dunbar MJ, Bohm ER et al (2013) Aspirin versus low-molecular weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med 158(11):800–806
Eikelboom JW, Quinlan DJ, Douketis JD (2001) Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 358(9275):9–15
Douketis JD, Eikelboom JW, Quinlan DJ et al (2002) Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes. Arch Intern Med 162(13):1465–1471
Pep Trial Collaborative Group (2000) Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin. Lancet 355:1295–1302
Devereaux PJ, Mrkobrada M, Sessler DI et al (2014) Aspirin in patients undergoing noncardiac surgery. N Engl J Med 370:1494–1503
Eikelboom JW, Kearon C, Guyatt G et al (2016) Perioperative aspirin for prevention of venous thromboembolism: the PeriOperative Ischemia Evaluation-2 Trial and a pooled analysis of the randomized trials. Anesthesiology 125(6):1121–1129
Palareti G (2014) How I treat isolated distal deep vein thrombosis (IDDVT). Blood 123:1802–1809
Porfidia A, Carnicelli A, Bonadia N, Pola R, Landolfi R (2016) Controversies in venous thromboembolism: the unique case of isolated distal deep vein thrombosis. Intern Emerg Med 11(6):775–779
Utter GH, Dhillon TS, Salcedo ES et al (2016) Therapeutic anticoagulation for isolated calf deep vein thrombosis. JAMA Surg 151(9):e161770
Robert-Ebadi H, Righini M (2017) Management of distal deep vein thrombosis. Thromb Res 149:48–55
Robert-Ebadi H, Righini M (2017) Should we diagnose and treat distal deep vein thrombosis? Hematology Am Soc Hematol Educ Program 2017(1):231–236
Weitz JI, Lensing AWA, Prins MH et al (2017) Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 376(13):1211–1222
Bien JY, Daughety MM, Tao DL et al (2017) The safety of aspirin vs. direct oral anticoagulants: a meta-analysis of currently published clinical trials. Blood 130:3720
Astermark J, Bjorgell O, Linden E et al (1998) Low recurrence rate after deep calf-vein thrombosis with 6 weeks of oral anticoagulation. J Intern Med 244:79–82
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Dr. Douketis is a consultant and advisory board participant for Janssen Pharmaceuticals, Bayer, Bristol Meyers Squibb, Sanofi, and Servier.
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Cervi, A., Douketis, J.D. Landmark trials in thrombotic vascular disease: a critical appraisal of potential practice-changing trials in 2016–2017. Intern Emerg Med 14, 355–363 (2019). https://doi.org/10.1007/s11739-018-1910-2
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DOI: https://doi.org/10.1007/s11739-018-1910-2