Venous thromboembolism: Past, present and future

Summary

Venous thromboembolism (VTE), the third most frequent acute cardiovascular syndrome, is associated with a considerable disease burden which continues to grow along with the longer life expectancy of the population worldwide. In the past century, parenteral heparin prophylaxis was established for hospitalised patients at elevated risk of VTE. More recently, non-vitamin K antagonist oral anticoagulants (NOACs) with a direct inhibiting effect on factor Xa or thrombin, underwent extensive testing in clinical trials and have been approved for patients undergoing hip or knee replacement. Clinical investigation is ongoing in further areas of thromboprophylaxis, including medical prophylaxis in patients and high-risk situations in the outpatient setting. The diagnostic approach to suspected VTE is now based on advanced imaging techniques and robust diagnostic algorithms which ensure high sensitivity and specificity. Nevertheless, the role of clinical, or pre-test, probability assessment remains crucial to avoid overdiagnosis and treatment errors. Advances in reperfusion strategies, along progressive establishment of the NOACs as the new standard of anticoagulation treatment, have simplified the management of VTE, improving outcomes and particularly safety. While new molecular targets for anticoagulation are being investigated in the quest to further reduce bleeding risk, adjusting the initial regimen to the patient’s risk and finding the optimal duration of anticoagulation after an index VTE event will be some of the top priorities in the years to come. Importantly, and in parallel to new drugs and technical advances in imaging, incentives such as hospital accreditation and funding based on evidence-based practice need to be implemented to increase guideline adherence.

Keywords

Venous thromboembolism - deep-vein thrombosis - pulmonary embolism - prophylaxis - diagnosis - imaging - treatment - anticoagulants - reperfusion

• References

• 1 Lennander KG. Über die Möglichkeit Thrombose in den Venen der unteren Extremitäten nach Operation zu verhüten nach denen längeres Still-liegen nötig ist. Zblatt Chir 1899; 20: 553-559.
• 2 Kümmel H. Abkürzung des Heilungsverlaufs laparotomierter durch frühzeitiges Aufstehen. Verh Dtsch Ges Chir 1908; 1.
• 3 Richardson MH. On certain unavoidable calamities following surgical operations. Boston Med Surg J 1904; 151-583.
• 4 Ries E. Some radical changes in the after treatment of cheliotomy cases. J Am Med Assoc 1899; 33: 454.
• 5 Westerborn A. Thrombi and emboli at early ambulation and mobilisation. Nord Med 1946; 29: 347.
• 6 Ochsner A, De Bakey M. Therapy of phlebothrombosis and thrombophlebitis. Arch Surg 1940; 40: 208.
• 7 Crafoord C. Preliminary report on post-operative treatment with heparin as a preventive of thrombosis. Acta Chir Scand 1937; 79: 407-426.
• 8 Murray DWG. et al. Heparin and the thrombosis of veins following injury. Surgery 1937; 2: 163-187.
• 9 Bruzelius S. Dicoumarin in clinical use. Studies on its prophylactic and therapeutic value in the treatment of thromboembolism. Acta Chir Scand 1945 ; Suppl 100
• 10 Sevitt S, Gallagher N. Prevention of venous thrombosis and pulmonary embolism in injured patients. Lancet 1959; 2: 981-985.
• 11 Koekenberg L. Experimental use of macrodex as a prophylaxis against postoperative thromboembolism. Exp Med Amst 1961; 40: 123.
• 12 Bergentz S-E. et al. Rheomacrodex in vascular surgery. J Cardiovasc Res 1963; 4: 388-392.
• 13 Strömbäck J. Några synpunkter på trombosetiologi och trombosprofylax. Nord Med 1942; 13: 522-523.
• 14 De Takats G. Anticoagulants in surgery. J Am Med Assoc 1950; 142: 527.
• 15 Kakkar VV. et al. Low doses of heparin in prevention of deep-vein thrombosis. Lancet 1971; 2: 669-671.
• 16 Sagar S. et al. Efficacy of low-dose heparin in prevention of extensive deep-vein thrombosis in patients undergoing total-hip replacement. Lancet 1976; 1: 1151-1154.
• 17 Kakkar VV. et al. Low-molecular-weight heparin and prevention of postoperative deep vein thrombosis. Br Med J 1982; 284: 375-379.
• 18 Topol EJ. et al. Recombinant hirudin for unstable angina pectoris. A multicenter, randomized angiographic trial. Circulation 1994; 89: 1557-1566.
• 19 Eriksson BI. et al. Direct thrombin inhibition with Rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip replacement. Thromb Haemost 1994; 72: 227-231.
• 20 Sharma T. et al. Update on fondaparinux: role in management of thromboembolic and acute coronary events. Cardiovasc Hematol Agents Med Chem 2010; 8: 96-103.
• 21 Yusuf S. et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354: 1464-1476.
• 22 Warkentin TE. et al. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost 2011; 9: 2389-2396.
• 23 Nieto JA. et al. Dabigatran, rivaroxaban and apixaban versus enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials. Thromb Res 2012; 130: 183-191.
• 24 Cohen AT. et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368: 513-523.
• 25 Goldhaber SZ. et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365: 2167-2177.
• 26 Cohen AT. et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 2016; 375: 534-544.
• 27 Levine MN. et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost 2012; 10: 807-814.
• 28 Cohen AT. et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008; 371: 387-394.
• 29 Friedman RJ. et al. Practice patterns in the use of venous thromboembolism prophylaxis after total joint arthroplasty--insights from the Multinational Global Orthopaedic Registry (GLORY). Am J Orthop 2010; 39 (Suppl. 09) 14-21.
• 30 Agnelli G. et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg 2006; 243: 89-95.
• 31 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.
• 32 Lyman GH. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol 2015; 33: 654-656.
• 33 Chopard P. et al. Venous thromboembolism prophylaxis in acutely ill medical patients: definite need for improvement. J Intern Med 2005; 257: 352-357.
• 34 Spencer FA. et al. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med 2006; 21: 722-727.
• 35 Hull RD. et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 2010; 153: 8-18.
• 36 Raskob GE. et al. The MARINER trial of rivaroxaban after hospital discharge for medical patients at high risk of VTE. Design, rationale, and clinical implications. Thromb Haemost 2016; 115: 1240-1248.
• 37 Pelzer U. et al. Efficacy of prophylactic low-molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO-004 trial. J Clin Oncol 2015; 33: 2028-2034.
• 38 Macbeth F. et al. Randomized phase III trial of standard therapy plus low molecular weight heparin in patients with lung cancer: FRAGMATIC trial. J Clin Oncol 2016; 34: 488-494.
• 39 Konstantinides SV. et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)Endorsed by the European Respiratory Society (ERS). Eur Heart J 2014; 35: 3033-3073.
• 40 Wells PS. et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795-1798.
• 41 Bates SM. et al. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e351S-e418S.
• 42 Wells PS. et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 1227-1235.
• 43 Wicki J. et al. Assessing clinical probability of pulmonary embolism in the emergency ward: a simple score. Arch Intern Med 2001; 161: 92-97.
• 44 Wells PS. et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83: 416-420.
• 45 Buller HR. et al. Safely ruling out deep venous thrombosis in primary care. Ann Intern Med 2009; 150: 229-235.
• 46 Ten Cate-Hoek AJ, Prins MH. Management studies using a combination of D-dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. J Thromb Haemost 2005; 3: 2465-2470.
• 47 Silveira PC. et al. Performance of Wells Score for Deep Vein Thrombosis in the Inpatient Setting. JAMA Intern Med 2015; 175: 1112-1117.
• 48 Di NM. et al. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. J Thromb Haemost 2007; 5: 296-304.
• 49 Bates SM. et al. Rapid quantitative D-dimer to exclude pulmonary embolism: a prospective cohort management study. J Thromb Haemost 2016; 14: 504-509.
• 50 Schouten HJ. et al. Diagnostic accuracy of conventional or age adjusted D-dimer cut-off values in older patients with suspected venous thromboembolism: systematic review and meta-analysis. Br Med J 2013; 346: f2492.
• 51 Penaloza A. et al. Performance of age-adjusted D-dimer cut-off to rule out pulmonary embolism. J Thromb Haemost 2012; 10: 1291-1296.
• 52 Hull R. et al. Replacement of venography in suspected venous thrombosis by impedance plethysmography and 125I-fibrinogen leg scanning: a less invasive approach. Ann Intern Med 1981; 94: 12-15.
• 53 Hull R. et al. Combined use of leg scanning and impedance plethysmography in suspected venous thrombosis. An alternative to venography. N Engl J Med 1977; 296: 1497-1500.
• 54 Goodacre S. et al. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging 2005; 5: 6.
• 55 Gibson NS. et al. Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study. J Thromb Haemost 2009; 7: 2035-2041.
• 56 Bernardi E. et al. Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial. J Am Med Assoc 2008; 300: 1653-1659.
• 57 Ageno W. et al. Analysis of an algorithm incorporating limited and whole-leg assessment of the deep venous system in symptomatic outpatients with suspected deep-vein thrombosis (PALLADIO): a prospective, multicentre, cohort study. Lancet Haematol 2015; 2: e474-e480.
• 58 Tan M. et al. Magnetic resonance direct thrombus imaging differentiates acute recurrent ipsilateral deep vein thrombosis from residual thrombosis. Blood 2014; 124: 623-627.
• 59 Investigators P. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). J Am Med Assoc 1990; 263: 2753-2759.
• 60 Mos IC. et al. Safety of ruling out acute pulmonary embolism by normal computed tomography pulmonary angiography in patients with an indication for computed tomography: systematic review and meta-analysis. J Thromb Haemost 2009; 7: 1491-1498.
• 61 Cronin P. et al. The role of multidetector computed tomography angiography for the diagnosis of pulmonary embolism. Semin Nucl Med 2008; 38: 418-431.
• 62 Patel S. et al. Pulmonary embolism: optimisation of small pulmonary artery visualisation at multi-detector row CT. Radiology 2003; 227: 455-460.
• 63 Hutchinson BD. et al. Overdiagnosis of Pulmonary Embolism by Pulmonary CT Angiography. AJR Am J Roentgenol 2015; 205: 271-277.
• 64 Stein PD. et al. Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III). Ann Intern Med 2010; 152: 434-433.
• 65 Stein PD. et al. SPECT in acute pulmonary embolism. J Nucl Med 2009; 50: 1999-2007.
• 66 Miller GA. et al. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. Br Heart J 1971; 33: 616.
• 67 Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med 2008; 359: 2804-2813.
• 68 The urokinase pulmonary embolism trial. A national cooperative study. Circulation 1973; 47 (Suppl. 02) II1-II108.
• 69 Goldhaber SZ. et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341: 507-511.
• 70 Jaff MR. et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123: 1788-1830.
• 71 Kearon C. et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149: 315-352.
• 72 Marti C. et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2015; 36: 605-614.
• 73 Meyer G. et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014; 370: 1402-1411.
• 74 Wang C. et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest 2010; 137: 254-262.
• 75 Sharifi M. et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT„ Trial). Am J Cardiol 2013; 111: 273-277.
• 76 Engelberger RP, Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. Eur Heart J 2014; 35: 758-764.
• 77 Kucher N. et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014; 129: 479-486.
• 78 Piazza G. et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv 2015; 8: 1382-1392.
• 79 Engelberger RP. et al. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis. Circ Cardiovasc Interv 2015; 8 pii: e002027..
• 80 Korin N. et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 2012; 337: 738-742.
• 81 Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960; 1: 1309-1312.
• 82 Becattini C, Agnelli G. Treatment of Venous Thromboembolism With New Anticoagulant Agents. J Am Coll Cardiol 2016; 67: 1941-1955.
• 83 Chan NC. et al. Evolving Treatments for Arterial and Venous Thrombosis: Role of the Direct Oral Anticoagulants. Circ Res 2016; 118: 1409-1424.
• 84 Prandoni P. et al. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica 1997; 82: 423-428.
• 85 Agnelli G. et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003; 139: 19-25.
• 86 Schulman S. et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med 1995; 332: 1661-1665.
• 87 Campbell IA. et al. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. Br Med J 2007; 334: 674.
• 88 Kearon C. et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism [see comments] [published erratum appears in N Engl J Med 1999; 341: 298]. N Engl J Med 1999; 340: 901-907.
• 89 Konstantinides SV. et al. Management of Pulmonary Embolism: An Update. J Am Coll Cardiol 2016; 67: 976-990.
• 90 Becattini C, Agnelli G. Treatment of Venous Thromboembolism With New Anticoagulant Agents. J Am Coll Cardiol 2016; 67: 1941-1955.
• 91 Couturaud F. et al. Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial. J Am Med Assoc 2015; 314: 31-40.
• 92 Pollack CV. Jr. et al. Idarucizumab for Dabigatran Reversal. N Engl J Med 2015; 373: 511-520.
• 93 Connolly SJ. et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2016 ; Epub ahead of print.
• 94 Weitz JI. Factor XI and factor XII as targets for new anticoagulants. Thromb Res 2016; 141 (Suppl. 02) S40-S45.
• 95 Foley JH. et al. Insights into thrombin activatable fibrinolysis inhibitor function and regulation. J Thromb Haemost 2013; 11 (Suppl. 01) 306-315.
• 96 Buller HR. et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372: 232-240.