Prediction of recurrent venous thromboembolism: The writing is on the wall

Acute pulmonary embolism (aPE) is one of the leading causes of morbidity and mortality and its global incidence is approximately 1/1000 persons per year [ [1] Kahn S.R. de Wit K. Pulmonary embolism. N Engl J Med. 2022; 387: 45-57 Crossref PubMed Scopus (28) Google Scholar ]. The estimated mortality of aPE is approximately 20% within 90 days [ [2] Lehnert P. Lange T. Møller C.H. Olsen P.S. Carlsen J. Acute pulmonary embolism in a national Danish cohort: increasing incidence and decreasing mortality. Thromb Haemost. 2018; 118: 539-546 Crossref PubMed Scopus (70) Google Scholar , [3] Calder K.K. Herbert M. Henderson S.O. The mortality of untreated pulmonary embolism in emergency department patients. Ann Emerg Med. 2005; 45: 302-310 Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar ]. Anticoagulation treatment for at least 3 months is recommended for patients with aPE to reduce the risks of recurrent venous thromboembolism (VTE) events. However, the risks of recurrence of VTE after stopping anticoagulation treatment are still 10% at 1 year and 36% at 10 years among unprovoked patients with a first aPE [ [4] Khan F. Rahman A. Carrier M. Kearon C. Weitz J.I. Schulman S. Couturaud F. Eichinger S. Kyrle P.A. Becattini C. Agnelli G. Brighton T.A. Lensing A.W.A. Prins M.H. Sabri E. Hutton B. Pinede L. Cushman M. Palareti G. Wells G.A. et al. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ. 2019; 366: l4363 Crossref PubMed Scopus (165) Google Scholar ]. Although clinical trials have demonstrated that extended anticoagulation is more useful to prevent recurrence of VTE [ [5] Kearon C. Kahn S.R. Long-term treatment of venous thromboembolism. Blood. 2020; 135: 317-325 Crossref PubMed Scopus (35) Google Scholar ], a meta-analysis (including 27 studies) performed by Khan et al. [ [6] Khan F. Tritschler T. Kimpton M. Wells P.S. Kearon C. Weitz J.I. Büller H.R. Raskob G.E. Ageno W. Couturaud F. Prandoni P. Palareti G. Legnani C. Kyrle P.A. Eichinger S. Eischer L. Becattini C. Agnelli G. Vedovati M.C. Geersing G.J. et al. Long-term risk for major bleeding during extended oral anticoagulant therapy for first unprovoked venous thromboembolism: a systematic review and meta-analysis. Ann Intern Med. 2012; 174: 1420-1429 Crossref Scopus (48) Google Scholar ] showed that extended anticoagulation increased the risk of major bleeding events regardless of new oral anticoagulant or warfarin. Therefore, the optimal duration of anticoagulant therapy for patients with a first aPE remains elusive, and whether treatment should be continued depends on the balance of benefits and risk of bleeding [ [5] Kearon C. Kahn S.R. Long-term treatment of venous thromboembolism. Blood. 2020; 135: 317-325 Crossref PubMed Scopus (35) Google Scholar , [7] Kearon C. A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism. J Thromb Haemost. 2012; 10: 507-511 Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar ]. Obviously, it is important to identify patients with a high risk of recurrent VTE [ [8] Kearon C. Iorio A. Palareti G. Subcommittee on Control of Anticoagulation of the SSC of the ISTH. Risk of recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting. J Thromb Haemost. 2010; 8: 2313-2315 Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar ]. The HERDOO2, DASH (D-dimer, age, sex, hormonal therapy), and Vienna recurrent venous thromboembolism prediction models have been proposed to identify low-recurrence risk patients after anticoagulation was stopped. But the C-statistics of these models have not been satisfactory in clinical validation [ [9] Raj L. Presles E. Le Mao R. Robin P. Sanchez O. Pernod G. Bertoletti L. Jego P. Lemarié C.A. Leven F. Hoffmann C. Planquette B. Le Roux P.Y. Slaun P.Y. Nonent M. Girard P. Lacut K. Melac S. Guégan M. Mismetti P. et al. PADIS-PE InvestigatorsEvaluation of venous thromboembolism recurrence scores in an unprovoked pulmonary embolism population: a post-hoc analysis of the PADIS-PE trial. Am J Med. 2020; 133 (e21): e406 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ]. More risk factors associated with VTE recurrence are needed.