Let’s Stop Dichotomizing Venous Thromboembolism as Provoked or Unprovoked
2018; Lippincott Williams & Wilkins; Volume: 138; Issue: 23 Linguagem: Inglês
10.1161/circulationaha.118.036548
ISSN1524-4539
AutoresIda Ehlers Albertsen, Gregory Piazza, Samuel Z. Goldhaber,
Tópico(s)Atrial Fibrillation Management and Outcomes
ResumoHomeCirculationVol. 138, No. 23Let’s Stop Dichotomizing Venous Thromboembolism as Provoked or Unprovoked Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBLet’s Stop Dichotomizing Venous Thromboembolism as Provoked or Unprovoked Ida Ehlers Albertsen, MD, Gregory Piazza, MD, MS and Samuel Z. Goldhaber, MD Ida Ehlers AlbertsenIda Ehlers Albertsen Ida Ehlers Albertsen, MD, Aalborg Thrombosis Research Unit, Aalborg University, Forskningens Hus, Søndre Skovvej 15, DK-9000 Aalborg, Denmark. Email E-mail Address: [email protected] Department of Cardiology, Aalborg University Hospital, Denmark (I.E.A.). Aalborg Thrombosis Research Unit, Aalborg University, Denmark (I.E.A.). Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (I.E.A., G.P., S.Z.G.). , Gregory PiazzaGregory Piazza Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (I.E.A., G.P., S.Z.G.). and Samuel Z. GoldhaberSamuel Z. Goldhaber Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (I.E.A., G.P., S.Z.G.). Originally published3 Dec 2018https://doi.org/10.1161/CIRCULATIONAHA.118.036548Circulation. 2018;138:2591–2593The optimal duration of anticoagulation for venous thromboembolism (VTE) remains uncertain. The benefit of anticoagulation to prevent recurrent VTE must be weighed against the risk of bleeding. Current guidelines dichotomize VTE as unprovoked or provoked. Guidelines for unprovoked VTE recommend extended-duration anticoagulation with no scheduled stop date and yearly assessment of bleeding risk, risk of recurrence, and patient preference. Guidelines for provoked VTE recommend 3 months of anticoagulation except for cancer patients, who generally receive extended-duration anticoagulation.Dichotomizing VTE into provoked and unprovoked categories to guide decisions about the duration of anticoagulation is appealing because of its simplicity. However, optimal VTE management frequently requires a more nuanced approach. VTE is a systemic vascular disease that can no longer be characterized as a red clot disease because the thrombus usually contains abundant polymorphonuclear leukocytes, neutrophil extracellular traps, and activated platelets. This pathophysiological observation ties together the longstanding epidemiological link between inflammatory disorders, such as psoriasis, rheumatoid arthritis, and Crohn’s disease, and VTE. When these inflammatory illnesses remain clinically or subclinically active, the risk of VTE recurrence remains high, although associated VTE is categorized as provoked rather than unprovoked.In 2016, the International Society of Thrombosis and Haemostasis made recommendations on how to define transient provoking and persistent risk factors. They defined minor transient risk factors as “associated with a 3 to 10-fold increased risk of having a first VTE” or “associated with half the risk of recurrent VTE after stopping anticoagulant therapy (compared with if there was no transient risk factor), when the risk factor occurred up to 2 months before the VTE.”1 According to these definitions, clinicians must estimate a patient’s risk of recurrence. However, such estimates are hampered by a paucity of data to serve as the foundation for calculating risk of recurrence. Consequently, this International Society of Thrombosis and Haemostasis statement, although well intentioned, can be difficult to translate into clinical practice.Defining unprovoked and provoked VTE is further challenged by the fact that there is a large grey zone for which precise categorization is not possible. Many VTE patients have multiple persistent (predisposing) and transient provoking factors. These factors carry large differences in recurrence risk. A hierarchy of minor persistent and transient risk factors can be based on analyses of randomized trials (Figure).Download figureDownload PowerPointFigure. Revised strategy for determining the optimal duration of anticoagulation after VTE. VTE indicates venous thromboembolism.The EINSTEIN CHOICE trial (Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism) randomized patients with prior provoked (59%) or unprovoked (41%) VTE to either rivaroxaban (20 mg or 10 mg) or low-dose aspirin after they had received 6 to 12 months of anticoagulation.2 In the 20 mg rivaroxaban group, 1.4% of the patients with provoked VTE had recurrence after the first year compared with 1.8% of the patients with unprovoked VTE. In the aspirin arm, 3.6% of the patients with provoked VTE had recurrence versus 5.6% with unprovoked VTE. The risk of recurrent VTE in patients with trauma or major surgery was 0% in both the rivaroxaban and aspirin groups. This finding argues in favor of adhering to time-limited anticoagulation for patients with VTE in whom the provoked factor was major surgery or trauma.In a Danish nationwide cohort study,3 incident VTE was categorized according to international guidelines as unprovoked, provoked, or cancer-related. Patients with cancer and those with unprovoked VTE had the highest risk of recurrence. However, recurrence rates in patients with provoked VTE did not lag far behind. At 6-month follow-up, rates per 100 person-years were 6.80, 6.92, and 9.06 for provoked, unprovoked, and cancer-related VTE, respectively. At 10-year follow-up, the corresponding rates were 2.22, 2.84, and 3.70, respectively.Optimal duration of anticoagulation is both a critical scientific and clinical concern. Furthermore, the direct oral anticoagulants offer an attractive safety profile with fewer bleeding complications and similar efficacy compared with warfarin. However, given the appreciable risk of recurrence among patients with nonsurgical provoked VTE, the standard recommendation of short-term anticoagulation should be reexamined. To help clarify treatment duration, a trial of exclusively provoked patients with VTE randomized after 3 months of anticoagulation to extended anticoagulation versus placebo is warranted.Determination of optimal duration of anticoagulation should be based on assessment of a patient’s individual risk factors. We propose an innovative strategy (Figure) in which risk of recurrent VTE increases as a continuum because of a combination of diverse risk factors. We should resist the temptation to dichotomize complicated pathophysiology and rather strive to more accurately formulate management strategies based on the likelihood of suffering another VTE in the absence of anticoagulation. Unfortunately, no studies to date have shown adequate discriminative power using the prevailing classifications of patients with incident VTE.2,3In the short term, we should base the optimal duration of anticoagulation in provoked patients with VTE on data from the extended-duration rivaroxaban trials. In the absence of extended-duration anticoagulation, the highest likelihood of recurrence after provoked VTE occurs with the persisting risk factors of heart failure, obesity, family history of VTE, or hereditary thrombophilia, or with the transient risk factors of leg injury or immobilization. In the intermediate term, we are initiating novel randomized trials of provoked patients with VTE to test extended-duration anticoagulation versus placebo. Over the long term, we envision identification of biomarkers of VTE risk, genetic screening, mathematical modeling, and further large-scale observational studies as key determinants that will provide more precision and guidance. However, in the meantime, let’s stop dichotomizing VTE as unprovoked and provoked and strive for more precise risk stratification.Sources of FundingThe Obel Family Foundation partly funded this research by an unrestricted grant. The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; writing of the article; and decision to submit the article for publication.DisclosuresDr Goldhaber receives honoraria for consulting activities from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Janssen, and Portola and receives research support from BMS, Boehringer Ingelheim, BTG EKOS, Daiichi, the National Heart, Lung, and Blood Institute of the National Institutes of Health, and Janssen. Dr Piazza has received research grant support from Bristol-Myers Squibb; Daiichi-Sankyo; EKOS Corporation, a BTG International group company; and Janssen. Dr Albertsen has received speaking fees from Pfizer.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circIda Ehlers Albertsen, MD, Aalborg Thrombosis Research Unit, Aalborg University, Forskningens Hus, Søndre Skovvej 15, DK-9000 Aalborg, Denmark. Email [email protected]comReferences1. Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA; Subcommittees on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic Disease. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH.J Thromb Haemost. 2016; 14:1480–1483. doi: 10.1111/jth.13336CrossrefMedlineGoogle Scholar2. Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK, Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism.N Engl J Med. 2017; 376:1211–1222.7.CrossrefMedlineGoogle Scholar3. Albertsen IE, Nielsen PB, Søgaard M, Goldhaber SZ, Overvad TF, Rasmussen LH, Larsen TB. 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Fernandes C, Calderaro D, Piloto B, Hoette S, Jardim C and Souza R (2019) Extended anticoagulation after venous thromboembolism: should it be done?, Therapeutic Advances in Respiratory Disease, 10.1177/1753466619878556, 13, (175346661987855), Online publication date: 1-Jan-2019. December 4, 2018Vol 138, Issue 23 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.036548PMID: 30571266 Originally publishedDecember 3, 2018 Keywordsunprovokedvenous thromboembolismrecurrencerisk stratificationprovokedPDF download Advertisement SubjectsEmbolismThrombosis
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