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      D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with non-vitamin K anticoagulants

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          Abstract

          Background

          D-dimer levels measured during and after vitamin K antagonist withdrawal may be used in clinical practice to assess the individual risk of recurrent venous thromboembolism. Currently, direct oral anticoagulants (DOACs) are frequently used in venous thromboembolism treatment; however, their pharmacokinetics and pharmacodynamics characteristics are completely different than vitamin K antagonists. The present study aimed at comparing the results of D-dimer levels during and after anticoagulation withdrawal in patients with venous thromboembolism treated with DOACs or warfarin.

          Material and methods

          D-dimer levels were measured in 527 patients (“cases”) during DOACs treatment (T0) and after 15 (T15), 30 (T30), 60 (T60) and 90 (T90) days after their discontinuation and in 527 patients (“controls”) enrolled in the DULCIS study (all treated with warfarin), matched for sex, age (+/-3 y), type of D-dimer assay and site of venous thromboembolism. Both cases and controls received anticoagulant treatment after a first venous thromboembolism event that was unprovoked or associated with weak risk factors.

          Results

          The rate of positive D-dimer results was significantly higher in cases than in controls at T0 (10.8% vs 5.1%, p = 0.002) and at T30 (18.8% vs 11.8%, p = 0.019), as well as at the other time-points, though not statistically significant.

          Conclusion

          D-dimer levels during and after stopping an anticoagulant treatment for a venous thromboembolism episode differ between patients treated with a DOAC than in those treated with warfarin. Specifically designed prospective studies are warranted to reassess the use of D-dimer as predictor of the risk of recurrent venous thromboembolism in patients treated with DOACs.

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          Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy.

          Marc Rodger, Susan R. Kahn, Philip Wells … (2008)
          Whether to continue oral anticoagulant therapy beyond 6 months after an "unprovoked" venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants. In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5-7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p or = 250 microg/L while taking warfarin; body mass index > or = 30 kg/m(2); or age > or = 65 years. These women had an annual risk of 1.6% (95% CI 0.3%-4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%-17.3%). Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men.
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            Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials

            Florent Boutitie, Laurent Pinede, Sam Schulman … (2011)
            Objective To determine how length of anticoagulation and clinical presentation of venous thromboembolism influence the risk of recurrence after anticoagulant treatment is stopped and to identify the shortest length of anticoagulation that reduces the risk of recurrence to its lowest level. Design Pooled analysis of individual participants’ data from seven randomised trials. Setting Outpatient anticoagulant clinics in academic centres. Population 2925 men or women with a first venous thromboembolism who did not have cancer and received different durations of anticoagulant treatment. Main outcome measure First recurrent venous thromboembolism after stopping anticoagulant treatment during up to 24 months of follow-up. Results Recurrence was lower after isolated distal deep vein thrombosis than after proximal deep vein thrombosis (hazard ratio 0.49, 95% confidence interval 0.34 to 0.71), similar after pulmonary embolism and proximal deep vein thrombosis (1.19, 0.87 to 1.63), and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis (0.55, 0.41 to 0.74). Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with at 3 months or later (hazard ratio 1.52, 1.14 to 2.02) and similar if treatment was stopped at 3 months compared with at 6 months or later (1.19, 0.86 to 1.65). High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment. Conclusion Three months of treatment achieves a similar risk of recurrent venous thromboembolism after stopping anticoagulation to a longer course of treatment. Unprovoked proximal deep vein thrombosis and pulmonary embolism have a high risk of recurrence whenever treatment is stopped.
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              Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators.

              Giancarlo Agnelli, Walter Ageno, … (2001)
              In patients with idiopathic deep venous thrombosis, continuing anticoagulant therapy beyond three months is associated with a reduced incidence of recurrent thrombosis during the period of therapy. Whether this benefit persists after anticoagulant therapy is discontinued is controversial. Patients with a first episode of idiopathic proximal deep venous thrombosis who had completed three months of oral anticoagulant therapy (with warfarin, in 97 percent of the cases and acenocoumarol in 3 percent) were randomly assigned to the discontinuation of oral anticoagulants or to their continuation for nine additional months. The primary study outcome was recurrence of symptomatic, objectively confirmed venous thromboembolism during at least two years of follow-up. The primary intention-to-treat analysis showed that of 134 patients assigned to continued oral anticoagulant therapy, 21 had a recurrence of venous thromboembolism (15.7 percent; average follow-up, 37.8 months), as compared with 21 of 133 patients assigned to the discontinuation of oral anticoagulant therapy (15.8 percent; average follow-up, 37.2 months), resulting in a relative risk of 0.99 (95 percent confidence interval, 0.57 to 1.73). During the initial nine months after randomization (after all patients received three months of therapy), 1 patient had a recurrence while receiving oral anticoagulant therapy (0.7 percent), as compared with 11 of the patients assigned to the discontinuation of oral anticoagulant therapy (8.3 percent; P=0.003). The incidence of recurrence after the discontinuation of treatment was 5.1 percent per patient-year in patients in whom oral anticoagulant therapy was discontinued after 3 months (95 percent confidence interval, 3.2 to 7.5 percent; average interval since discontinuation, 37.2 months) and 5.0 percent per patient-year in patients who received an additional 9 months of oral anticoagulant therapy (95 percent confidence interval, 3.1 to 7.8 percent; average interval since discontinuation, 29.4 months). None of the recurrences were fatal. Four patients had non-fatal major bleeding during the extended period of anticoagulant therapy (3.0 percent). In patients with idiopathic deep venous thrombosis, the clinical benefit associated with extending the duration of anticoagulant therapy to one year is not maintained after the therapy is discontinued.
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                Author and article information

                Contributors
                Cristina Legnani:
                ORCID: http://orcid.org/0000-0003-1999-7800
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Writing – original draft
                Ida Martinelli: Role: ConceptualizationRole: Writing – review & editing
                Gualtiero Palareti: Role: ConceptualizationRole: Writing – original draft
                Alessandro Ciavarella: Role: ConceptualizationRole: Writing – review & editing
                Daniela Poli: Role: ConceptualizationRole: Writing – review & editing
                Walter Ageno: Role: ConceptualizationRole: Writing – review & editing
                Sophie Testa: Role: ConceptualizationRole: Writing – review & editing
                Daniela Mastroiacovo: Role: ConceptualizationRole: Writing – review & editing
                Maurizio Ciammaichella:
                ORCID: http://orcid.org/0000-0003-4456-8784
                Role: ConceptualizationRole: Writing – review & editing
                Eugenio Bucherini: Role: ConceptualizationRole: Writing – review & editing
                Nicola Mumoli:
                ORCID: http://orcid.org/0000-0001-7166-5630
                Role: ConceptualizationRole: Writing – review & editing
                Benilde Cosmi: Role: ConceptualizationRole: Writing – review & editing
                Pablo Garcia de Frutos: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 16 July 2019
                Publication date Collection: 2019
                Volume: 14
                Issue: 7
                Electronic Location Identifier: e0219751
                Affiliations
                [1 ] Fondazione Arianna Anticoagulazione, Bologna, Italy
                [2 ] Fondazione Ca’ Granda (Istituto di Ricovero e Cura a Carattere Scientifico) - Ospedale Maggiore Policlinico - A. Bianchi Bonomi Hemophilia and Thrombosis Center, Milano, Italy
                [3 ] Malattie Aterotrombotiche - Azienda Ospedaliero Universitaria Careggi, Firenze, Italy
                [4 ] Degenza Breve Internistica e Centro Trombosi ed Emostasi - Azienda Socio Sanitaria Territoriale dei Sette Laghi, Varese, Italy
                [5 ] Centro Emostasi e Trombosi - Laboratorio Analisi chimico-cliniche e microbiologiche - Azienda Socio Sanitaria Territoriale di Cremona, Cremona, Italy
                [6 ] Unità Operativa Semplice Dipartimentale di Angiologia e Diagnostica Vascolare - Ospedale Civile S.S. Filippo e Nicola, Avezzano, L’Aquila, Italy
                [7 ] Unità Operativa Complessa di Medicina d’Urgenza - Azienda Ospedaliera S. Giovanni Addolorata, Roma, Italy
                [8 ] Struttura Semplice Dipartimentale - Medicina Vascolare – Angiologia – Ospedale Civile Faenza, Faenza, Ravenna, Italy
                [9 ] Unità Operativa Complessa di Medicina Interna - Ospedale Fornaroli, Magenta, Milan, Italy
                [10 ] Unità Operativa Angiologia e Malattie della Coagulazione - Azienda Ospedaliero Universitaria di Bologna - Policlinico S. Orsola - Malpighi, Bologna, Italy
                Institut d’Investigacions Biomediques de Barcelona, SPAIN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-1999-7800
                http://orcid.org/0000-0003-4456-8784
                http://orcid.org/0000-0001-7166-5630
                Article
                Publisher ID: PONE-D-19-11316
                DOI: 10.1371/journal.pone.0219751
                PMC ID: 6634858
                PubMed ID: 31310608
                SO-VID: 40cb9b17-813c-4b4c-ae58-18c0231290fa
                Copyright © © 2019 Legnani et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 21 April 2019
                Date accepted : 1 July 2019
                Page count
                Figures: 1, Tables: 3, Pages: 9
                Funding
                The authors received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Thromboembolism
                Subject: Venous Thromboembolism
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Cardiovascular Therapy
                Subject: Anticoagulant Therapy
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Thromboembolism
                Subject: Venous Thromboembolism
                Subject: Deep Vein Thrombosis
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Drugs
                Subject: Anticoagulants
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Chemical compounds
                Subject: Organic compounds
                Subject: Vitamins
                Subject: B vitamins
                Subject: Vitamin K
                Subject: Physical sciences
                Subject: Chemistry
                Subject: Organic chemistry
                Subject: Organic compounds
                Subject: Vitamins
                Subject: B vitamins
                Subject: Vitamin K
                Subject: Medicine and Health Sciences
                Subject: Pharmaceutics
                Subject: Drug Therapy
                Subject: Medicine and Health Sciences
                Subject: Pulmonology
                Subject: Pulmonary Embolism
                Subject: Medicine and Health Sciences
                Subject: Vascular Medicine
                Subject: Thromboembolism
                Subject: Venous Thromboembolism
                Subject: Pulmonary Embolism
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Glycobiology
                Subject: Glycoproteins
                Subject: Fibrinogen
                Custom metadata
                Data Availability All relevant data are within the manuscript.

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