Rationale and design of a study on D-dimer use to stratify patients after a first unprovoked venous thromboembolism for their risk of recurrence: extended low-dose Apixaban given only to patients with positive D-dimer results
The Apidulcis study
Accepted: 9 February 2022
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Optimal duration of anticoagulation in patients with a first venous thromboembolism (VTE) is still uncertain. Extended anticoagulant treatment beyond the first 3 to 6 months is recommended in patients with unprovoked VTE for their high risk of recurrence, provided the risk of bleeding during anticoagulation is not high. Recent meta-analyses indicated that only one-third of these patients have a recurrence 10 years after anticoagulation is stopped, whereas the risk of major bleeding is consistent and persistent during anticoagulation. We designed the prospective, multicenter Apidulcis study to test whether serial D-dimer measurements, using commercial assays with predefined sex-specific cutoffs (350 ng/mL and 500 ng/mL for men and women, respectively, for assays expressing results as fibrinogen equivalent units), may be useful to stratify patients for the risk of recurrence. Those presenting positive D-dimer results, considered at higher risk, will receive low dose Apixaban, 2.5 mg tablets BID for 18 months, whereas those with persistently negative D-dimer results, considered at lower risk, will remain without anticoagulant treatment. Outpatients with a first VTE (unprovoked or associated with weak risk factors), aged 18 to 74 years, who have already received anticoagulation for at least 12 months are eligible for the study.
Pinede L, Ninet J, Duhaut P, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001;103:2453-60. DOI: https://doi.org/10.1161/01.CIR.103.20.2453
Agnelli G, Prandoni P, Santamaria MG, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001;345:165-9. DOI: https://doi.org/10.1056/NEJM200107193450302
Couturaud F, Sanchez O, Pernod G, et al. Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial. JAMA 2015;314: 31-40. DOI: https://doi.org/10.1001/jama.2015.7046
Couturaud F, Pernod G, Presles E, et al. Six months versus two years of oral anticoagulation after a first episode of unprovoked deep-vein thrombosis. The PADIS-DVT randomized clinical trial. Haematologica 2019;104:1493-501. DOI: https://doi.org/10.3324/haematol.2018.210971
Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 2010;170:1710-6. DOI: https://doi.org/10.1001/archinternmed.2010.367
Prandoni P, Lensing AWA, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-8. DOI: https://doi.org/10.1182/blood-2002-01-0108
Khan F, Rahman A, Carrier M, 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. DOI: https://doi.org/10.1136/bmj.l4363
Khan F, Tritschler T, Kimpton M, 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 2021;174:1420-9. DOI: https://doi.org/10.7326/M21-1094
Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med 2006;355:1780-9. DOI: https://doi.org/10.1056/NEJMoa054444
Douketis J, Tosetto A, Marcucci M, et al. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 2010;153:523-31. DOI: https://doi.org/10.7326/0003-4819-153-8-201010190-00009
Cosmi B, Legnani C, Tosetto A, et al. Usefulness of repeated D-dimer testing after stopping anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II prospective study. Blood 2010;115:481-8. DOI: https://doi.org/10.1182/blood-2009-08-237354
Kearon C, Spencer FA, O'Keeffe D, et al. D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study. Ann Intern Med 2015;162:27-34. DOI: https://doi.org/10.7326/M14-1275
Kearon C, Iorio A, Palareti G. Risk of recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting. J Thromb Haemost 2010;8:2313-5. DOI: https://doi.org/10.1111/j.1538-7836.2010.03991.x
Palareti G, Cosmi B, Legnani C, et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood 2014;124:196-203. DOI: https://doi.org/10.1182/blood-2014-01-548065
Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708. DOI: https://doi.org/10.1056/NEJMoa1207541
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692-4. DOI: https://doi.org/10.1111/j.1538-7836.2005.01204.x
Kaatz S, Ahmad D, Spyropoulos AC, et al. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:2119-26. DOI: https://doi.org/10.1111/jth.13140
Villalta S BP, Piccioli A, Lensing AWA, et al. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis 1994;24:158a.
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52. DOI: https://doi.org/10.1016/j.chest.2015.11.026
Prandoni P, Cogo A, Bernardi E, et al. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation 1993;88:1730-5. DOI: https://doi.org/10.1161/01.CIR.88.4.1730
Fedullo PF, Tapson VF. The evaluation of suspected pulmonary embolism. N Engl J Med 2003;349:1247-56. DOI: https://doi.org/10.1056/NEJMcp035442
Kearon C. Diagnosis of pulmonary embolism. Can Med Assoc J 2003;168:183-94.
Shen LZ. Sample size determination for controlling the upper confidence limit of incidence rate of a binomial endpoint. J Biopharm Stat 1998;8:489-96. DOI: https://doi.org/10.1080/10543409808835254
Albertsen IE, Piazza G, Goldhaber SZ. Let's Stop Dichotomizing Venous Thromboembolism as Provoked or Unprovoked. Circulation 2018;138:2591-3. DOI: https://doi.org/10.1161/CIRCULATIONAHA.118.036548
Prins MH, Lensing AWA, Prandoni P, et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Adv 2018;2:788-96. DOI: https://doi.org/10.1182/bloodadvances.2018017160
Tosetto A, Testa S, Martinelli I, et al. External validation of the DASH prediction rule: a retrospective cohort study. J Thromb Haemost 2017;15:1963-70. DOI: https://doi.org/10.1111/jth.13781
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