Age-adjusted D-dimer cutoffs to guide anticoagulation in COVID-19 – Authors' reply
Authors: Renato D Lopes, Pedro Gabriel Melo de Barros e Silva, Remo H M Furtado, John H Alexander, Otavio Berwanger
Journal: The Lancet (2021)

We appreciate the issues related to normal age-related D-dimer concentrations raised by Marco Zuin and colleagues. The ACTION study1Lopes RD de Barros e Silva PGM Furtado RHM et al.Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.Lancet. 2021; 397: 2253-2263Summary Full Text Full Text PDF PubMed Scopus (351) Google Scholar is a randomised trial designed pragmatically to answer the question of whether patients hospitalised with COVID-19 and elevated D-dimer concentration, without another indication for anticoagulation, should routinely receive therapeutic anticoagulation with the factor Xa inhibitor, rivaroxaban. We found that rivaroxaban 20 mg once daily for 30 days had no benefit and significantly increased bleeding compared with in-hospital prophylactic heparin. Early in the COVID-19 pandemic, observational data suggested that thrombotic events were high in patients with COVID-19 and even higher among patients with an elevated D-dimer concentration.2Tang N Li D Wang X Sun Z Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (4064) Google Scholar In light of the available information at the time, coupled with the fact that the D-dimer concentration of many patients with COVID-19 was measured when they were hospitalised, we included an elevated D-dimer concentration, defined as above the assay (not age-adjusted) upper limit of normal in each site, as an inclusion criterion for the ACTION trial. D-dimer concentrations are not routinely measured to guide therapeutic anticoagulation decision making in patients without COVID-19,3Ortel TL Neumann I Ageno W et al.American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism.Blood Adv. 2020; 4: 4693-4738Crossref PubMed Scopus (643) Google Scholar and the purpose of enrolling patients with an elevated D-dimer concentration in ACTION was to increase the trial population's risk of thrombotic events and not to establish D-dimer concentrations as a diagnostic tool to guide therapeutic anticoagulation in patients hospitalised with COVID-19. A prespecified subgroup analysis of ACTION showed that the main results were consistent, irrespective of D-dimer concentrations.1Lopes RD de Barros e Silva PGM Furtado RHM et al.Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.Lancet. 2021; 397: 2253-2263Summary Full Text Full Text PDF PubMed Scopus (351) Google Scholar Similar results have been shown in other randomised trials investigating anticoagulation in patients with COVID-19, in which D-dimer concentrations at presentation (elevated vs normal vs not collected) did not influence the main results.4The REMAP-CAP, ACTIV-4a, and ATTACC InvestigatorsTherapeutic anticoagulation with heparin in critically ill patients with COVID-19.N Engl J Med. 2021; (published online Aug 4.)https://doi.org/10.1056/NEJMoa2103417Crossref Scopus (645) Google Scholar, 5The ATTACC, ACTIV-4a, and REMAP-CAP InvestigatorsTherapeutic anticoagulation with heparin in noncritically ill patients with COVID-19.N Engl J Med. 2021; (published online Aug 4.)https://doi.org/10.1056/NEJMoa2105911Crossref Scopus (628) Google Scholar Furthermore, when we used age-adjusted D-dimer upper limits of normal, as proposed by Zuin and colleagues, we found that most (>90%) patients over the age of 50 years still had an elevated age-adjusted D-dimer concentration at study entry. Not surprisingly, when we excluded the fewer than 10% of patients who did not have an elevated age-adjusted D-dimer concentration, our main results remained consistent with those in the overall population (win ratio 0·87 [95% CI 0·59–1·26]). Therefore, the results from the ACTION trial are relevant, robust, and provide high-quality evidence to avoid the routine use of therapeutic rivaroxaban—in the absence of another evidence-based indication for oral anticoagulation—in patients hospitalised with COVID-19, irrespective of D-dimer concentration. RDL reports institutional research grants from Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; consulting fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, Sanofi, and Eidos; honoraria from Bristol Myers Squibb and Pfizer; support for attending meetings, travel, or both, from Bristol Myers Squibb and Pfizer; and data safety monitoring board or advisory board participation for IQVIA. PGMdBeS reports institutional research grants from Bayer, Pfizer, and Roche Diagnostics; and honoraria from Roche Diagnostics. RHMF reports institutional research grants from Bayer, Aché, Health Canada, CytoDin, EMS, Pfizer, AstraZeneca, and the Brazilian Ministry of Health; consulting fees from Servier; honoraria from AstraZeneca, Bayer, and Servier; support for attending meetings, travel, or both, from AstraZeneca and Bayer; and advisory board participation for Biomm. JHA reports institutional research grants from Bayer, Bristol Myers Squibb, Cryolife, CSL Behring, Ferring, Humacyte, GlaxoSmithKline, and XaTek; consulting fees from Akros, AtriCure, Bristol Myers Squibb, Cryolife, Ferring, GlaxoSmithKline, Janssen, Pfizer, and Portola; honoraria from Akros, AtriCure, Bristol Myers Squibb, Ferring, GlaxoSmithKline, Janssen, Pfizer, and Portola; support for attending meetings, travel, or both, from Bristol Myers Squibb and CryoLife; and data safety monitoring board or advisory board participation for AbbVie. OB reports institutional research grants from AstraZeneca, Pfizer, Bayer, Boehringer Ingelheim, Amgen, Novartis, and Servier. Age-adjusted D-dimer cutoffs to guide anticoagulation in COVID-19We read with great interest the Article by Renato D Lopes and colleagues1 showing that, among patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes but increased bleeding compared with prophylactic anticoagulation. However, in their analysis, the authors do not appear to have adequately considered the potential influence of the D-dimer concentration calculated with an age-adjusted cutoff. Full-Text PDF Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trialIn patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. Full-Text PDF