key: cord-0989849-4xa0sdmo authors: Zuin, Marco; Rigatelli, Gianluca; Zuliani, Giovanni; Roncon, Loris title: Age-adjusted D-dimer cutoffs to guide anticoagulation in COVID-19 date: 2021-10-07 journal: Lancet DOI: 10.1016/s0140-6736(21)01859-6 sha: 341760ecbbf1ac312dcf00f4256cde07a35171be doc_id: 989849 cord_uid: 4xa0sdmo nan We read with great interest the Article by Renato D Lopes and colleagues 1 showing that, among patients hospitalised with COVID-19 and elevated D-dimer concentration, inhospital 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. 2 According to current international guidelines, 3,4 an age-adjusted D-dimer test threshold must be considered for people older than 50 years, as in the case of this study, in which the mean age was 56·6 years (SD 14·3). Furthermore, considering that risk of mortality and severe forms of COVID-19 pneumonia increase with ageing, 5 it seems reasonable to prefer the adoption of an ageadjusted cutoff in this patient group. Therefore, the results of this large, multicentre, randomised trial should be interpreted cautiously for patients with COVID-19. We declare no competing interests. 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. 1 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. 4, 5 Furthermore, when we used ageadjusted 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 ageadjusted 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 highquality 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. Tracing the origin and history of the HIV-2 epidemic Origins of HIV and the AIDS pandemic Broad and differential animal ACE2 receptor usage by SARS-CoV-2 Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species SARS-CoV-2 exposure in wild white-tailed deer (Odocoileus virginianus) Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia Evidence of SARS-CoV-2 RNA in an oropharyngeal swab specimen SARS-CoV-2 has been circulating in northern Italy since December 2019: evidence from environmental monitoring COVID-19-related dermatosis in November 2019: could this case be Italy's patient zero? Molecular evidence for SARS-CoV-2 in samples collected from patients with morbilliform eruptions since late summer SARS-CoV-2 was already spreading in France in late Evidence of early circulation of SARS-CoV-2 in France: findings from the population-based "CONSTANCES" cohort The presence of SARS-CoV-2 RNA in human sewage in Santa Catarina, Brazil Serologic testing of US blood donations to identify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-reactive antibodies Antibodies to SARS-CoV-2 in All of Us research program participants Rapid response to an outbreak in Qingdao, China Cold-chain transportation in the frozen food industry may have caused a recurrence of COVID-19 cases in destination: successful isolation of SARS-CoV-2 virus from the imported frozen cod package surface Venous thromboembolic diseases: diagnosis, management and thrombophilia testing ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the Age-adjusted D-dimer cut-off levels to rule out venous thromboembolism in COVID-19 patients We appreciate the issues related to normal age-related D-dimer concentrations raised by Marco Zuin and colleagues. The ACTION study 1 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 inhospital 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. 2 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, 3 and the purpose of enrolling patients with an elevated D-dimer concentration in ACTION was to increase the trial population's risk of thrombotic Shikino K, Sato R, Hanazawa N, Ikusaka M. Chronic clicking tinnitus due to palatal tremor: essential or secondary? Lancet 2021; 397: e16-In this Clinical Picture, Manato Yasuda has been added as an author. In the second sentence of the fifth paragraph, treatment dose has been corrected to 3 mg clonazepam orally per day. These corrections have been made to the online version as of Oct 7, 2021.