key: cord-1016909-52ta7tiu authors: Lewis, Paul; Tharp, Jennifer L. title: Breakthrough venous thromboembolic events in five patients with COVID‐19 on direct oral anticoagulants date: 2020-11-20 journal: J Clin Pharm Ther DOI: 10.1111/jcpt.13311 sha: 7f1c81566e8f0fa03c2130f3bb56156af0f07468 doc_id: 1016909 cord_uid: 52ta7tiu WHAT IS KNOWN AND OBJECTIVE: Coronavirus disease 2019 (COVID‐19) is associated with increased risk of venous thromboembolism (VTE). Guidance for VTE prophylaxis continues to evolve, including addressing direct oral anticoagulants (DOACs) continued upon hospitalization. CASE SUMMARIES: We present 5 patients hospitalized for COVID‐19 while on DOACs. Four patients had atrial fibrillation and had a previous VTE. Four patients developed acute VTE and one developed stroke‐like symptoms. Monitoring D‐dimer assisted with the detection of VTE. Three patients died, and two were discharged alive. WHAT IS NEW AND CONCLUSION: Therapeutic failure with DOACs appears to be commonplace in COVID‐19. Further research is needed to determine whether there is an underlying cause to this association. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has created unique challenges since its discovery in Wuhan, China. 1 Evidence demonstrates significant cardiovascular complications, particularly coagulopathy. A hypercoagulable state predisposes patients to venous thromboemboli (VTE) via endothelial dysfunction, inflammation, platelet activation and venous stasis. 2 For hospitalized patients not previously on anticoagulation, the need for VTE prophylaxis is well-established. 3 Therapeutic options include unfractionated heparin (UHF), low-molecular-weight heparin (LMWH) or fondaparinux. The International Society on Thrombosis and Haemostasis (ISTH) gives preference to UHF or LMWH for VTE prophylaxis in both critically ill and non-critically ill patients. 4, 5 Vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACS) are cautioned due to drug-drug interactions. 4 The American College of Chest Physicians recommends LMWH, UHF and fondaparinux over DOACs and LMWH and fondaparinux over UHF to limit healthcare worker exposure. 6 Caution with DOACs is again advised due to the possibility of hemodynamic instability, drug-drug interactions and risk of acute kidney injury altering pharmacokinetics and increasing bleeding risk. 6 Despite the abundance of guidance for initiating VTE prophylaxis in patients not previously on anticoagulation, there is little direction for patients admitted on therapeutic DOACs for other indications (nonvalvular atrial fibrillation and previous VTE). Current evidence cautions against DOACs for increased bleeding rather than therapeutic failure. Guidance for anticoagulation in this scenario is not well-established, and thus directed to standard of care for hospitalized non-COVID patients. 3 Herein, we describe 5 cases of patients taking DOACs for other indications who developed breakthrough VTEs. This case series occurred at a regional COVID care facility. As part of standard hospitalized care, all patients are evaluated for appropriate VTE prophylaxis or treatment therapy daily. Patients who are TA B L E 1 Patient details Care was withdrawn, per his wishes. is recommended over oral therapy. 6 For patients that clot while on home therapies, the chest guidelines provide a framework for management. 6 Specifically, if VTE occurs on a DOAC, a change to full dose LMWH or UHF is warranted. If VTE occurs on LMHW, dose increase of 25 to 30% should be considered. 6 There are several limitations including this being an all-male, all-white, elderly population. Given our small cohort, it is unknown whether age, race and sex contributed to these findings. Data regarding prehospital outpatient management are unavailable, and we are unable to speculate on non-hospitalized rates. The timing of patient 4 is somewhat obscure. We debated not including this case. But ultimately the prescribers felt, in their professional judgement, that this was rivaroxaban failure and was therefore included. Additionally, association does not prove causality. Further research is needed from larger institutions to validate or refute our findings. In the interim, we are considering converting patients admitted with COVID-19 on DOACs to therapeutic UHF or LMWH, which is currently a circulating proposal. 16, 17 The United Kingdom National Health Service is closest to adopting the recommendation to convert DOACs to therapeutic UHF or LMWH. 18 They again highlight the possibility of drug-drug interactions with DOACs, elude to the additional anti-inflammatory properties of UHF and LMWH, and recommend that DOACs "could be switched" to a LMWH. 18 However, the United States National Institutes of Health make no recommendations outside of standard of care. 3 The American College of Cardiology does not mention DOACs and states that the optimal prophylactic strategy requires further investigation. 2 Based on this case series, there appears to be the possibility that COVID-19 may lead to higher rates of DOAC failure. Although an exact mechanism is unknown, DOACs have no effect on endotheliitis while UHF and LMWH have pleiotropic anti-inflammatory properties. Further research is needed to evaluate these claims. In the interim, we suggest a low threshold for changing hospitalized patients with COVID-19 on DOACs to UHF or LMWH. The authors report no funding and no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Paul Lewis https://orcid.org/0000-0002-2626-7390 Clinical features of patients infected with 2019 novel coronavirus in Wuhan COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC Stateof-the-Art Review COVID-19) Treatment Guidelines. National Institutes of Health Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: Clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19 ISTH interim guidance on recognition and management of coagulopathy in COVID-19 Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease Late Pulmonary Embolism after COVID-19 Pneumonia despite Adequate Rivaroxaban Treatment Endothelial cell infection and endotheliitis in COVID-19 Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review The anti-inflammatory effects of heparin and related compounds The role of heparin in sepsis: much more than just an anticoagulant More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Targeting factor Xa and thrombin: impact on coagulation and beyond Versatile role of heparanase in inflammation Clinical differentiation of anticoagulant and non-anticoagulant properties of heparin Switch from oral anticoagulants to parenteral heparin in SARS-CoV-2 hospitalized patients Switch from oral anticoagulants to parenteral heparin in SARS-CoV-2 hospitalized patients: comment Guide lines -SOPs-clini cal-info/ Docs/Clini cal-guide line/CG103 93-COVID -Throm bopro phyla xis-and-Antic oagul ation -in-COVID -19-infec tions