Is Post-Discharge VTE Prophylaxis Necessary for Patients With COVID-19?

In hospitalized patients with COVID-19, the risk of venous thromboembolism (VTE) following discharge was not significantly greater compared with the VTE risk in patients admitted for reasons other than COVID-19, according to study findings published in Blood.1,2 “These findings challenge the approach recommended by some expert guidance documents and implemented at some centers to routinely provide post-discharge VTE prophylaxis,” study author Lara Roberts, MD, of King’s College Hospital NHS Foundation Trust in London, told ASH Clinical News.

“There is quite a bit of evidence that the rates of thrombosis are high during hospitalization with COVID-19,” added study author Jeffrey Zwicker, MD, of the Beth Israel Deaconess Medical Center in Boston and Associate Professor of Medicine at Harvard Medical School, “but whether that risk persisted after discharge was not known.”

In two separate studies, Drs. Roberts and Zwicker retrospectively examined post-discharge VTE data among patients with and without COVID-19 infection.

In the study led by Dr. Zwicker, 163 consecutive patients hospitalized with a COVID-19 diagnosis were analyzed. These patients had an overall median time from discharge to last follow-up of 30 days and a median index hospitalization duration of 6 days. Approximately 26% of the patients required intensive care.

At 30 days after discharge, the cumulative incidence of thromboembolic and bleeding events was:

  • thrombosis: 2.5%
  • VTE only: 0.6%
  • major hemorrhage: 0.7%
  • clinically relevant non-major bleeds: 2.9%

“The findings were surprising in that we expected the proclivity to suffer thrombotic events with COVID-19 would persist even after discharge,” noted Dr. Zwicker. “It appears that after recovery of acute illness with COVID-19, thrombotic risk is actually similar to the risk following hospitalization for acute medical illness.”

In their study, Dr. Roberts and colleagues examined post-discharge data for 1,877 patients with COVID-19 who were discharged from 2 U.K. hospital sites on or before May 2020. This included 208 patients who were admitted to critical care. A total of 9 episodes of hospital-associated VTE (HA-VTE) were diagnosed within 42 days following discharge, corresponding with a post-discharge HA-VTE rate of 4.8 per 1,000 discharges. In comparison, there were 56 episodes of HA-VTE within 42 days of discharge in 18,159 cases during 2019, corresponding with a post-discharge rate of 3.1 per 1,000 discharges in the pre–COVID-19 era. In an analysis that compared post-discharge HA-VTE associated with COVID-19 compared with the 2019 discharge data, the odds ratio for post-discharge HA-VTE was 1.6.

“It is widely recognized that COVID-19 is associated with a thrombo-inflammatory response and an increased risk of VTE, which appears to be significantly increased in critically ill patients,” said Dr. Roberts. Despite a lack of data supporting such an approach, she added, “Many clinicians have intensified their approach to thromboprophylaxis in hospitalized patients with COVID-19, particularly for those admitted to intensive care units, with some also offering continued thromboprophylaxis following hospital discharge.”

Limitations of these studies included their retrospective natures, the lack of systematic follow-up, as well as the smaller sample size in Dr. Zwicker’s study.

“There is equipoise whether patients hospitalized with COVID-19 should receive thromboprophylaxis post discharge,” concluded Dr. Zwicker. “These data should be informative for the design of prospective clinical trials and bring attention to the heightened risk of hemorrhage in this population.”

Study authors report no relevant conflicts of interest.

References

  1. Patell R, Bogue T, Koshy AG, et al. Post-discharge thrombosis and hemorrhage in patients with COVID-19. Blood. 2020;136:1342-1346.
  2. Roberts LN, Whyte MB, Georgiou L, et al. Post-discharge venous thromboembolism following hospital admission with COVID-19. Blood. 2020 August 3. [Epub ahead of print]

Infection with SARS-CoV-2 is associated with increased levels of procoagulants including fibrinogen, factor VIII, and von Willebrand factor, as well as an increase in D-dimer.1 The magnitude of increase is correlated with degree of inflammation; increasing interleukin-6 levels correlate with increasing fibrinogen levels.2 Patients with more severe symptoms and inflammatory response requiring intensive care unit (ICU) admission experience higher rates of thrombosis than less severely ill patients admitted to the ward, as shown in many single-center analyses of patients receiving standard-dose VTE prophylaxis.3-5

Although the use of higher doses of anticoagulants in patients in the ICU compared with those in the ward is controversial given the lack of supporting randomized controlled trial data, the use of standard-dose VTE prophylaxis in all patients hospitalized with COVID-19 is not contested. Whether discharged patients also have an increased risk of post-discharge VTE is addressed by Dr. Roberts and colleagues.

Post-discharge VTE prophylaxis with direct oral anticoagulants (DOACs) can decrease rates of symptomatic VTE in medically ill patients, but the baseline risk is low in unselected patients; in some trials, the increased rate of bleeding with DOACs compared with placebo resulted in minimal net clinical benefit. Selection of patients with increased risk of VTE and minimal bleeding risk can alter the balance, favoring the use of extended duration of post-discharge VTE prophylaxis.6

Do COVID-19 positive patients have a higher risk for post-discharge VTE than historic medically ill patients? In the report by Dr. Roberts and colleagues, there was a low incidence of post-discharge VTE in COVID-19 patients at 45 days, similar to that of more than 18,000 discharged patients in 2019. Limitations include the possibility of decreased detection of events in COVID-19 patients, but the authors calculate that even if 50% of events were missed in the COVID-19 patients, the incidence of post-discharge VTE would still be low.

In these two hospital collaborations, in-hospital treatment variables such as use of antiviral agents, dexamethasone, anti-inflammatory agents, and other treatments, were not available at all hospitals, which may have affected post-discharge VTE rates. While the data from Dr. Roberts and coauthors are reassuring in that the post-discharge VTE rate is low, randomized controlled trials to address this question are needed. Until such results are available, careful risk-benefit assessment for the individual discharged COVID-19 patient is required.

Jean Marie Connors, MD
Dana-Farber Cancer Institute
Boston, MA

References

  1. Helms J, Tacquard C, Severac F, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46:1089-1098.
  2. Ranucci M, Ballotta A, Di Dedda U, et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost. 2020;18:1747-1751.
  3. Klok FA, Kruip MJHA, van der Meer NJM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-150.
  4. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18:1995-2002.
  5. Moll M, Zon RL, Sylvester KW, et al. VTE in ICU Patients With COVID-19. Chest. 2020;S0012-3692.
  6. Spyropoulos AC, Lipardi C, Xu J, et al. Modified IMPROVE VTE risk score and elevated D-dimer identify a high venous thromboembolism risk in acutely ill medical population for extended thromboprophylaxis. TH Open. 2020;4:e59-e65.

NIH Launches ACTIV Trials to Study Anticoagulation in Patients With COVID-19

The National Institutes of Health has launched two of three planned phase III clinical trials to test the safety and efficacy of anticoagulants, including heparin and apixaban, in adults hospitalized with COVID-19. The trials are part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative and will be conducted at more than 100 sites around the world.

Collectively known as ACTIV-4 Antithrombotics, the trials will provide critical insights that could help guide the care of patients with COVID-19, particularly those who suffer from life-threatening blood clots. Two ongoing trials will study the effects of anticoagulation in the inpatient and outpatient setting; a third planned trial will examine anticoagulants in patients who have been hospitalized and discharged.

These trials are part of the U.S. government’s Operation Warp Speed program to accelerate the development of coronavirus treatments, tests, and vaccines. Trial planning and development work is being done through a collaborative effort with a number of universities, including the University of Pittsburgh; University of Michigan, Ann Arbor; New York University, New York City; Brigham and Women’s Hospital, Boston; University of Illinois at Chicago; University of North Carolina at Chapel Hill; and the University of Vermont, Burlington. The NIH is seeking additional sites to participate in the ACTIV initiative. For more information, visit nih.gov/activ.