Rate of Recurrence After Discontinuing Anticoagulation Therapy in Patients With COVID-19–Associated Venous Thromboembolism

There is uncertainty regarding the optimal duration of anticoagulation therapy (AT) after COVID-19–associated venous thromboembolism (VTE). We analyzed the rate of VTE recurrence in patients with COVID-19–associated VTE who discontinued AT.^1-3

This prospective, multinational cohort study used data from the Registro Informatizado de la Enfermedad Tromboembolica (RIETE) registry, which prospectively collects information on patients with VTE.⁴ Since March 25, 2020, RIETE has incorporated data on COVID-19–associated VTE. This study included patients who developed proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) within 30 days of confirmed COVID-19 between March 25, 2020, and April 23, 2021, and discontinued AT after at least 3 months (eMethods in the Supplement).^1-3 Patients with upper limb or unusual sites of DVT, those who did not receive at least 3 months of AT, and those who were followed up for less than 15 days after AT discontinuation were excluded. The observation period for the inception cohort began on the day of AT discontinuation and ended with recurrent VTE, death, or on November 24, 2021. This study was approved by the Ethics Committee of Hospital Germans Trias i Pujol. Oral informed consent was obtained. This study followed the STROBE reporting guideline.

The primary outcome was the rate of symptomatic recurrent VTE per 100 patient-years of follow-up. Testing for VTE was triggered by patient-reported symptoms and ascertained by local clinicians without central validation. Analyses were conducted with SPSS, version 25.0, and Stata, version 17.1.

Of 1372 enrolled patients with COVID-19–associated VTE, 664 (48.4%) were receiving AT at the end of the study period and 708 (51.6%) had discontinued AT. After excluding 109 patients who had less than 15 days of follow-up after AT discontinuation, 147 who received less than 3 months of AT, and 21 with upper limb DVTs, 431 remained (mean [SD] age, 61.6 [14.3] years; 60.3% men) (Table). Median duration of AT was 4.6 months (IQR, 3.5-6.3 months). There were no significant differences in clinical characteristics of patients who discontinued vs continued anticoagulation.

Over a median postdiscontinuation follow-up of 5.8 months (IQR, 3.4-10.0 months), 11 patients (2.6%; 95% CI, 1.3%-4.5%) had recurrent VTE (6 DVT, 3 PE, and 2 DVT and PE). At 30 days, 1 patient had PE and DVT and 1 had DVT only). The rate of recurrent VTE was 4.8 (95% CI, 2.4-8.6) per 100 patient-years (Figure).

During follow-up, there were 11 deaths (2.5%; 95% CI, 1.3%-4.4%), with no cases of recurrent fatal PE. The case-fatality rate of VTE recurrences was 0% (95% CI, 0%-28.5%).

In patients with COVID-19–associated VTE who discontinued AT, the rate of VTE recurrences (4.8 per 100 patient-years) was similar to that in patients with VTE associated with a transient nonsurgical factor (5.8% [95% CI, 3.2%-8.3%] per patient-year)⁵ and may be in line with the inflammatory response and acute illness in the context of COVID-19 improving over time. Our findings support the practice of providing a limited course of AT to these patients.³

Data about duration of AT for this population are scarce. A single-center study reported that 39 patients with COVID-19–associated VTE discontinued AT after a median duration of 6 months (range 3-6 months), and no symptomatic VTE recurrences were reported at 6 months (range, 5.5-6.6 months).⁶

Limitations are that follow-up beyond the first 3 months in RIETE is according to routine care and outcomes were ascertained by local clinicians without central validation. However, patients were monitored regularly by their clinicians and encouraged to report changes in symptoms that might warrant additional diagnostic tests. Routine screening for asymptomatic recurrences is not the standard of care in practice or in most clinical studies. Although our study assessed, to our knowledge, the largest sample of patients with COVID-19–associated VTE who discontinued AT, the 95% CIs were wide. Additional epidemiological and comparative effectiveness studies may improve the confidence and clarity of our findings.

Accepted for Publication: September 12, 2022.

Published Online: November 7, 2022. doi:10.1001/jamainternmed.2022.4954

Corresponding Author: Luis Jara-Palomares, MD, PhD, Medical Surgical Unit of Respiratory Diseases, Hospital Virgen del Rocio. Av. Manuel Siurot s/n, Seville 41013, Spain (luisoneumo@hotmail.com).

Author Contributions: Drs Jara-Palomares, Bikdeli, and Jiménez contributed equally. Dr Jara-Palomares had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Jara-Palomares, Bikdeli, Jimenez, Martin del Pozo, Monreal.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Jara-Palomares, Jimenez, Martin del Pozo.

Critical revision of the manuscript for important intellectual content: Bikdeli, Jimenez, Muriel, Martin del Pozo, Demelo-Rodríguez, Monreal.

Statistical analysis: Jara-Palomares, Jimenez, Muriel.

Obtained funding: Martin del Pozo, Monreal.

Administrative, technical, or material support: Martin del Pozo.

Supervision: Jara-Palomares, Bikdeli, Monreal.

Conflict of Interest Disclosures: Dr Jara-Palomares reported receiving grants from Leo Pharma and MSD and receiving personal fees from Daichii, Rovi, GlaxoSmithKline, and Actellion outside the submitted work. Dr Bikdeli reported being a consulting expert on behalf of the plaintiff for litigation related to 2 brand models of inferior vena cava filters. Dr Jimenez reported receiving personal fees from Pfizer, Bristol Myers Squibb, Daiichi Sankyo, Rovi, and Leo Pharma outside the submitted work. Dr Demelo-Rodríguez reported receiving personal fees from Sanofi, Leo Pharma, Bayer, ROVI, Menarini, and Pfizer outside the submitted work. Dr Monreal reported grants from Sanofi and Rovi outside the submitted work. No other disclosures were reported.

Funding/Support: Dr Bikdeli reported receiving support from the Scott Schoen and Nancy Adams IGNITE Award, and the Mary Ann Tynan Research Scientist award through the Mary Horrigan Connors Center for Women’s Health and Gender Biology, as well as the Heart and Vascular Center Junior Faculty Award, all at Brigham and Women’s Hospital; receiving Career Development Award 928814 from the American Heart Association and VIVA Physicians.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: The Registro Informatizado de la Enfermedad Tromboembolica Registry Coordinating Center, S&H Medical Science Service, provided quality control data and logistic and administrative support. Sanofi Spain, LEO Pharma, and ROVI supported the registry with an unrestricted educational grant.