Relationship Between Subtherapeutic Warfarin Anticoagulation and the Development of Post Thrombotic Syndrome After a First Unprovoked Deep Vein Thrombosis: Results From the REVERSE Cohort Study
Authors: Chitsike Rufaro S. , Kahn Susan R. , Kovacs Michael J. , Betancourt Marisol T. , Wells Philip S , Anderson David , Chagnon Isabelle , Le Gal Gregoire , Solymoss Susan , Crowther Mark A. , Perrier Arnaud , White Richard H. , Vickars Linda , Ramsay Tim , Rodger Marc A. 
Published: October 2019

Abstract
Abstract 712

Background & Objective:
Risk factors for the post-thrombotic syndrome (PTS) remain poorly understood. In a prospective multinational multicenter cohort study of patients with a first episode of unprovoked deep venous thrombosis (DVT), we sought to evaluate whether subtherapeutic anticoagulation was associated with the development of PTS.

Methods:
The study population was derived from the REVERSE study, a prospective cohort study done to develop a clinical prediction rule to identify patients with unprovoked venous thromboembolism (VTE) at low risk of recurrent VTE. Patients with a first unprovoked VTE (index event) were treated with standard anticoagulant therapy with a target INR of 2–3 for a period of 5–7 months. Patients were then enrolled in the REVERSE study, anticoagulation was stopped, and patients were monitored for VTE recurrence.
For the present study, patients with DVT as their index VTE event were assessed for PTS at enrollment into the REVERSE study, using the validated Villalta scale. PTS was defined by a score of > 4. Mild PTS was defined by a score of 5–9, moderate PTS by a score of 10–14 and severe PTS was defined by a score of ≥15 or presence of an ipsilateral leg ulcer. Using international normalized ratio (INR) data from the full period of warfarin anticoagulation, time in therapeutic range (TTR) was calculated by the Rosendaal method of linear interpolation. TTR data were analyzed to evaluate whether there was an association between sub-therapeutic INR values during various time windows since the index DVT and development of PTS. Based on published trials of warfarin anticoagulation for VTE, INR <2 for more than 20% of the time was considered to represent subtherapeutic anticoagulation. Univariate analysis was performed to determine the odds ratio (OR) for development of PTS if anticoagulation was considered subtherapeutic. Multivariate analysis was then performed to adjust for known confounding variables.

Results:
646 patients were enrolled into the REVERSE study, of whom 410 had DVT as their index event. Of these, 61 were excluded for insufficient INR or PTS data. Hence, the study population comprised 349 patients. The average age was 54.2 years, and 55.6% of the patients were male. Patients were on oral anticoagulation for a mean (SD) of 199 (17) days. Ninety-seven patients (27.8%) developed PTS; of these, 77 (74.7%) had mild PTS, 16 (15.5%) had moderate PTS and 4 (3.9%) had severe PTS.
For the study population, the overall mean (SD) TTR during oral anticoagulation was 64.3% (19.4%) and the overall mean (SD) percentage time spent with an INR under 2 was 23.7% (18.7%). For the time window ‘first 3 months of anticoagulation', patients who developed PTS had an INR of <2 for 30% of the time vs. 24% of the time in patients without PTS (p=0.023). For the time window ‘full period of anticoagulation', patients who developed PTS had INR <2 for 27% of the time vs. 23% of the time in patients without PTS (p=0.08). Using our predefined cut-off for subtherapeutic anticoagulation (i.e. INR <2 for more than 20% of the time), patients with PTS were more likely to have received subtherapeutic anticoagulation than those without PTS during the first 3 months of anticoagulation (62.9% vs. 48.8%; p=0.02) and during the full period of anticoagulation (62.9% vs. 48.0%; p=0.01). The incidence of PTS in patients with an INR below 2 for >20% of the full time period was 33.5% compared to 21.6% in those with an INR below 2 for ≥20% of the time (p=0.02).
In univariate analysis, the OR for development of PTS if the INR was <2 for more than 20% of the time during the first 3 months of anticoagulation was 1.78 (95% CI 1.10–2.87). In multivariate analysis adjusting for age, sex, body mass index, concurrent PE, previous secondary VTE and use of graduated compression stockings, the association between subtherapeutic anticoagulation and PTS remained robust (1.84 95% CI 1.13–3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14–3.00) [crude] and 1.88 (95% CI 1.15–3.07) [adjusted].

Conclusion:
Subtherapeutic warfarin anticoagulation after a first unprovoked DVT may be a risk factor for the development of PTS. Careful attention to INR control may have value in preventing PTS. Further study of the risk of PTS associated with oral or parenteral anticoagulants that offer more predictable anticoagulation than warfarin may be of value.

Disclosures:
No relevant conflicts of interest to declare.