Association between initial and residual pulmonary vascular obstruction and pulmonary embolism recurrence, a pooled analysis

Abstract

Introduction The best treatment option (short-term or extended anticoagulant treatment) after a first unprovoked pulmonary embolism (PE) is debated. Pulmonary vascular obstruction, measured by the pulmonary vascular obstruction index (PVOI) at diagnosis or during the follow-up, has been associated with an increased risk of venous thromboembolism (VTE) recurrence when anticoagulants are stopped [1] . But results are not entirely consistent [2] , and PVOI classification cut-offs vary among studies. We therefore conducted a pooled analysis of 3 studies of the F-CRIN INNOVTE network. The primary objective of this work is to assess if elevated PVOI at the time of PE diagnosis and after months of anticoagulation are independent risk factors of VTE recurrence after a first episode of PE, and if so, to estimate which PVOI cut-off values would be the most discriminating for predicting VTE recurrence. Method We performed a pooled analysis of individual data from 3 French studies conducted within the F-CRIN INNOVTE network: a randomised double-blind controlled clinical trial and two observational longitudinal cohort studies. PVOI was measured by ventilation/perfusion lung scan during two periods; one at the time of index PE (initial PVOI), and one several months later, after anticoagulation treatment of the acute phase (post-treatment PVOI). PVOI was expressed in percentage of vascular obstruction. VTE recurrence was defined as objectively confirmed PE episode or deep vein thrombosis. The associations between PVOI (both initial and post-treatment) and VTE recurrence were jointly estimated using a multivariate Cox proportional hazards regression model. To manage confounding, the model was further stratified on the study, as well as adjusted on anticoagulant treatment duration, which could have been affected by PVOI measurement in the two observational cohort studies. By this means, the direct effect of PVOI on VTE recurrence may be estimated. Optimal PVOI thresholds were estimated by 10-fold cross-validation, using areas under curve (AUC) computed from time-dependant receiver-operating characteristic (ROC) curves. Results The total number of patients was 922. The median duration of follow-up was 42 months (IQR: 38–60). Mean age was 60 ± 18 years, 56% of patients were female. VTE recurrences occurred in 149 patients (4.2 events per 100 person-years). The most discriminating cut-offs were > 35% for initial PVOI (AUC: 0.71, 95% CI: 0.71–0.71), and > 5% for post-treatment PVOI (AUC: 0.69, 95% CI: 0.68–0.69). Initial PVOI > 35% and post-treatment PVOI > 5% were significantly associated with the risk of VTE recurrences (HR 1.61, 95% CI: 1.07–2.43 and HR 1.63, 95% CI: 1.06–2.50, respectively). Conclusion After a first episode of PE, initial PVOI > 35% and post-treatment PVOI > 5% were found to be independent predictors of VTE recurrence. Those results could in the future help detect more accurately patients with high-risk of VTE recurrence, and thus provide help in clinical decision-making for adapting anticoagulation therapy.