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F. Couturaud et al.
2-3% per year. The risk of recurrence in the warfarin group was lower than in the placebo group during the first months after anticoagulation discontinuation (cumulative risk, 9.4; 95% CI: 2.87-15.9 at 12 months); however, if no rebound effect was observed as compared to the risk of recurrence in the placebo group in the first months follow- ing randomization, this risk increased linearly throughout the 24-month post-treatment period, resulting in an annu- al incidence of recurrence close to that observed in the placebo group during the entire study period. Finally, the loss of extended therapy benefit after cessation of antico- agulation corroborates that observed in other randomized trials evaluating extended therapy in patients with unpro- voked venous thromboembolism.4-7
Finally, our results suggest that patients with a first episode of unprovoked proximal deep-vein thrombosis should receive indefinite anticoagulation; however, such an assumption is tempered by the following observation. Consistent with the results of the PADIS-PE and other tri- als,4-7,16 venous thromboembolism predominantly recurred in the same form as the index episode: regardless of whether patients had been treated for 6 or 24 months, 90% of recurrences were symptomatic deep-vein throm- bosis, of which 3% (1 of 31 episodes) were fatal, and 97% of all recurrences were unprovoked. Thus, most recur- rences were certainly unpreventable but they represented the less severe form of venous thromboembolism.
Our study had several strengths: (i) we used a double- blind, randomized design in a carefully predefined and characterized population; (ii) we achieved a very long and complete follow-up for all patients included; (iii) patients adhered closely to the study protocol during the treatment period and subsequent follow-up; and (iv) all outcomes were reviewed and validated blindly by an independent centralized adjudication committee.
The most important limitation is the small sample size of the study due to the premature discontinuation of study enrollment decided by the steering committee. This decision respected the safety committee’s recommendations based on the slow recruitment rate, rendering attainment of the expected sample size unrealistic. However, all patients
included had a complete follow up and our relative risk reduction estimates are consistent with those reported in our previous study in patients with unprovoked pulmonary embolism and other studies.4-6 Another limitation is that the primary outcome included two different outcome measures that may not be clinically equivalent, as the case-fatality rate of recurrent deep-vein thrombosis is inferior to that of major bleeding.15 However, the advantage of the composite end- point is to provide a net benefit estimate encompassing the two main complications of venous thrombosis management (i.e., recurrent thrombosis and bleeding). In this setting, our results were essentially driven by a strong increase in the risk of recurrence that was unlikely to be offset by the risk of bleeding. Furthermore, a D-dimer-guided strategy was not used in our study, but this was not recommended when we designed the protocol and is still considered controversial.25,26 Lastly, extended therapy was evaluated using warfarin, not with direct oral anticoagulants. Our results suggest that patients such as ours require continued treatment. Whether direct oral anticoagulants, at full or low dose,10-12 could con- stitute an effective and safe alternative to warfarin or could be tailored according to patients’ risk factors (including ele- vated D-dimer levels),27 will need further investigation.
In conclusion, after a first episode of unprovoked proxi- mal deep-vein thrombosis initially treated for 6 months, the major benefit of an additional 18 months of treatment with warfarin on the composite of recurrent venous thromboembolism and major bleeding was not main- tained after discontinuation of anticoagulant therapy. Extended therapy did not modify the clinical presentation of recurrence, i.e., mostly unprovoked non-fatal proximal deep-vein thrombosis. Whether these findings apply to direct oral anticoagulants remains to be determined.
Funding
This study was supported by grants from the "Programme Hospitalier de Recherche Clinique" (French Department of Health) and the “Fondation de France”. The study sponsor was the University Hospital of Brest. The study sponsor, had no role in the design or conduct of the trial, data analysis, or preparation of the manuscript.
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