Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism ‘ The PADIS-PE Trial’ Nate Peyton

Study information Randomized, double blind clinical trial Multicenter -- Completed in 14 French centers Between July 2007 and Sept 2014 Published in JAMA 2015

Objective To determine the benefits and harms of an additional 18-month treatment with warfarin vs placebo, after an initial 6 month nonrandomized treatment period on a vitamin K antagonist

Study Participants Age 18 or older, who experienced a first episode of symptomatic unprovoked PE and had been treated initially for 6 uninterrupted months with a vitamin K antagonist (INR 2-3)

Study Participants Unprovoked PE defined as objectively confirmed symptomatic PE occurring in the absence of any major reversible risk factor for VTE within 3 months before diagnosis, including: – surgery with local, regional or general anesthesia lasting > 30 minutes – trauma with or without plaster cast of lower limbs, – absence of bed rest for more than 72 hours, – absence of active cancer or cancer resolved within the 2 years prior to diagnosis Objective tests confirming PE – v/q lung scanning, spiral CT angiography

Study Participants Main Exclusion Criteria: – Previously confirmed PE or proximal DVT – Recurrent VTE – Bleeding during initial 6 month anticoagulation – Known major thrombophilia – Indication for vit K antagonist therapy for reasons other than VTE – Increased bleeding risk – Platelet count less than 100 – Major surgery planned within 18 months from randomization – Life expectancy less than 18 months

Study design Unprovoked PE  6 months RX c Vit K antagonist Randomization  warfarin vs placebo x 18mo 24 mo follow up period 42 months total

Study design Vit K antagonist continued for treatment group, discontinued in placebo group INR monitoring at least monthly; placebo group received sham INR – Goal INR 2-3 Face to face visit at 3, 6, 12, 18, 30 and 42 mo

Primary Outcome Composite of: – Recurrent venous thromboembolism – Nonfatal or fatal major bleeding

Results During 18 month treatment – Primary outcome occurred in 6 of 184 (3.3%) in warfarin group – Occurred in 25 of 187 (13.5%) in the placebo group – Significant difference

Results: treatment period Warfarin group (n=184 pts) – 3 pts (1.7%) had symptomatic recurrent VTE (manifested after warfarin discontinued) – Major bleeding occurred in 4 patients (1 epistaxis, 1 retroperitoneal, 1 upper GI bleed, 1 intraocular bleed 1mo after stopping warfarin)

Results: treatment period Placebo group (n=187) – 25 (13.5%) recurrent VTE 21 symptomatic nonfatal PE 4 symptomatic proximal DVT – 1 bleed, which presented after patient discontinued from placebo and started on warfarin

Results: after treatment period 24 month follow up period – Composite outcome in 27 warfarin treated patients (17.7%) 25 symptomatic VTE, all in absence of anticoag; 4 fatal – Composite outcome in 17 placebo treated patients (10.3%) 14 symptomatic VTE, all in absence of anticoag; nonfatal

Results: overall study period Composite outcome noted in 75 patients – 33 patients (20.8%) treated with warfarin – 42 patients (24%) treated with placebo – No significant difference (0.75, CI , p.22)

Takeaways Higher rate of recurrent VTE in placebo group Low risk of major bleeding in both groups Recurrent VTE increased in warfarin group during post-treatment period Again, no difference in intervention and placebo arm at study conclusion

Limitations Primary outcome included 2 different outcome measures that may not be clinically equivalent The study required 7 yrs to compete, probably reflecting its design and patient reluctance to participate in a 42 month follow up The characteristics of patients who declined to participate were unavailable (selection bias?) Did not include newer oral anticoagulants Small (n) for outcome of interest

Future studies Longer, or possible lifelong treatment duration for patients with first unprovoked PE may be necessary. Newer oral anticoagulants should be tested in a similar randomized control trial in longer durations for comparison.

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