Prolonged Anticoagulation During Eighteen Months vs. Placebo After Initial Six-Month Treatment for a First Episode of Idiopathic Pulmonary Embolism - PADIS-PE

Jul 07, 2015
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
French Department of Health
Date Published:
07/07/2015
Original Posted Date:
07/07/2015
References

Description:

The goal of this trial was to assess safety and efficacy of extended duration of anticoagulation—an additional 18 months beyond the planned initial 6-month duration—in patients with a first episode of idiopathic pulmonary embolism (PE).

Contribution to the Literature: The PADIS-PE trial shows that extended duration of anticoagulation is beneficial in patients with a first episode of idiopathic PE.

Study Design

Patients with a first episode of idiopathic PE and who had successfully completed 6 months of anticoagulation were randomized in a 1:1 fashion to receive warfarin for another 18 months (n = 184) or placebo (n = 187).

  • Total number of enrollees: 374
  • Duration of follow-up: 42 months
  • Mean patient age: 58 years
  • Percentage female: 51%
  • Previous cancer: 4%
  • Previous distal deep vein thrombosis (DVT) or superficial vein thrombosis: 8%
  • Associated DVT at the time of PE diagnosis: 31%
  • Low bleeding risk: 24%, moderate: 32%, high: 44%

Inclusion criteria:

  • Age 18 years or older
  • First episode of symptomatic unprovoked PE
  • Treatment for 6 months with vitamin K antagonist (VKA) with target international normalized ratio (INR) 2-3

Exclusion criteria:

  • Previous confirmed PE/ DVT
  • Recurrent venous thromboembolism (VTE)
  • Bleeding during initial 6-month anticoagulation
  • Known major thrombophilia, higher bleeding risk, platelet count <100,000/µL, major surgery planned within 18 months
  • Life expectancy <18 months
  • Indication for VKA therapy for reasons other than VTE

Principal Findings:

Primary efficacy endpoint:

  • Symptomatic recurrent VTE and nonfatal + fatal major bleeding at 18 months: 3.3% vs. 13.5%, p = 0.001
  • Recurrent VTE: 1.7% vs. 13.5%, p < 0.001
  • Major bleeding: 2.2% vs. 0.5%, p = 0.22
  • At 41 months: 20.8% vs. 24.0%, p = 0.22
  • Recurrent VTE: 17.9% vs. 22.1%, p = 0.14
  • Major bleeding: 3.5% vs. 3.0%, p = 0.85

Other endpoints:

  • Fatal PE at 18 months: 0 vs. 0
  • Symptomatic proximal DVT at 18 months: 0.5% vs. 2.1%

Interpretation:

The results of this trial indicate that prolonged anticoagulation up to 24 months is superior in reducing recurrent PE compared with routine anticoagulation for 6 months in patients with a first episode of unprovoked PE. This strategy, however, is associated with a higher risk of bleeding. This effect is lost once anticoagulation is stopped; on longer-term follow-up up to nearly 3.5 years, the beneficial effect of anticoagulation was no longer observed.

These are very important findings, and suggest that prolonged duration of anticoagulation should be preferred over the standard 6 months of treatment in patients with unprovoked PE. This benefit has been reported in all-comers with VTE before, but this trial focuses on patients with PE primarily. Although this trial studied 18 months of treatment, the optimal duration is unclear. Most of the recurrent PEs were unprovoked as well, raising the possibility that an indefinite or “as long as possible” strategy may be prudent in these patients. Although this trial studied warfarin exclusively, it is likely that the novel oral anticoagulants will provide a similar efficacy result, and perhaps lower long-term bleeding.

References:

Couturaud F, Sanchez O, Pernod G, et al., on behalf of the PADIS-PE Investigators. Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial. JAMA 2015;314:31-40.

Keywords: Anticoagulants, Hemorrhage, International Normalized Ratio, Pulmonary Embolism, Thrombophilia, Venous Thromboembolism, Venous Thrombosis, Vitamin K, Warfarin


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