Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial

Ashley Choi, Mercer University College of Pharmacy

According to the 2014 the European Society of Cardiology (ESC) guidelines, venous thromboembolism (VTE), which encompasses the deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most frequent cardiovascular disease.  The guidelines suggest at least three months of anticoagulation in patients with acute PE with the effect of both early death and recurrent symptomatic or fatal VTE prevention.  An extended duration of anticoagulation therapy beyond the first three months, or even indefinitely, for secondary prevention is recommended in some cases after weighing the individual’s risk of recurrence vs. bleeding risk.1

The American College of Chest Physicians (CHEST) guidelines focusing on antithrombotic therapy for venous thromboembolism (VTE) disease recommend a long-term anticoagulant therapy over stopping the therapy after about one week of initial therapy in patients with acute VTE.  The guidelines suggest three months of anticoagulant therapy over (1) treatment of shorter period, (2) treatment of a longer time-limited period, or (3) treatment with an extended duration of therapy in patients with a proximal DVT of the leg provoked by a risk factor. However, in some cases, such as in patients with an unprovoked DVT of the leg, the CHEST guidelines suggest an evaluation of the risk-benefit ratio of an extended therapy. Once an extended anticoagulant therapy is initiated, patients are strongly encouraged to be reassessed at a periodic interval.2

Title: Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial3
Design A multicenter, randomized, double-blind trial; N = 374
Objective To determine the benefits and harms of an additional 18-month treatment with warfarin vs placebo, after an initial six month nonrandomized treatment period on a vitamin K antagonist
Study Groups ·    Subjects received warfarin 2 mg or 5 mg (n = 184)

·    Subjects received placebo (n = 187)

Methods Participants who had experienced a first episode of symptomatic unprovoked PE and had been treated initially for six uninterrupted months with a vitamin K antagonist were randomized to receive either warfarin or placebo for 18 months. All patients underwent baseline screening and examination at day 0.  They were then followed up for a median of 24 months after without anticoagulant therapy after the end of the treatment period.  All analyses were performed using the intention-to-treat population.
Duration Between July 2007 and September 2014
Primary Outcome Measure The composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization
Baseline Characteristics Categories Warfarin Placebo
Age, mean (standard deviation – SD), year 58.7 (17.9) 57.3 (17.4)
Women, No. (%) 106 (57.6) 84 (44.9)
Body mass index, mean (SD), kg/m2 27.8 (5.9) 27.1 (5.1)
Results During the 18-month study No. (%) of patients with events Hazard ratio p-value
Warfarin Placebo
Primary composite outcome 6 (3.3) 25 (13.5) 0.22 0.001
Recurrent venous thromboembolism 3 (1.7) 25 (13.5) 0.15 <0.001
Major bleeding 4 (2.2) 1 (0.5) 3.96 0.22
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: 0.54% from warfarin group
Study Author Conclusions Among patients with a first episode of unprovoked pulmonary embolism who received six months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy.

This study found a reduction in the risk of recurrent venous thromboembolism and the risk of bleeding increasing to a minimal extent in favor of additional warfarin therapy during 18 months. However, this benefit was lost after discontinuation of anticoagulation.  About 80% of recurrences included another episode of symptomatic pulmonary embolism, of which 8% (4 of 52 episodes) were fatal. Furthermore, more than 80% of recurrences were unprovoked, and represented the more severe form of venous thromboembolism in both study groups. Because the risk of major bleeding was low and similar in both groups in this study, the benefit of extended anticoagulation on the composite outcome was lost.

References

  1. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69, 3069a-3069k.
  2. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e419S-94S.
  3. Couturaud F, Sanchez O, Pernod G, et al. Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial. JAMA. 2015;314(1):31-40.
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