In patients with previous vitamin K antagonist therapy after their first episode of unprovoked pulmonary embolism, does an additional 18 months of warfarin therapy versus placebo reduce the risk of recurrent venous thromboembolism?
In patients using at least 6 months of vitamin K antagonist therapy following their first case of unprovoked pulmonary embolism, an additional 18 months of warfarin reduced the incidence of recurrent venous thromboembolism and major bleeding. However, effects were not sustained after discontinuation of therapy.
This randomized, double-blind study associated warfarin versus placebo with reduced rates of composite symptomatic and recurrent VTE within the 18 month treatment period. However, rates of recurrent VTE, major bleeds and deaths from other causes did not differ between the warfarin and placebo groups in the 42 month study. The benefits of anticoagulation therapy with warfarin were not sustained after discontinuation of therapy. The high absolute risk of recurrent VTE in the placebo group was greatest during the 18 month treatment period, with a hazard ratio of 0.15 for the risk of such events in the warfarin treatment group.
- ESC guidelines for the treatment of acute pulmonary embolism recommends that patients receive anticoagulant therapy for a minimum of 3 months, although indefinite treatment reduces the risk of recurrent venous thromboembolism by about 90% 2. The risk of recurrent VTE after discontinuation of anticoagulant therapy is expected to be similar to that after 3 months.
- Multicenter, randomized, double-blind study
- N= 371
- Warfarin treated (n= 184)
- Placebo (n = 187)
- Setting: All participants were ambulatory patients who had been enrolled in 1 of 14 French hospitals.
- Enrollment: July 13, 2007 to March 15, 2012.
- Mean follow up: 24 months
- Primary Outcomes
- Composite of symptomatic recurrent VTE
- Nonfatal and fatal major bleeds
- First episode of symptomatic idiopathic pulmonary embolism initially treated for 6 uninterrupted months with a vitamin K antagonist
- Target INR range 2.0-3.0.
- Age < 18 years,
- Allergy to warfarin
- Refusal or incapacity to give a written informed consent to participate to the study
- Isolated proximal or distal DVT
- PE provoked by a major reversible risk factor
- Occurrence of a documented recurrent VTE while on VKA in the therapeutic range or an anticoagulant-related bleeding during the first 6 months of anticoagulation
- Presence of known major thrombophilia (protein C, S or antithrombin deficiency, antiphospholipid antibodies, homozygous factor V Leiden),
- Previous documented PE or proximal DVT
- Indication of VKA treatment for another reason than VTE (atrial fibrillation, mechanic valves…)
- Patients in whom antiplatelet agents were stopped at the initial phase of PE treatment and for whom antiplatelet agents should be restarted after stopping VKA
- Present pregnancy or expected pregnancy in the 18 months of the study treatment
- Childbearing without proper contraceptive measures
- Major surgery planned the 18 months of the study treatment
- Active cancer or cancer resolved for less than two years
- High risk of bleeding (e.g.; active gastric ulcer, recent hemorrhagic cerebral
attack) and other contraindications to VKA
- Platelets < 100 x 109/L
- Life expectancy of less than 18 months
Comparison between Warfarin and Placebo groups (except for female sex (P=0.02), no other values were clinically significant)
- Mean age: 58.7 (17.9%) vs. 57.3 (7.4%)
- > 65 yrs: 74 (40.2%) vs. 70 (37.4%)
- Women: 106 (57.6%) vs. 84 (44.9%)
- Mean Body Mass Index: 27.8 (5.9%) vs. 27.1 (5.1%)
- BMI ≥ 30: 53 (28.8%) vs. 39 (20.9%)
- Creatinine clearance < 30: 0 vs. 0
- Creatinine clearance ≥30-50: 16 (8.9%) vs. 7 (3.9%)
- Creatinine clearance ≥50: 164 (91.1%) vs. 173 (96.1%)
- Medical conditions, No. (%)
- Previous cancer: 8 (4.3) vs. 6 (3.2)
- Previous distal deep-vein thrombosis or superficial-vein thrombosis: 17 (9.2) vs. 14 (7.5)
- Chronic heart failure: 4 (2.2) vs. 9 (4.8)
- Chronic respiratory failure: 40 (21.7) vs. 35 (18.7)
- Method used to diagnose the incident pulmonary embolism, No. (%)
- High-probability ventilation/perfusion lung scanning: 47 (25.5) vs. 39 (20.9)
- Spiral computed tomography angiography: 137 (74.5) vs. 148 (79.1)
- Associated proximal deep-vein thrombosis at diagnosis, No, (%): 56 (31.1) vs.56 (31.6)
- Characteristics of pulmonary embolism at inclusion
- Residual perfusion defect ≥10% on lung scan, No. (%): 68 (37.6) vs. 56 (30.8)
- Residual deep-vein thrombosis, No. (%): 25 (13.7) vs. 36 (19.7)
- Systolic pulmonary arterial pressure, mean (SD), mm Hg: 30.6 (8.2) vs. 29.9 (8.2)
- D-dimer level, mean (SD), ng/mLd: 382.3 (555.9) vs. 322 (336.4)
- Thrombophilia, No. (%)e
- Minor: 46 (26.0) vs. 35 (20.1)
- Major: 6 (3.4) vs. 8 (4.6)
- Treatment of pulmonary embolism prior to randomization
- Warfarin, No. (%): 135 (73.4) vs. 115 (61.5)
- Fluindione, No. (%): 49 (26.6) vs. 74 (39.6)
- Acecoumarol, No. (%): 2 (1.1) vs. 4 (2.1)
- Duration of initial anticoagulation, mean (SD), mo: 6.3 (0.5) vs. 6.4 (0.5)
- Percentage of time in therapeutic INR range, mean (SD): 69.1 (23.3) vs. 67.8 (22.7)
- Use of compression stockings, No. (%): 113 (61.7) vs. 120 (64.2)
- Main concomitant treatments, No. (%)
- Antiplatelet agent: 16 (8.7) vs. 11 (5.9)
- Statins: 35 (19.0) 34 vs. (18.2)
- ACCP bleeding risk at inclusion, No. (%)f
- Low (no risk factor): 39 (22.5) vs. 45 (26.2)
- Moderate (1 risk factor): 55 (31.8) vs. 57 (33.1)
- High (≥2 risk factor): 79 (45.7) vs. 70 (40.7)
- Patients were randomized using a central computerized internet-based system to either warfarin therapy (target INR 2.0-3.0) or placebo (sham INR 2.0-3.0).
- Patients in the placebo group had computer generated sham INR results created according to predefined scenarios.
- Written consent was obtained after all laboratory testing, after which anticoagulant dose was established and patients were randomized.
- Patients provided with either 2mg or 5mg warfarin tablets or identical placebo tablets, INR was monitored at least monthly and after each dose change.
- Patients were followed for a median of 24 months without anticoagulation therapy, with scheduled face-to-face visits at 3, 6, 12, 18, 30 and 42 months. Telephone calls were made at 24 and 36 months.
Comparisons are Warfarin vs. placebo therapy
- Symptomatic recurrent venous thromboembolism or nonfatal or fatal major bleeding during the 18 month treatment period and the entire study period
- 18 months: 6 (3.3%) vs. 25 (13.5%) (HR 0.22; 95% CI 0.09-0.55; P= 0.001 NNT: 3)
- Recurrent venous thromboembolism: 3 (1.7%) vs. 25 (13.5%) (HR 0.15; 95% CI 0.05-0.43; P= <0.001 NNT: 3)
- Major Bleeding: 4 (2.2%) vs. 1 (0.5%) (HR 3.96; 95% CI 0.19-9.35; P= 0.22)
- Entire study period (median 41 months): 33 (20.8%) vs. 42 (24.0%) (HR 0.75; 95% CI 0.47-1.18; P= 0.22)
- Recurrent venous thromboembolism: 28 (17.9%) vs. 39 (22.1%) (HR 0.69; 95% CI 0.42-1.12; P= 0.14)
- Major Bleeding: 6 (3.5%) vs. 5 (3.0%) (HR 1.12; 95% CI 0.34-3.71; P= 0.85)
The secondary outcomes were death unrelated to pulmonary embolism or major bleeding during the 18 month treatment period and 42 month study period.
During the 18 month study:
- Death from causes other than VTE or major bleeding
- 18 months: 2 (1.1%) vs. 2 (1.1%) (HR 1.32; 95% CI 0.19-9.35; P= 0.78)
- Entire study period: 8 (9.1%) vs. 6 (3.6%) (HR 1.51; 95% CI 0.52-4.38; P= 0.45)
There were no adverse events listed other than those from the primary and secondary outcomes.
- Primary outcome included composite recurrent VTE and major bleeding, two different outcomes that may not be clinically equivalent.
- D-dimer levels were not used to guide therapy, however use of this marker was not recommended in the study and is considered investigational.
- Evaluated the efficacy of warfarin, however other newer oral anticoagulants and aspirin were not included in the study.
- The study was supported by grants from the Programme Hospitalier de Recherche Clinique (French Department of Health) and the sponsor was the University Hospital of Brest.
1. 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. doi:10.1001/jama.2015.7046.
2. Konstantinides SV, Torbicki A, Agnelli G, et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3069,3069a-3069k.