PADIS-PE

Published

Couturaud F, 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.
PubMed • Full text • PDF

Clinical Question

In patients who have completed 6 months of warfarin for first unprovoked PE, does an additional 18 months of warfarin therapy versus placebo reduce the risk of recurrent VTE?

Bottom Line

In patients who have completed at least 6 months of warfarin for first unprovoked PE, an additional 18 months of warfarin reduced the composite risk of recurrent VTE and major bleeding, but the benefits were not maintained after discontinuation of anticoagulation.

Major Points

The optimal duration of anticoagulation after unprovoked venous thromboembolism (VTE) has been studied in a number of trials. Published in 2015, the PADIS-PE study evaluated outcomes in patients with first unprovoked PE. Patients who had completed at least 6 months of warfarin (or similar vitamin K antagonist) were randomized to an extended 18 months of warfarin (about 24 months total) or to placebo. The primary endpoint was the composite risk of recurrent VTE or major bleeding during the 18-month study period. Secondary endpoints included rates of the composite outcome after a further 24 months of follow-up. During the 18-month study period, the primary composite outcome favored the extended warfarin group (3.3% vs. 13.5%; HR 0.22), which was driven by a reduction in recurrent VTE. However, the benefit was not maintained after a further 24 months following discontinuation of extended anticoagulation.

These outcomes indicate that extended anticoagulation reduces VTE recurrence among patients with first unprovoked PE, with a modest risk of major bleeding. However, the recurrence risk returns to unacceptably high levels after discontinuation of even extended anticoagulation. This forms the basic argument for indefinite anticoagulation in patients with unprovoked VTE, as has been supported by various guideline-issuing bodies.

Guidelines

ESC Guidelines for Treatment of Acute PE (2019, adapted)

• Recommend minimum 3 months of anticoagulation
• Indefinite anticoagulation reduces the risk of recurrent VTE by about 90%
• Risk of recurrent VTE after discontinuation of anticoagulant therapy is similar after 3 months

Design

• Multicenter, randomized, double-blind study
• N= 371 patients with first unprovoked PE who completed 6 months of warfarin
  • Extended warfarin (n=184)
  • Placebo (n=187)
• Setting: Ambulatory patients who had been enrolled in 1 of 14 French hospitals.
• Enrollment: 2007-2012
• Mean follow up: 24 months
• Primary Outcomes
  • Composite of symptomatic recurrent VTE plus major bleeding

Inclusion Criteria

• 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

Exclusion Criteria

• 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 (eg, active gastric ulcer, recent hemorrhagic stroke) and other contraindications to VKA
• Platelets <100K/L
• Life expectancy of less than 18 months

Baseline Characteristics

Comparison between Warfarin and Placebo groups (except for female sex (P=0.02), no other values were clinically significant)

• Mean age (y): 58.7 (17.9%) vs. 57.3 (7.4%)
• Age >65 y: 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)
  • Acenocoumarol, 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. (%)
  • 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)

Intervention

• 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.

Outcomes

Comparisons are Warfarin vs. placebo therapy

Primary Outcomes

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)

Secondary Outcomes

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)

Adverse Events

There were no adverse events listed other than those from the primary and secondary outcomes.

Criticisms

• 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.

Funding

• 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.