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JAMA. 2015 Jul 7;314(1):31-40. doi: 10.1001/jama.2015.7046.

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

Author information

1
Département de Médecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, and EA 3878, CIC INSERM 1412, Brest, France2Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose).
2
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)3Service de Pneumologie, Hôpital Européen Georges Pompidou, AP-HP; Université Paris Descartes, Sorbonne Paris Cité, and INSERM UMR S 970, Paris, France.
3
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)4Département de Médecine Vasculaire, Centre Hospitalo-Universitaire de Grenoble, Université de Grenoble 1, Grenoble, France.
4
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)5Service de Médecine et Thérapeutique, Unité de Pharmacologie Clinique, Centre Hospitalo-Universitaire de Saint-Etienne, and EA3065, Université Jean Monnet, Saint-Etienne, Fr.
5
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)6Service de Médecine Interne, Centre Hospitalo-Universitaire de Rennes, Université de Rennes 1, Rennes, France.
6
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)7Service de Médecine Interne, Centre Hospitalier Général de Saint-Brieuc, Saint-Brieuc, France.
7
Service de Cardiologie, Centre Hospitalier Général de Lannion, Lannion, France.
8
Clinique des Anticoagulants d'Ile de France (C.R.E.A.T.I.F.), Centre Hospitalo-Universitaire de Lariboisière, Paris, France.
9
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)10Unité de recherche clinique, Innovation et pharmacologie, Centre Hospitalo-Universitaire de Saint-Etienne, and EA3065, Université Jean Monnet, Saint-Etienne, France.
10
Service de Cardiologie and EA 4324, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest, France.
11
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)12Service de Pneumologie and INSERM 999, Centre Hospitalo-Universitaire de Kremlin Bicêtre, Kremlin Bicêtre, France.
12
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)13Service de Médecine Nucléaire and EA 3878, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest France.
13
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)14Service d'Echo-doppler Vasculaire, and EA 3878, CIC INSERM 1412, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest, France.
14
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)15Service de Radiologie, and EA 3878, CIC INSERM 1412, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest, France.
15
Pharmacie Centrale, Centre Hospitalo-Universitaire de Brest, Université de Bretagne Occidentale, Brest, France.
16
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)17Département Thoracique, Institut Mutualiste Montsouris; Paris, France.
17
Groupe d'Investigation et de Recherche Clinique sur la Thrombose (GIRC Thrombose)18Centre d'Investigation Clinique and UMR CNRS 5525, Centre Hospitalo-Universitaire de Grenoble, Université de Grenoble 1, Grenoble, France.

Abstract

IMPORTANCE:

The optimal duration of anticoagulation after a first episode of unprovoked pulmonary embolism is uncertain.

OBJECTIVES:

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.

DESIGN, SETTING, AND PARTICIPANTS:

Randomized, double-blind trial (treatment period, 18 months; median follow-up, 24 months); 371 adult patients who had experienced a first episode of symptomatic unprovoked pulmonary embolism (ie, with no major risk factor for thrombosis) and had been treated initially for 6 uninterrupted months with a vitamin K antagonist were randomized and followed up between July 2007 and September 2014 in 14 French centers.

INTERVENTIONS:

Warfarin or placebo for 18 months.

MAIN OUTCOMES AND MEASURES:

The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization. Secondary outcomes were the composite at 42 months (treatment period plus 24-month follow-up), as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months.

RESULTS:

After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group (hazard ratio [HR], 0.22; 95% CI, 0.09-0.55; P = .001). Recurrent venous thromboembolism occurred in 3 patients in the warfarin group and 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05-0.43); major bleeding occurred in 4 patients in the warfarin group and in 1 patient in the placebo group (HR, 3.96; 95% CI, 0.44 to 35.89). During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24.0%) in the placebo group (HR, 0.75; 95% CI, 0.47-1.18). Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups.

CONCLUSIONS AND RELEVANCE:

Among patients with a first episode of unprovoked pulmonary embolism who received 6 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.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT00740883.

PMID:
26151264
DOI:
10.1001/jama.2015.7046
[Indexed for MEDLINE]

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