Optimal Duration of Anticoagulation in Deep Venous Thrombosis (MORGAGNI)

Identification of the Optimal Duration of Anticoagulation in Patients With Deep Venous Thrombosis of the Lower Extremities With the Use of Residual Vein Thrombosis in Combination With D-Dimer

Prospective cohort study aimed at optimizing the duration of anticoagulant treatment in patients at their first episode of proximal deep venous thrombosis (DVT) of the lower extremities, whose pathogenesis is either unknown (idiopathic DVT) or associated with minimal risk factors for thrombosis, with the help of an algorithm which incorporates both ultrasonography and D-dimer information. All patients will be followed-up until 1) the achievement of a major end-point; 2) the date of lost to to followup; 3) the date of death; 4) the date of study stop. The purpose of this study is to demonstrate the safety of withholding anticoagulation from a subgroup of patients with proximal DVT whose veins have recanalized and present with a repeatedly negative D-dimer (at baseline, after 1 and 3 months). The approach will be deemed to be safe if the annual rate of recurrent VTE in patients who will have their anticoagulation discontinued is lower than 5%.

Study Overview

• Status: Completed
• Conditions: Deep Vein Thrombosis of Lower Limb; Lower Extremity Deep Venous Thrombosis Recurrent
• Intervention / Treatment: Drug: Sodium warfarin

Detailed Description

After giving informed consent, patients will receive an ultrasound investigation of the proximal-vein system (common femoral vein at groin, popliteal vein up to its trifurcation):

• Patients with residual thrombosis (defined as a diameter of at least 4 mm in at least one spot) will have their anticoagulation continued. A repeat ultrasound is scheduled after 6, 12, 18, 24 and 36 months. In patients with persistently residual thrombosis anticoagulation will not be discontinued, while those whose veins have recanalized will have a decision making process based on the behaviour of D-dimer (see below).
• Patients whose veins have recanalized (either at the recruitment or later on) will receive the D-dimer determination before discontinuing anticoagulation. In those with negative D-dimer anticoagulation will be discontinued. These patients will have two further determinations of D-dimer (after 1 and 3 months, respectively). While patients with persistently negative D-dimer will no longer receive anticoagulation, those in whom D-dimer becomes positive will have their anticoagulation resumed and no longer discontinued.
• All patients will be followed up to completion of 4 years since recruitment. For the purpose of this study each quantitative D-dimer is allowed. The criterion for D-dimer interpretation will rely on the cut-off that is recommended by manufacturers for diagnostic purposes.

D-dimer.For the purpose of this study each quantitative D-dimer is allowed. The criterion for D-dimer interpretation will rely on the cut-off that is recommended by manufacturers for diagnostic purposes.

Sample size 1000 years of observation without anticoagulation are required to demonstrate (power 90%, type I error 0.05, two sided) that with this approach the annual rate of recurrent VTE is lower than 5%. Approximately 600 patients with proximal DVT satisfying the eligibility criteria are required to obtain 1000 years of observation without anticoagulation.

• Study Type: Interventional
• Enrollment (Actual): 584
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Padua, Italy, 35028
    • Paolo Prandoni

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with proximal DVT that is idiopathic or secondary to minor factors for thrombosis, with or without contemporary manifestations of PE, who have completed an uneventful 3 to 24-month period of anticoagulation and are available for an overall 48-month follow-up at the study centre.

Exclusion Criteria:

• previous thromboembolism
• recent (less than 3 months) major trauma or surgery
• active cancer
• immobilization resulting from chronic irreversible medical diseases
• need for indefinite anticoagulation for medical reasons other than VTE
• impossibility to attend the follow-up visits or to have D-dimer determinations
• already known major thrombophilia: carriage of deficiencies of natural anticoagulants, lupus-like anticoagulants, homozygosis for factor V Leiden or prothrombin mutation, heterozygosis for both abnormalities
• short (less than 1 year) life expectancy
• pregnancy
• age younger than 18
• refusal of informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Proximal DVT; Patients whose veins have recanalized (either at the recruitment or later on during the follow-up) will receive the D-dimer determination before discontinuing sodium warfarin. Veins are defined as recanalized when the vein diameter under maximum compressibility is lower than 4 mm both at the common femoral and at the popliteal vein. In those with negative D-dimer sodium warfarin will be discontinued. These patients will have two further determinations of D-dimer (after 1 and 3 months, respectively). While patients with persistently negative D-dimer will no longer receive sodium warfarin, those in whom D-dimer is positive or reverts to positive values in the following determinations will have their sodium warfarin resumed and no longer discontinued.

Drug: Sodium warfarin; Patients with early vein recanalization, as shown by ultrasonography, and repeatedly negative D-dimer will have anticoagulation discontinued. They will be followed-up for up to 4 years after recruitment in order to assess the rate of recurrent symptomatic VTE. In all other patients anticoagulation will not be discontinued.; Other Names: Vitamin K antagonists; Oral anticoagulants

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrent venous thromboembolism (VTE)	To assess the rate of recurrent symptomatic VTE (expressed as rate/1000 patients-yeas) occurring after discontinuation of oral anticoagulant therapy up to the study conclusion.	Up to the study conclusion (see the study protocol)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Development of major bleeding complications	To assess the rate of major or clinically relevant bleeding complications (expressed as rate/1000 patients-years) occurring during oral anticoagilant therapy up to the study conclusion	Up to the study conclusion (see the study protocol)

Collaborators and Investigators

• Sponsor: University of Padova
• Investigators: Principal Investigator: Paolo Prandoni, Department of Cardiothoracic and Vascular Sciences, University of Padua

Publications and helpful links

General Publications

• Prandoni P, Vedovetto V, Ciammaichella M, Bucherini E, Corradini S, Enea I, Cosmi B, Mumoli N, Visona A, Barillari G, Bova C, Quintavalla R, Zanatta N, Pedrini S, Villalta S, Camporese G, Testa S, Parisi R, Becattini C, Cuppini S, Pengo V, Palareti G; Morgagni Investigators. Residual vein thrombosis and serial D-dimer for the long-term management of patients with deep venous thrombosis. Thromb Res. 2017 Jun;154:35-41. doi: 10.1016/j.thromres.2017.04.002. Epub 2017 Apr 4.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: April 30, 2010
• First Submitted That Met QC Criteria: January 26, 2011
• First Posted (ESTIMATE): January 28, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): July 19, 2016
• Last Update Submitted That Met QC Criteria: July 17, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Bleeding; Pulmonary embolism; Ultrasonography; D-dimer; Deep venous thrombosis; Venous thromboembolism
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Venous Thrombosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Micronutrients; Vitamins; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Warfarin; Anticoagulants
• Other Study ID Numbers: 2001P