Clinical Decision Rule Validation Study to Predict Low Recurrent Risk in Patients With Unprovoked Venous Thromboembolism (REVERSEII)

REVERSEII: Validation of the "Men and HERDOO2"- A Clinical Decision Rule to Identify Patients With "Unprovoked" Venous Thromboembolism Who Can Discontinue Anticoagulants After 6 Months of Treatment.

The main objective of this study is to verify whether a new clinical decision rule identifying patients diagnosed with unprovoked blood clots who have a low risk of recurrence can safely stop oral anticoagulant therapy after 5-7 months of treatment.

Study Overview

• Status: Completed
• Conditions: Idiopathic Venous Thromboembolism
• Intervention / Treatment: Other: Application of the"Men continue and HER DOO2" rule

Detailed Description

Up to 50% of patients with a first episode of venous thromboembolism (VTE) have no identifiable cause (i.e. are unprovoked VTEs). The risk of recurrent VTE in this large group of patients with unprovoked VTE after 3-6 months of anticoagulant therapy is 5-10.8% in the year following discontinuation of oral anticoagulant therapy. One in six to one in twenty recurrences of a new VTE are fatal. Given the intermediate risks of recurrence in unselected unprovoked VTE patients, clinicians do not have clear guidance on whether to continue or discontinue anticoagulants in patients with unprovoked VTE. Recently attention has turned to the concept of risk stratification to identify subgroups of patients with unprovoked VTE who could safely discontinue oral anticoagulation therapy (OAT).

In the REVERSE I study, a clinical decision rule derivation study conducted from 2001 to 2006, we developed and internally validated the clinical decision rule "Men continue and HER DOO2" that identifies patients with a first unprovoked VTE who likely have a low risk of recurrent VTE and could safely discontinue OAT subsequent to 5-7 months of OAT. The present study will evaluate if the "Men continue and HER DOO2" rule (comprised of gender, elevated D-dimer levels, post-thrombotic signs, obesity, and older age) is safe, clinically useful, and reproducible when prospectively implemented in multiple centers and a variety of settings. If this clinical decision rule is validated, it will provide physicians with important information to allow them to more confidently identify unprovoked VTE patients at low risk of VTE recurrence who may not need to continue OAT.

• Study Type: Interventional
• Enrollment (Actual): 2779
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia
      • Prince of Wales Hospital
• Belgium
  • Brussels, Belgium
    • CUB Hôpital Erasme
• Canada
  • Quebec, Canada
    • Hopital Enfant Jesus
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H2Y9
      • CDHA-Queen Elizabeth II Health Science Centre
  • Ontario
    • Hamilton, Ontario, Canada
      • Hamilton Health Sciences Center
    • Hamilton, Ontario, Canada
      • Hamilton Health Sciences Corporation
    • London, Ontario, Canada, N6A 4G5
      • Victoria Hospital
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Health Research Institute
    • Toronto, Ontario, Canada
      • University Health Network
  • Quebec
    • Montreal, Quebec, Canada
      • McGill University Health Centre
    • Montreal, Quebec, Canada, H3T 1E2
      • SMBD Jewish General Hospital
    • Montreal, Quebec, Canada
      • Hopital Sacre Coeur
    • Montreal, Quebec, Canada
      • St. Mary's Hospital - CHUM
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Saskatchewan Drug Research Institute
• France
  • Brest, France
    • Centre hospitalier régional universitaire de Brest
• India
  • Nirmaya, India
    • Orange Lifesciences
  • Pune, India
    • Sahyadri Speciality Hospital
  • Shefali, India
    • Shefali Centre
  • Surat, India
    • Jashvant Patel Clinic
• Switzerland
  • Geneva, Switzerland
    • Hopitaux Universitaires de Geneve
• United States
  • California
    • Santa Monica, California, United States
      • UC Davis
  • Maine
    • Rockport, Maine, United States
      • Penobscot Bay Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University

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:

• First episode of major unprovoked VTE
• VTE objectively proven
• VTE treated for 5-12 months with anticoagulant therapy authorized for the REVERSE II study (initial or ongoing therapy)
• Absence of recurrent VTE during the treatment period

Exclusion Criteria:

• Less than 18 years of age
• Patients who have already discontinued anticoagulant therapy
• Patients requiring ongoing anticoagulation for reasons other than VTE
• Being treated for a recurrent unprovoked VTE
• Patients with high risk thrombophilia
• patients who plan on using exogenous estrogen(OCP,HRT)if anticoagulant therapy is discontinued
• Patients with pregnancy associated VTE
• Geographically inaccessible for follow-up
• Patients unable or unwilling to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1 Discontinue OAT or AAA; Patients classified as being at low risk of recurrent VTE by the "HER DOO2"rule. If the clinical decision rule indicates that a patient is at low recurrence risk (<3% per year); anticoagulant therapy will be withdrawn and the participant will then be followed for 1 year for any VTE recurrence and/or bleeding.	Other: Application of the"Men continue and HER DOO2" rule; Consecutive patients will have the"Men continue and HER DOO2" rule applied by the attending physician between 5 - 12 months after treatment for a first unprovoked objectively proven major VTE. "Men continue and HER DOO2" rule: all men continue oral anticoagulants and women with 2 or more of the following features after 5-7 months of OAT should continue oral anticoagulants:1) HER - any Hyperpigmentation, Edema and Redness of either lower extremity, 2) Vidas D-dimer ≥250ug/L, 3) Obesity - BMI ≥30 kg/m2 and 4) Older age - Age ≥65 years.; Other Names: Clinical Decision Rule
No Intervention: 2 Observation arm; Men and patients classified as being at high risk of recurrent VTE by the "HER DOO2"rule. If the clinical decision rule indicates that a patient is at high recurrence risk then the decision to continue or discontinue anticoagulant therapy will be left to the discretion of physicians and patients as per current standard of care and this decision recorded. High risk patients (females classified as being at high risk of recurrent VTE by the CDR, and all males) will then be followed as an observational cohort for 1 year for any VTE recurrence and/or bleeding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary study outcome is the incidence of adjudicated recurrent major VTE at 1 year in patients deemed by the "Men and HER DOO2" CDR to be at low risk of recurrent VTE.	One year

Secondary Outcome Measures

Outcome Measure	Time Frame
Any VTE 1 year event rate in low risk patients	One year
Major bleeding 1 year event rate in un-anticoagulated low risk patients	One year
Major VTE 1 year event rate in high risk patients who continue anticoagulant therapy	One year
Major VTE 1 year event rate in high risk patients who discontinue anticoagulant therapy	One year
Major Bleeding 1 year event rate in high risk patients	One year
Clinical utility of the rule	One year
Inter-observer reliability of the clinical decision rule	One year

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: BioMérieux; Centre Hospitalier Régional et Universitaire de Brest
• Investigators: Study Chair: Marc Rodger, MD, MSc, Ottawa Hospital Research Institute

Publications and helpful links

General Publications

• Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008 Aug 26;179(5):417-26. doi: 10.1503/cmaj.080493.
• Rodger MA, Le Gal G, Anderson DR, Schmidt J, Pernod G, Kahn SR, Righini M, Mismetti P, Kearon C, Meyer G, Elias A, Ramsay T, Ortel TL, Huisman MV, Kovacs MJ; REVERSE II Study Investigators. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ. 2017 Mar 17;356:j1065. doi: 10.1136/bmj.j1065.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: August 26, 2009
• First Submitted That Met QC Criteria: August 26, 2009
• First Posted (Estimate): August 27, 2009

Study Record Updates

• Last Update Posted (Estimate): September 1, 2016
• Last Update Submitted That Met QC Criteria: August 31, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Recurrence; Risk stratification; Anticoagulants; Clinical decision rule; Unprovoked Venous thromboembolism; Prognostic
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism
• Other Study ID Numbers: 2008039-01H