Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management studyBMJ 2017; 356 doi: https://doi.org/10.1136/bmj.j1065 (Published 17 March 2017) Cite this as: BMJ 2017;356:j1065
- Marc A Rodger, professor of medicine and epidemiology1 2 3,
- Gregoire Le Gal, professor of medicine and epidemiology1 2 3 4,
- David R Anderson, professor of medicine5,
- Jeannot Schmidt, professor of medicine6,
- Gilles Pernod, professor of vascular medicine7,
- Susan R Kahn, professor of medicine8,
- Marc Righini, professor of vascular medicine9,
- Patrick Mismetti, professor of medicine10,
- Clive Kearon, professor of medicine11,
- Guy Meyer, professor of medicine12,
- Antoine Elias, vascular medicine physician13,
- Tim Ramsay, associate professor of epidemiology2 3,
- Thomas L Ortel, professor of medicine and pathology14,
- Menno V Huisman, professor of medicine15,
- Michael J Kovacs,, professor of medicine16
- for the REVERSE II Study Investigators
- 1Thrombosis Program, Division of Hematology, Ottawa Blood Disease Center, Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada
- 2Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- 3School of Epidemiology, Public Health and Preventative Medicine, University of Ottawa, Ottawa, ON, Canada
- 4EA 3878, INSERM CIC 1412, Université de Brest, Brest, France
- 5Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
- 6Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont, France
- 7Centre Hospitalier Universitaire de Grenoble, Grenoble, France
- 8Jewish General Hospital, McGill University, Montreal, QC, Canada
- 9Division of Angiology and Hemostasis, Geneva University Hospital, Geneva, Switzerland
- 10Centre Hospitalier Universitaire de Saint Etienne Bellevue, Saint Etienne, France
- 11Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada
- 12Respiratory Department, Hopital Europeen Georges-Pompidou, APHP, Université Paris Descartes Sorbonne, Paris Cité: INSERM UMRS 970, Paris, and INNOVTE, Saint-Etienne, France
- 13Centre Hospitalier Intercommunal de Toulon, Toulon, France
- 14Department of Medicine, Duke University Medical Center, Durham, NC, USA
- 15Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, Netherlands
- 16London Health Sciences Centre, Western University, London, ON, Canada
- Correspondence to: M A Rodger
- Accepted 15 February 2017
Objective To prospectively validate the HERDOO2 rule (Hyperpigmentation, Edema, or Redness in either leg; D-dimer level ≥250 μg/L; Obesity with body mass index ≥30; or Older age, ≥65 years), which states that women with none or one of the criteria can safely discontinue anticoagulants after short term treatment.
Design Prospective cohort management study.
Setting 44 secondary or tertiary care centres in seven countries.
Participants Of 3155 consecutive eligible participants with a first unprovoked venous thromboembolism (VTE, proximal leg deep vein thrombosis or pulmonary embolism) who completed 5-12 months of short term anticoagulant treatment, 370 declined to participate, leaving 2785 enrolled participants. 2.3% were lost to follow-up.
Interventions Women with none or one of the HERDOO2 criteria were classified as at low risk of recurrent VTE and discontinued anticoagulants (intervention arm), whereas anticoagulant management for high risk women (≥2 HERDOO2 criteria) and men was left to the discretion of the clinicians and patients (observation arm).
Main outcome measure Recurrent symptomatic VTE (independently and blindly adjudicated) over one year of follow-up.
Results Of 1213 women, 631 (51.3%) were classified as low risk and 591 discontinued oral anticoagulant treatment. In the primary analysis, 17 low risk women who discontinued anticoagulants developed recurrent VTE during 564 patient years of follow-up (3.0% per patient year, 95% confidence interval 1.8% to 4.8%). In 323 high risk women and men who discontinued anticoagulants, 25 had VTE during 309 patient years of follow-up (8.1%, 5.2% to 11.9%), whereas in 1802 high risk women and men who continued anticoagulants 28 had recurrent VTE during 1758 patient years of follow-up (1.6%, 1.1% to 2.3%).
Conclusions Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment.
Trial registration clinicaltrials.gov NCT00967304.
We thank the staff and patients from the thrombosis clinics who participated in the study; the central study team, including Tammy Beaudoin, Marisol Betancourt, Faizan Khan, Anne Marie Clement, Megan Inskip, and Isabelle Pichon; and Wim Houdijk, Alicia Rico-Lazarowski, and Franck Berthier from bioMerieux for support throughout study development and implementation. In France, participating centres are members of the INNOVTE Network; in Canada, participating centres are members of the CanVECTOR Network; and in Australia, participating members are members of the Australasian Society of Thrombosis and Hemostasis Clinical Trials Group. These national networks are members of INVENT-VTE, the International Network of Venous Thromboembolism Clinical Research Networks (www.invent-VTE.com). The results reported in this paper were presented in part at the European Society of Cardiology meeting in August 2016 in Rome, Italy.
Contributors: MAR (lead investigator worldwide) conceived the study; obtained peer reviewed and non-peer reviewed funding; chaired the steering committee; wrote the first draft of the protocol; recruited patients; wrote the first draft of the manuscript; developed the analysis plan; and interpreted the study results. GLeG (lead investigator in France) conceived the study; obtained peer reviewed and non-peer reviewed funding; was a member of the steering committee; wrote the first draft of the protocol and first draft of the manuscript; developed the analysis plan; and interpreted the study results. MJK conceived the study; obtained non-peer reviewed funding; was a member of the steering committee; wrote the first draft of the protocol and first draft of the manuscript; developed the analysis plan; and interpreted the study results. DRA and SRK contributed to the study design and recruited patients. JS, GP, PM, CK, and GM were responsible for local study implementation and recruited patients. MR and TLO contributed to the study design; recruited patients; and was a member of the steering committee. TR contributed to the study design, particularly the data analysis plan (lead statistician) and supervised the statistical analysis. AE recruited patients. MVH contributed to the study design and was a member of the steering committee. All authors critically revised and approved the final manuscript.
REVERSE II Study Investigators were responsible for local implementation of the study; recruited patients; and critically revised and approved the final manuscript.
REVERSE II study adjudicators reviewed suspected study events and critically revised and approved the final manuscript.
REVERSE II study data safety monitoring committee reviewed study safety reports and critically revised and approved the final manuscript.
Funding: MAR holds a career investigator award from the Heart and Stroke Foundation of Canada (CI 7441) and the University of Ottawa Faculty of Medicine clinical research chair in thrombosis and thrombophilia. CK holds a career investigator award from the Heart and Stroke Foundation of Canada (CI 7438) and the Jack Hirsh professorship in thromboembolism. SRK is a tier 1 Canada research chairholder. GLeG holds a clinician scientist award from the Heart and Stroke Foundation of Ontario and the University of Ottawa Faculty of Medicine clinical research chain in diagnosis of venous thromboembolism. This investigator initiated study was sponsored by the Ottawa Hospital Research Institute and funded by a grant from the French Ministry of Health (PHRC 2009-08-05) and bioMérieux. MAR, TR, and Ranjeeta Mallick had full access to all study data and take responsibility for the integrity of the data and the accuracy of the data analysis. MAR, TR, and Ranjeeta Mallick from the Ottawa Hospital Research Institute conducted the analyses, independent of the funders. The funders did not have access to the data and did not influence the decision to publish.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: the study was partially funded by bioMérieux the manufacturer of the Vidas D-Dimer (used in the current study); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. All authors fulfilled the conditions required for authorship and the final manuscript has been seen and approved by all authors (see authorship appendix for detailed contributions).
Ethical approval: Institutional research ethics board approval was obtained in the lead centre (Ottawa Health Sciences Network Research Ethics Board ID No 2008039-01H) and at all participating centres.
Data sharing: De-anonymised patient level data and the full dataset with low risk of identification are available on reasonable request after approval by the trial steering committee, Ottawa Health Research Institute, and Ottawa Health Sciences Network research ethics board.
Transparency: The lead author (MAR) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. No medical writer was engaged to write any part of this manuscript.
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