DODS

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Kearon C, et al. "Long-term risk of recurrence in patients with a first unprovoked venous thromboembolism managed according to D-dimer results: a cohort study". Journal of Thrombosis and Hemostasis. 2019. 17(7):1144-52.
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Clinical Question

Among patients with a first unprovoked VTE episode who have completed 3 months of anticoagulation, does a D-dimer based anticoagulation cessation strategy result in favorable outcomes?

Bottom Line

Among patients with a first unprovoked VTE episode who had a negative D-dimer on therapy and again 1 month after discontinuation of therapy, the rate of VTE recurrence was lower in women than in men.

Major Points

The D-dimer assay is an important component of the diagnostic workup of a patient with suspected VTE, and it can also help estimate the risk of recurrent VTE in patients who have completed anticoagulation for unprovoked VTE.

The D-dimer Optimal Duration Study (DODS) was a prospective interventional cohort study evaluating whether end-of-treatment D-dimer testing may be used to guide cessation of anticoagulation in patients with first unprovoked VTE. The study enrolled approximately 400 patients with first unprovoked VTE who had received 3-7 months of anticoagulation according to routine practice. Patients with a negative D-dimer discontinued anticoagulation and a repeat D-dimer was obtained 1 month later; if this remained negative, anticoagulation was discontinued permanently. Patients with a first positive D-dimer remained on anticoagulation, and those whose D-dimer turned positive off anticoagulation resumed anticoagulation. Warfarin and non-vitamin K antagonists were allowed. The primary outcome was recurrent symptomatic VTE in patients with two negative D-dimer tests after discontinuation of anticoagulation. At a median of 5 years of follow-up in this report, the rates of recurrent symptomatic VTE were 5.1% per patient-year in the negative D-dimer group off anticoagulation, and 1.6% per patient-year in the positive D-dimer group who remained on anticoagulation. In the negative D-dimer group off anticoagulation, differences in recurrence rates were noted between sex and estrogen status: the rate of recurrence was 7.5% per patient-year in men, compared with 3.8% per patient-year in women not exposed to estrogen, and 0.4% per patient-year in women exposed to estrogen.

This prospective cohort study builds upon a growing literature supporting the use of D-dimer based risk stratification and anticoagulant management in patients with unprovoked VTE. The observed sex- and hormone-based differences in VTE recurrence risk suggest that these factors should also be incorporated into risk stratification, and perhaps that routine D-dimer based risk stratification should be restricted to women.

Guidelines

ACCP/Chest Guidelines (2016, adapted)[1]

In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).

Remarks: Patient sex and D-dimer level measured a month after stopping anticoagulant therapy may influence the decision to stop or extend anticoagulant therapy (see text). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).

Design

  • Prospective, interventional cohort study
  • N=Initially 410 patients with first unprovoked VTE who completed 3-7 months of anticoagulation, smaller number of patients followed for 5 years
    • Discontinue anticoagulation after negative D-dimer (n=231)
    • Continue anticoagulation after positive D-dimer (n=51)
  • Setting: 13 tertiary care centers
  • Enrollment: 2008-2012
  • Median follow-up: 5 years
  • Analysis: Descriptive
  • Primary outcome: Recurrent symptomatic VTE

Population

Inclusion Criteria

  • Age ≥18 years
  • First episode of symptomatic unprovoked proximal DVT of legs or PE
  • Completed 3-7 months of anticoagulation

Exclusion Criteria

  • Age ≥75 years
  • Other indication for anticoagulant therapy
  • High risk of bleeding
  • D-dimer testing within past 2 months

Baseline Characteristics

  • Age: 51 years (mean)
  • Duration of anticoagulation: 5 months (mean)
  • Prior provoked VTE: 4%
  • Qualifying event: proximal DVT only 45%, PE with or without DVT (55%)
  • Number of risk factors for bleeding: 0 (87%), 1 (11%), 2 (2%), 3 (<1%)
  • Antiplatelet therapy: 7%
  • Compression stockings: 30%
  • Family history of VTE: 21%
  • Performance status: fully active 91%

Interventions

  • All patients had already completed 3-7 months of anticoagulation
  • All patients underwent D-dimer testing while on anticoagulation
    • If D-dimer was negative on anticoagulation, then anticoagulation was discontinued and D-dimer was repeated
      • If D-dimer was again negative off anticoagulation, then anticoagulation remained off permanently
      • If D-dimer turned positive, then anticoagulation was resumed
    • If D-dimer was positive on anticoagulation, then anticoagulation was continued

Outcomes

Primary Outcome

Recurrent symptomatic VTE in patients who discontinued anticoagulation with 2 negative D-dimer results
5.1% per patient-year
Recurrent symptomatic VTE in patients who continued anticoagulation with a positive D-dimer result
1.6% per patient-year

Secondary Outcomes

Patients with 2 negative D-dimer results
321 of 410
Patients with a positive D-dimer result
69 of 410

Subgroup Analysis

Recurrent symptomatic VTE in men with 2 negative D-dimer results
7.5% per patient-year
Recurrent symptomatic VTE in non-estrogen women with 2 negative D-dimer results
3.8% per patient-year
Recurrent symptomatic VTE in estrogen women with 2 negative D-dimer results
0.4% per patient-year

Adverse Events

Major bleeding
0.5% per patient-year
Minor bleeding
1.2% per patient-year

Criticisms

  • Possibility that trial results may not be generalizable to other D-dimer assays.
  • Excluded patients older than 75 years, preventing sound extrapolation to these patients.
  • 5 years of follow-up was only available for 75% of patients, which may introduce confounding/bias.

Funding

Canadian Institutes of Health Research funded the study, and D-dimer assays were provided by the manufacturer. No conflicts of interest were identified by the authors.

Further Reading

  1. Kearon C et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016. 149:315-52.