PROLONG

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Palareti G, et al. "d-Dimer Testing to Determine the Duration of Anticoagulation Therapy". The New England Journal of Medicine. 2006. 355(17):1780-1789.
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Clinical Question

Among patients with unprovoked VTE, does the end-of-treatment D-dimer level predict for future thrombosis and allow for tailored therapy?

Bottom Line

Among patients with unprovoked VTE, an elevated end-of-treatment D-dimer level is associated with an increased risk of recurrent VTE which can be reduced with continuation of anticoagulation.

Major Points

Unprovoked VTE is associated with a high rate of recurrent VTE, such that approximately one third of such patients will develop a recurrence within the 5 years after stopping anticoagulation. A number of studies have therefore evaluated the role of extended anticoagulation in patients with unprovoked VTE, including AMPLIFY-EXT and EINSTEIN CHOICE. But whether all patients with unprovoked VTE require indefinite anticoagulation is not known. Efforts are therefore underway to generate clinical and laboratory risk assessment tools for determining who is at the highest risk of recurrence, and tailoring therapy accordingly. The D-dimer assay, which directly measures the byproducts of thrombus formation, is an attractive candidate marker, the hypothesis being that patients with unprovoked VTE who have an elevated D-dimer after anticoagulation therapy may have a higher risk of recurrent VTE in the future. This had been demonstrated previously,[1] but a prospective randomized trial was necessary.

The PROLONG study, published in 2006, enrolled 619 patients who completed ≥3 months of vitamin K antagonist therapy for first unprovoked VTE, defined as PE, proximal lower extremity DVT, or both. One month after completing anticoagulation, patients underwent D-dimer testing and those with a negative result discontinued therapy (n=392, 63.3%). Those with an elevated D-dimer at 1 month after completion of anticoagulation were randomized to either discontinue anticoagulation (n=122) or resume anticoagulation for up to 18 months (n=105). Patients were followed for the primary composite outcome of recurrent VTE or major bleeding. With a median follow-up of 1.4 years, patients with an abnormal D-dimer who discontinued anticoagulation had a significantly increased risk of recurrent VTE or major bleeding compared to patients with an abnormal D-dimer who resumed anticoagulation (10.9 vs. 2.0 events per 100 person-years; adjusted HR 4.26; P=0.02). There were no differences in the rates of major bleeding during study follow-up, although the event rates were low.

Subgroup analyses from the PROLONG extension study suggest that D-dimer results should be interpreted alongside age and sex when estimating VTE recurrence risk.[2] For example, among patients with an abnormal D-dimer who discontinued anticoagulation, male sex impacted VTE recurrence rates (7.4 vs. 4.3 per 100 person-years) as did age older than 65 years (50 vs. 3.6 per 100 person-years). In fact, even among young patients with normal D-dimer who discontinued anticoagulation, male sex continued to be a risk factor for recurrence (5.1 vs. 0.4 per 100 person-years).

The DASH model incorporates these and other risk factors into a prediction rule which can be used to estimate recurrence risk in individuals with first unprovoked VTE episode.[3] The score assigns points to abnormal D-dimer after stopping anticoagulation (+2), age <50 years (+1), male sex (+1), and VTE associated with hormonal therapy (-2). Those with a composite score of ≤1 have a 3.1% annual risk of recurrent VTE compared to those with a score >1 who have an annual risk of 9.3%.

Guidelines

The 2016 Chest Guidelines on VTE management discuss end-of-therapy D-dimer testing, but specifically provide no recommendations regarding its use in patients with unprovoked VTE.[4]

Design

  • Multicenter, randomized prospective trial
  • N=227 patients with positive D-dimer after ≥3 months of anticoagulation
    • Resume anticoagulation (n=105)
    • Discontinue anticoagulation (n=122)
  • Setting: 30 clinical centers
  • Enrollment: 2002-2005
  • Mean follow-up: 1.4 years (all had ≥9 months of follow-up)
  • Analysis: Intention-to-treat
  • Primary outcome: Composite of confirmed recurrent VTE and major bleeding

Population

Inclusion Criteria

  • Age 18-85 years
  • First episode of symptomatic, unprovoked VTE (proximal lower extremity DVT, PE, or both)
  • Have completed ≥3 months of vitamin K antagonist therapy with target INR 2-3

Exclusion Criteria

  • Risk factors for VTE including pregnancy or the puerperium, recent fracture or casting, immobilization, surgery, cancer, antiphospholipid antibody syndrome, antithrombin deficiency
  • Serious liver disease or renal insufficiency
  • Contraindication to anticoagulation
  • Limited life expectancy

Baseline Characteristics

From the abnormal D-dimer cohort.

  • Female sex: 52.9%
  • Age, mean: 59.3 years (74% were ≥65 years)
  • Type of VTE:
    • VTE without PE: 62.8%
    • DVT plus PE: 18.4%
    • Isolated PE: 18.8%
  • Inherited thrombophilia risk factors:
    • Factor V Leiden mutation: 12%
    • Prothrombin gene mutation: 7.4%
    • ≥2 mutations: 1.4%
  • Duration of prior anticoagulation:
    • 3-6 months: 15.7%
    • 7-12 months: 55.2%
    • >12 months: 29.1%

There were no major differences between those with elevated D-dimer who were randomized to resume anticoagulation versus those randomized to discontinue of anticoagulation.

Interventions

  • All patients underwent US of the legs at study enrollment as a baseline assessment
  • Patients were instructed to discontinue anticoagulation for 1 month (patients who developed a thrombosis during this 1-month period were excluded from analysis)
  • After 1 month off anticoagulation, D-dimer was evaluated using a qualitative assay
    • Patients with a normal D-dimer did not continue anticoagulation
    • Patients with an elevated D-dimer were randomized to resume or to discontinue vitamin K antagonist (INR goal 2-3) for up to 18 months
  • Patients were followed for the primary composite outcome of recurrent VTE or major bleeding (which were centrally adjudicated)
    • Major bleeding was defined as hemorrhage into the retroperitoneal or intracranial space, caused a 2-g/dL hemoglobin decrease, required 2 units of RBCs transfused, or those that required a surgery or other invasive procedure to stop bleeding

Outcomes

Comparisons are abnormal D-dimer without anticoagulation group vs. abnormal D-dimer with anticoagulation group.

Primary Outcome

Recurrent VTE or major bleeding
10.9 vs. 2.0 events per 100 person-years (adjusted HR 4.26, 95% CI 1.23-14.6; P=0.02)

Secondary Outcomes

Recurrent DVT
11 versus 1 patient
Recurrent DVT with PE
4 versus 0 patients
Isolated PE recurrence
3 versus 1 patients

Adverse Events

Major bleeding
0 versus 1 patients

Criticisms

  • Not blinded
  • Use of qualitative rather than quantitative D-dimer assay may have limited sensitivity
  • D-dimer performed only once, rather than serially as has been used in other studies
  • Only patients with first unprovoked VTE were enrolled, which limits generalizability

Funding

Italian Federation of Anticoagulation Clinics and Department of Angiology and Blood Coagulation. Instrumentation Laboratory in Italy provided the Clearview Simplify D-dimer assay kits.

Further Reading

  1. Palareti G et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anticoagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 2003. 108:313-8.
  2. Cosmi B et al. Sex, age and normal post-anticoagulation D-dimer as risk factors for recurrence after idiopathic venous thromboembolism in the Prolong study extension. J. Thromb. Haemost. 2010. 8:1933-42.
  3. Tosetto A et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J. Thromb. Haemost. 2012. 10:1019-25. (Calculator available via MDCalc.)
  4. Kearon C et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016. 149:315-52.