Medical Discussions

A D-dimer molecule, abutting ends at the D:D junction as part of the fibrinogen gallery at UCSD. 

Background

• The optimal duration of warfarin treatment after deep venous thromboembolism (DVT) for the purpose of preventing future DVTs in unclear
• The risk of recurrance is greatest in the first 6 to 12 months after the initial episode and then gradually decreases.
• Previous studies have suggested that elevated D-dimer levels may predict the risk of developing DVTs in the future
• To test this hypothesis, patients with unprovoked DVTs and a positive D-dimer who were treated with vit. K antagonist for three months were randomized to recieve anticoagulation or to discontinue anticoagulation.  Patients that had a normal positive D-dimers test after three months of anticoagulation therapy did not receive further treatment.

Methods

• All patients were treated with a minimum of 3 months of vitamin K antagonist  therapy after an unprovoked DVT.
• Inclusion Criteria – Patients who are between the ages of 18 and 85 who had a first episode of symptomatic, unprovoked venous thromboembolism, defined as proximal DVT of the lower legs, pulmonary embolism, or both, all patients needed to be treated with a vit. K antagonist for three months with a target INR of 2.5 (range of 2-3)
• Unprovoked DVT was defined as a DVT not associated with pregnancy, fracture, immobilization, surgery, cancer, antiphospholipid antibody syndrome, or antithrombin deficiency.
• Other exclusion criteria inculded patients who had serious liver disease, renal insufficiency, other indications or contraindications for anticoagulation, or limited life expectancy.
• Pt’s with Factor V Leiden deficiency were allowed in the study.
• Finally, all patients underwent ultrasound to assess the proximal deep veins after three months of treatment with vit. K antagonists.  If they had a recurrent DVT, during this time period, then they were excluded from the study.
• All patients were studied for a period of 18 months and were seen at the clinic at intervals of 3 to 6 months.
• This is an intention-to-treat analysis.
• This study was not blinded, though committee members were unaware of the results of the D-dimer test.

Results

• A total of 619 patients underwent D-dimer testing and a thrombophilia workup.  Of these, 11 patients were ultimately excluded  because they were positive for lupus anticoagulant or antithrombin deficiency.
• Of the 608 patients that were included, 63% had a normal D-dimer level.
• Of the remaining 223 patients with an abnormal D-dimer level , 103 were randomly assigned to receive anticoagulation and 120 were assigned to receive no anticoagulation.
• Of the pts with positive D-dimers
  • Of the 120 pts who d/c’d anticoagulation –> 15% developed recurrent venous thromboembolism
  •  Of the 103 pts who resumed anticoagulation, one had a major bleeding event and 2 had a recurrent venous thromboembolism.
  • Adjusted hazard ratio 4.26 (95% CI: 1.23-14.6) with p 0.007
• There was no significant difference in the rate recurrent venous thrmboembolism between the group with normal d-dimers compared to the group with abnormal d-dimers who were anticoagulated (adjusted hazard ratio, 2.46; 95% CI, 0.71 – 8.46), but the absolute difference (6.2% vs 2.9%) may be clinically significant.

Discussion

• The PROLONG study shows that patients with abnormal D-dimer test who were not anticoagulated had high rates of recurrance venous thromboembolism (15%), while pts with normal D-dimer had a significantly lower chance of developing a recurrent thromboembolism (6.2%).  The adjusted hazard ratio comparing the rates of recurrance was 2.27 (95% CI 1.15-4.46, p 0.02) 
• In patients with a positive D-dimer,  when comparing those that were anticoagulated to the those that were not, the group that was anticoagulated had a low rate of bleeding and recurrence of thromboembolism (combined endpoint of 2.9%, p 0.005) 
• Patients with abnormal D-dimer were significantly older than patients with a normal D dimer test (average age 70 yo versus  59 yo, p<0.001)  
• The study was not powered to make a definitive assessment of the risk of bleeding, since the risk increases with time, the risk/benefit ratio may change as anticoagulation is prolonged.

THE BOTTOM LINE:  In patients who have completed at least 3 months of anticoagulation therapy after an unprovoked venous thromboembolism, a positive D-dimer one month after discontinuation of anticoagulation therapy is correlated with the risk of recurrence.  In patients with a positive D-dimer test, continuing anticoagulation therapy decreases the risk of recurrent venous thromboembolism when compared to patients who are not anticoagulated regardless of their D-dimer.   In sum, this study shows that the D-dimer assay may help guide clinicians on the length of anticoagulation therapy, but it does not definitively establish the optimal course of therapy.