A recent study by Rathbun and colleagues investigated the use of D-dimer measurement in excluding recurrent VTE, finding that of former VTE patients presenting with symptoms, only 0.75% with a negative D-dimer level had recurrent VTE on ultrasound, compared to 6.0% with a positive test who had recurrent VTE. This study, conducted by Palareti and colleagues, tries to go a step further and assess whether D-dimer testing can be used to risk stratify VTE patients who are asymptomatic following treatment for an initial episode of VTE, as well as whether or not it can be used to determine the need to continue anticoagulation.
The PROLONG study was a multicenter prospective study of patients between 18 and 85 who had had their first episode of unprovoked, symptomatic VTE (including pulmonary embolism). Patients were enrolled in this study after completing treatment with vitamin K antagonists (VKA) for at least three months with a target INR (international normalized ratio) in the range of 2-3. Exclusion criteria included severe liver insufficiency, renal insufficiency with serum creatinine >2, or clear indications/contraindications for anticoagulation.
Six hundred twenty-four patients treated for VTE were enrolled in the study. All underwent compressive ultrasound in both legs to establish a baseline at the start of the study and were then instructed to stop anticoagulation. Follow-up occurred in one month, with another ultrasound to assess recurrence of VTE. Five patients were found to have VTE and were excluded. The remaining 619 patients were tested for D-dimer levels and were given thrombophilia tests. A further 11 patients were excluded due to antiphospholipid antibodies or antithrombin deficiency. Patients with factor V Leidin and G20210A mutation on the prothrombin gene were allowed to participate in the study.
Three hundred and eighty-five patients had normal D-dimer levels and were not placed on anticoagulation. The 223 patients with abnormal D-dimer levels were randomized to receive VKA (103 patients) or no treatment (120 patients). All patients were followed for minimum of 18 months. Of the 120 patients with abnormal D-dimer levels who were randomized to no treatment, 18 patients (15.0%) had recurrent VTE. Of the 103 patients with abnormal D-dimer levels who resumed anticoagulation, one had a major bleeding episode and two had recurrent VTE, for a composite result of 2.9%—a statistically significant difference (P<0.005). The group with normal D-dimer levels after initial treatment had 24 episodes of recurrent VTE (6.2%).
The study suggested that the patients with abnormal D-dimer levels who stopped anticoagulation had a statistically significant higher rate of recurrent VTE than those who continued anticoagulation. There was also a statistically significant difference in the recurrent VTE rate in the two groups who did not resume anticoagulation. Interestingly, while the absolute difference between the normal D-dimer group and the abnormal D-dimer group who resumed anticoagulation was evident (6.2% versus 2.9%), this did not reach statistical significance.
This study is promising; however, there are some caveats to take into account when trying to apply these results to current clinical practice. First, the trial was not blinded and only evaluated patients with the first unprovoked episode of VTE. It is unknown if these results will apply to secondary VTE. Older people in this study had a higher incidence of elevated D-dimer at enrollment. The authors utilized a qualitative assay for D-dimer to obtain uniform results across the multiple testing centers. Applying these results to centers that use quantitative measurements of D-dimer then becomes more difficult due to the variability inherent in the interpretation of these quantitative results. Because this study excluded patients with either severe liver disease or renal insufficiency (Cr >2.0), it remains unknown if the results are applicable to these populations.