d-Dimer Levels Help Determine Duration of Anticoagulation

BOLOGNA, Italy, Oct. 25 -- A month after stopping anticoagulant therapy, patients with an abnormal d-dimer level have a significant rate of recurrent venous thromboembolism, according to researchers here.

The adjusted risk for recurrent thromboembolism among those with an abnormal d-dimer level was more than twice that of those with normal levels, Gualtiero Palareti, M.D., of S. Orsola-Malpighi University Hospital here, and colleagues, reported in the Oct. 26 issue of The New England Journal of Medicine.

The rate was reduced by the resumption of anticoagulation, said Dr. Palareti for the multicenter, prospective PROLONG study. On the other hand, they added, the optimal course of anticoagulation in patients with normal levels has not been clearly established.

Because the risk of recurrence is greatest in the first six to 12 months after the initial episode and gradually diminishes after that, the researchers emphasized that the benefit of an extended course of anticoagulation may be offset over time by the risk of clinically important bleeding.

The PROLONG investigators studied patients ages 18 to 85 who had had a first episode of symptomatic, unprovoked venous thromboembolism, including proximal DVT of the lower limbs, pulmonary embolism, or both. Patients had taken a vitamin K antagonist for at least three months. D-dimer testing was done one month after discontinuation of anticoagulation therapy.

At baseline, 47.9% of the patients were women, and 55.3% were 65 or older (mean age 63). As expected, abnormal d-dimer levels were significantly more frequent among older patients, the researcher reported.

Of 608 patients, 385 with a normal d-dimer level one month after discontinuation of anticoagulation did not resume anticoagulation. The 223 patients (36.7%) with an abnormal d-dimer level were randomly assigned either to resume or to discontinue treatment.

During an average follow-up of 1.4 years, 18 of 120 patients with abnormal d-dimer results who stopped anticoagulation had a recurrent event (15.0%, or 10.9 events per 100 person-years).

This 15% rate compared with only three events among 103 patients who resumed anticoagulation (2.9%, or 2.0 events per 100 person-years), for an adjusted hazard ratio of 4.26 (95% confidence interval [CI], 1.23 to 14.6; P = 0.02).

The rate of recurrence in the cohort with a normal d-dimer was also significantly lower than that for patients with an abnormal d-dimer level who stopped anticoagulants. Thromboembolism recurred in only 24 of the 385 patients with a normal d-dimer level (6.2%, or 4.4 events per 100 person-years).

This 6.2% rate for the normal d-dimer patients, the researchers said, was not significantly different from the 2.9% rate for patients with an abnormal d-dimer level who resumed anticoagulation, although the absolute difference between the two points was large enough to be clinically significant.

The risk-benefit relationship of prolonged anticoagulation in patients with a normal d-dimer level is therefore uncertain, the researchers concluded.

Overall, among patients who stopped anticoagulation, the adjusted hazard ratio for recurrent thromboembolism among those with an abnormal d-dimer level, as compared with those with a normal level, was 2.27 (CI, 1.15 to 4.46; P = 0.02).

Patients with an abnormal d-dimer level were significantly older than those with normal levels. However, no differences were found for sex, duration of anticoagulation before enrollment, the type of index event, or the presence or absence of inherited thrombophilias.

These results may be useful in guiding the duration of anticoagulation by helping clinicians select patients who may benefit the most from the prolongation of this demanding and risky therapy, Dr. Palareti said.

A strength of this study, the researchers said was the qualitative (normal or abnormal) rather than a quantitative method for d-dimer testing, which provided a uniform approach across participating centers.

Study imitations included the fact that the trial was not blinded and that because d-dimer testing was done 30 days after treatment was discontinued, earlier events could not be tallied.

Also, the investigators wrote that the assay was done only once, with follow-up scheduled to last for the next 18 months. However, it is possible, they said, that some patients with normal results at the outset could have had an abnormal result on repeated testing, serving as an early warning sign.

In addition, because the study was not large enough, it was not possible to make a definitive assessment of the relative risk of bleeding, considered alone, with continued anticoagulation.

Finally, the investigators said, they included only patients with a first unprovoked event. However, a management strategy for all groups of patients regardless of the nature and number of previous events would be of great practical use. These issues, they concluded, remain to be addressed by specifically designed clinical studies.

The study authors reported that the Instrumentation Laboratory in Milan provided the kits for d-dimer measurement (Clearview Simplify d-dimer assay). Dr. Palareti, and several coauthors reported having received lecture fees from the Instrumentation Laboratory.