We developed and internally validated a clinical decision rule that may ultimately provide clinicians with guidance as to whether oral anticoagulation therapy can be discontinued after 5–7 months of treatment for an “unprovoked” venous thromboembolism. This clinical decision rule identifies women with an annual risk of venous thromboembolism less than 3% who can likely safely discontinue anticoagulant therapy ().
Despite research about the duration of anticoagulant treatment for unprovoked venous thromboembolism3,4,11,17,18
and the identification of risk factors for its recurrence,19–26
clinicians remain vexed as to who should continue taking anticoagulants after an initial 3–6 months of therapy. In fact, practice guidelines have remained unchanged despite a decade of research.2
This failure to change practice is likely because a therapy has not been identified that reduces the risk of bleeding below the level of risk of recurrent venous thromboembolism after 3–6 months of anticoagulant therapy (e.g., lower intensity international normalized ratio, new anticoagulants). This failure is also likely because of a failure to identify high-risk groups in which the benefits of standard therapies clearly outweighed the risks and to identify low-risk groups for whom no further therapy is necessary.
A number of variables to stratify risk of recurrent venous thromboembolism in patients with an unprovoked index event have been investigated, including sex,22
plasma D-dimer levels measured 1–2 months after discontinuation of oral anticoagulants,19,20,23,24
residual venous obstruction using venous ultrasonography19,25,26
and elevated plasma levels of factor VIII.21
Studies investigating these variables have all been hampered by the inclusion of patients with heterogeneous risk of recurrence (e.g., a variable duration of oral anticoagulation therapy,19–21,23,24
both provoked and unprovoked index events,19,20,23
both distal and proximal deep vein thrombosis23
). Only the use of D-dimer levels as a predictor variable has been studied in a prospective management study.24
In this study, a normal D-dimer value after stopping oral anticoagulants was not sufficient to identify patients at low risk (i.e., < 3% annual risk) to be clinically useful.24
Furthermore, stopping anticoagulants, testing D-dimer levels 1 month later and restarting anticoagulant therapy if necessary, is impractical for the majority of patients and exposes high-risk patients to a long period without anticoagulants. We did not find that residual venous obstruction (detected by leg vein imaging) was an important predictor of recurrent venous thromboembolism. We found that elevated levels of factor VIII was a significant univariable predictor, but it was not an independent predictor in the multivariable analysis. In our study, no single predictor identified a sufficiently low-risk group to be clinically useful. A multivariable clinical decision rule is a more powerful approach because it combines the predictive power of multiple independent variables.
We identified 3 major novel findings. First, post-thrombotic findings after 5–7 months of oral anticoagulant therapy are the strongest predictors of recurrent venous thromboembolism. Second, for women, but not for men, D-dimer levels (measured while taking oral anticoagulants) are an important predictor of recurrence after the patient has stopped taking anticoagulants. Third, we have identified a clinical decision rule that can be used to identify women at low risk of recurrence.
Our study has a number of strengths. To date, this is the largest and most comprehensive clinical study that has evaluated risk factors for recurrent venous thromboembolism in patients with unprovoked proximal deep vein thrombosis or pulmonary embolism. We prospectively measured all important risk factors potentially associated with recurrent venous thromboembolism in a standardized fashion. Our study included patients for whom the clinical decision to discontinue oral anticoagulation therapy is most uncertain, and we analyzed risk factors at the time when a decision is usually made. In addition, our study included a representative sample of patients from multiple centres and countries. These patients were consecutively enrolled without bias. The clinically relevant primary outcome of recurrent venous thromboembolism was clearly defined and independently adjudicated. We included only reproducible clinical variables in the final decision rule (age, BMI,27
post-thrombotic symptoms findings of hyperpigmentation, edema and redness29
), which likely enhances the interobserver reproducibility of the rule. In addition, the 4 variables included in our decision rule all have face validity (i.e., make sense to clinicians) as predictors of recurrent venous thromboembolism. D-dimer levels, older age and increased BMI have been consistently shown to be predictors of recurrent venous thromboembolism.19,20,22–24,30
Venous stasis changes of hyperpigmentation, edema or redness have been previously suggested to be predictors of recurrent venous thromboembolism.31,32
Because venous damage predisposes patients to slower and abnormal blood flow, the risk of recurrent venous thromboembolism should be increased among these patients.
Our study has several limitations. First, to avoid over-fitting, not all potentially significant variables (p
< 0.20) were included in our multivariable modelling. Second, not all patient data sets in the derivation group were complete. Third, D-dimer levels were measured and the optimal cut-off point (D-dimer ≥ 250 μg/L) was identified by use of 1 reagent on 1 instrument. The use of other D-dimer tests will require separate studies to identify optimal cut-off points and performance in predicting recurrent venous thromboembolism within the context of this clinical decision rule. Fourth, our clinical decision rule does not predict how long anticoagulants should be continued for patients in the high-risk group. Randomized controlled trials that compare therapeutic options (shorter v. longer duration, higher v. lower intensity therapy, alternative anticoagulants) or risk stratification at a later time may be required to define optimal therapeutic management for high-risk patients. Fifth, we excluded patients with known high-risk thrombophilia, and few of our patients were nonwhite (< 8%), hence our clinical decision rule may not apply to patients in these groups. Finally, and most importantly, additional important methodologic criteria33,34
must be met before our decision rule can be widely adopted: the interobserver agreement of the rule must be determined, and the safety of this rule must be prospectively validated in a separate population to ensure that the low-risk group has less than 3% annual risk of recurrence.
We were unable to derive a rule that identified men at low risk who can safely discontinue anticoagulants after 5–7 months of therapy. It is possible that a larger sample would have permitted us to identify a low-risk group of men; however, it is likely that this subgroup would represent a small proportion of men given our sample size and that men had more recurrences than women (giving us more power to derive a rule in men). However, until a successful risk stratification tool is developed that identifies low-risk men, it appears that all men are at high risk of recurrence, particularly men with hyperpigmentation, edema or redness in either leg.
In conclusion, it may be safe for women who have taken oral anticoagulants for 5–7 months after an unprovoked venous thromboembolism to discontinue therapy if they have 0 or 1 of the following signs or symptoms: hyperpigmentation, edema or redness of either leg; a D-dimer level of 250 μg/L or more while taking warfarin; BMI 30 kg/m2 or more; and age 65 years or more.
@@ See related commentary by Kearon, page 401