VTE (venous thromboembolic) disease is a potentially chronic disorder. In one study, the eight year risk of recurrent VTE was 30% in patients with unprovoked events.
The challenge physicians face is to decide who needs longer duration of therapy, and who doesn't, since there is the potential for fatal thrombotic complications in the former group, and serious bleeding complications in the latter. Optimum duration of warfarin therapy has been debated for years, and several different approaches have been taken to make a decision about treatment duration.
In patients whose VTE is provoked by an identifiable and reversible factor (e.g., pregnancy, BCP's, estrogen replacement, recent surgery, recent fracture, long distance air travel, prolonged hospitalization) the duration of therapy can be limited to three to six months. (Recent guidelines published in Chest (http://www.chestjournal.org/content/133/6_suppl) include the option of only three months of therapy for provoked P.E.)
The problem arises in those whose VTE is seemingly unprovoked, or in whom the provocative factor may be a little iffy. These are the patients who deserve a work-up for underlying hypercoagulable state, and who may also benefit from prolonged warfarin therapy, perhaps even lifelong in duration.
In 2003, the NEJM published two articles only several months apart, looking at the results of using prolonged low intensity warfarin therapy (target INR 1.5-2.0), which came to opposing conclusions. In one, the results of the PREVENT trial (http://content.nejm.org/cgi/content/abstract/348/15/1425), a benefit was found in giving prolonged low intensity warfarin even when compared to full intensity anticoagulation. The other trial, named ELATE (http://content.nejm.org/cgi/content/abstract/349/7/631), did not show such a benefit. Thus, the practice of prolonged low intensity warfarin therapy has not really caught on much, although it's something that I do in my practice.
On the other hand, measurement of D-dimer following completion of a specified period of anti-vitamin K therapy, was found to be helpful in predicting whether a person would have recurrence of VTE. The PROLONG study was published in the NEJM in 2006 (http://cme.nejm.org/cgi/content/abstract/nejm;355/17/1780), and this showed that patients with an abnormal D-dimer level one month after the discontinuation of warfarin had a significant incidence of recurrent VTE which can be reduced by the continuation of anticoagulation. Interestingly, the group of patients who had a normal D-dimer had a higher hazard rate of recurrence, compared to the high D-dimer group that received anticoagulation, suggesting that there are yet other factors that may predict long term outcome. Good reviews of the science and clinical application of D-dimer can be found in the journal Blood (http://bloodjournal.hematologylibrary.org/cgi/content/short/113/13/2878) and in the Annals of Internal Medicine (http://www.annals.org/cgi/content/abstract/149/7/481)
Another study (http://jama.ama-assn.org/cgi/content/abstract/296/4/397) looked at thrombin generation time after discontinuation of anticoagulation as a means of determining risk; the patients with lower incidence of recurrent VTE had lower mean peak thrombin generation times. This study, although interesting, has low practical value at the present time.
Most recently, the Annals of Internal Medicine (http://www.annals.org/cgi/content/short/150/9/577) published a provocative article suggesting that the presence of recanalization of veins on follow-up ultrasonography (UTS) is a predictor of long term outcomes for patients with DVT. In this study, 538 patients who had received an initial three months of anticoagulation were randomly assigned to receive either a fixed duration of anticoagulation therapy or flexible duration of therapy whose length was determined by UTS findings at pre-determined intervals. In both the fixed group and the flexible group, the patients were further subdivided into those who had unprovoked DVT or provoked DVT. In the fixed group, the patients with unprovoked DVT received an additional three months of anticoagulation (for a total of six months.) Both groups of patients were subjected to serial UTS up to 21 months if vein recanalization was not observed.
But in the flexible group, the decision to continue anticoagulation was based solely upon serial UTS performed at 3, 9, 15 and 21 months. If the UTS showed resolution of thrombus (defined as vein recanalization), then anticoagulation was discontinued. The mean duration of anticoagulation in the flexible group with provoked DVT was 3.7 months and in unprovoked DVT was 5 months.
There were 78 episodes of recurrent VTE in the 538 patients. The incidence was 17.2% treated in the fixed duration arm, and 11.9% in the flexible duration arm. The cumulative incidence of recurrent VTE was less in the flexible group than in the fixed group. Bleeding complications were higher in the flexible group than in the fixed, but not significantly so.
These results suggested that "assessment of residual thrombosis by ultrasonography improves the identification of patients who are at highest risk for recurrence, and it allowed decisions on anticoagulation that led to a substantial reduction in recurrent events." An interesting note is that prolonging anticoagulation seemed to accelerate vein recanalization, because there was a significantly smaller proportion of patients with persistent vein obstruction in the fixed group than in the flexible group after the last UTS exam in both groups. The authors further conclude that residual thrombosis is a marker of hypercoagulability and that it may predict late cardiovascular death.
This study is a very interesting one (with some limitations) and suggests that follow-up UTS may be a useful adjunct to other clinical evaluations that are used in making the decision whether to continue anticoagulation in patients with DVT. (Note that this study was not about patients with P.E.) In my opinion, this study does suggest that residual thrombi on follow-up UTS should be taken seriously and should prompt continued anticoagulation, and so it does confirm to me the value of my usual practice of obtaining a follow-up UTS after a prescribed course of anticoagulation.
What I was not able to tell from this paper was whether the predictive value of a follow-up ultrasound could be determined early on, or if multiple serial UTS was absolutely required. Clearly this has important economic implications, as well as patient compliance and utilization questions.
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