The July 2009 issue of the American Journal of Obstetrics and Gynecology will report the results of a September 2007 consensus conference, with participation by experts in ob-gyn and hematology on the diagnosis and management of reproductive tract bleeding in women with bleeding disorders http://www.ajog.org/article/S0002-9378(09)00410-4/fulltext. The conference was predicated on the belief that the lack of awareness of the potential of bleeding disorders to exacerbate or cause abnormal bleeding leads to underdiagnosis and suboptimal treatment of women with bleeding disorders.
The report brings to light some interesting numbers. For example, the prevalence of menorrhagia in women with von Willebrand Disease (vWD) is between 74 and 92%; conversely, the prevalence of vWD in women with menorrhagia is between 5-24% A study was cited that reported a 33% prevalence of vWD is adolescents with menorrhagia.
The fact that as many as one in every four women with menorrhagia could have a diagnosis of vWD is an impressive one, and surprising. The statistic of one in three for adolescents is even more striking.
The report points out that most women with menorrhagia do not have a bleeding disorder and that even in women with a known bleeding disorder, a gyn evaluation for other causes of bleeding is still mandatory. An underlying bleeding disorder should be considered, however, if any of the following indicators are present:
menorrhagia since menarche
family history of bleeding disorder
personal history of epistaxis lasting more than 10 minutes or necessitating packing or cautery
"notable" bruising without injury
minor wound bleeding, e.g. from trivial cuts, lasting for more than five minutes
bleeding from an oral cavity or GI tract without obvious anatomic lesion
prolonged bleeding after dental extraction
unexpected postsurgical bleeding
hemorrhage from ovarian cysts or corpus luteum, with or without Mittelschmerz
hemorrhage requiring blood transfusion
postpartum hemorrhage, especially when delayed
failure of response to conventional management of menorrhagia
Hematologic evaluation is most sensitive during menstruation, when coagulation factors are at their lowest. However, evaluation should not be delayed until menstruation. Tests can be repeated during menstruation if initial testing is at low normal. Patients should not be removed from contraceptives to permit testing although patients with mild vWD may have normal results when contraceptives are being used. A concluding comment from this article includes the following: "collaboration among obstetrician-gynecologists and hematologists ...could lead to a decrease in the diagnosis of "idiopathic" menorrhagia and allow more effective management of bleeding events." Another conclusion reached is that consideration of bleeding disorders in menorrhagia can lead to improved management of post-partum hemorrhage.
Saturday, June 13, 2009
Wednesday, June 3, 2009
What is the optimum duration of warfarin therapy? Only your ultrasonographer knows for sure...
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.
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.
Subscribe to:
Posts (Atom)
