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Residual thrombosis and recurrent thromboembolism
Submit responseIn response to the letter by Kim et al, we would like to emphasize that in patients with acute symptomatic proximal deep venous thrombosis (DVT) who have been treated for 3-to-6 months with conventional anticoagulation residual thrombosis on ultrasonography was consistently shown to occur in 60%, 40%, and 30% at 6, 12 and 24 months, respectively (1,2). Indeed, in our present study 29.5% of patients randomized to the recommended fixed duration of anticoagulation still had residual thrombosis at their last ultrasound assessment, which was performed after 1 year in patients with secondary DVT, and after 2 years in those with unprovoked DVT (3). This rate was significantly higher than that (20.0%) found in patients randomized to the flexible duration. As the two study populations had fully comparable baseline characteristics, it is likely that the prolonged use of anticoagulants in the flexible duration group contributed to the lower observed rate of residual vein thrombosis. Since residual thrombus after DVT treatment is a well known risk factor for recurrent DVT (2,4,5), we agree with Kim et al that the reduction in recurrent venous thromboembolism (VTE) observed in the flexible group may have resulted from the lower rate of residual thrombosis. We agree with Imfeld et al. that the better outcome in patients randomized to the flexible duration of anticoagulation, as compared with those randomized to the fixed conventional duration, reflects the longer duration of anticoagulation (3). The advantage of our approach lies in the identification of a subgroup of patients who can benefit from prolonging anticoagulation without exposing a large group of patients that is less likely to develop recurrent VTE to the risk of anticoagulants. Our decision model that stipulates continuation or cessation of anticoagulation in response to ultrasound results over time, reflects increasing understanding that post-baseline variables may be as (or more) important for predicting risk of VTE recurrences as baseline characteristics such as gender, thrombophilia and type of DVT. As far as the statistical approach is concerned the primary analysis was performed with a Cox-proportional hazard model, which allows for adjustment for confounders. The p-value in a Kaplan-Meier log-rank analysis showed similar results (p-value 0.047).
References
1. Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P, et al. A simple ultrasound approach for detection of recurrent proximal -vein thrombosis. Circulation. 1993;88:730-5.
2. Prandoni P, Lensing AWA, Prins MH, Bernardi E, Marchiori A, Bagatella P, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med. 2002;137:955-60.
3. Prandoni P, Prins MH, Lensing AWA, Ghirarduzzi A, Ageno W, Imberti D, et al. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009;150:577-85.
4. Piovella F, Crippa L, Barone M, Vigano D'Angelo S, Serafini S, Galli L, et al. Normalization rates of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with recurrence and new thrombosis. Haematologica. 2002;87:515-22.
5. Young L, Ockelford P, Milne D, Rolfe-Vyson V, McKelvie S, Harper P. Post treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality. J Thromb Haemost. 2006;4:1919-24.
Conflict of Interest:
None declared
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Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients with DVT
Submit responseTO THE EDITOR:
We have read with interest the recent study by Prandoni and colleagues (1), who compared a fixed-duration versus a flexible-duration of anticoagulation in patients with proximal DVT. Fixed-duration was defined according to guidelines as 3 months for secondary and 6 months for unprovoked DVT, whereas flexible-duration was prolonged until complete recanalisation occurred for up to 12 and 24 months, respectively. The topic is of high interest, especially because current guidelines (2) recommend a reevaluation of DVT patients after three months of anticoagulation, but give no clear recommendations about how it should be performed.
Even though the study was set up as a randomized trial and could have helped tackling this important question, it has some drawbacks that we believe seriously threaten the validity of the results obtained. First, mean anticoagulation treatment in the fixed-duration group was 4.7 months, whereas in the flexible-duration group mean length of therapy was almost doubled with 7.4 months. It is well known that the risk for thromboembolic recurrence is highest shortly after a first event and after cessation of anticoagulation and diminishes with time (3,4). Hence a prolongation of anticoagulation in one study arm inevitably leads to a decreased event rate, independent of the criteria used for deciding on prolongation of the treatment. This means that even completely unrelated criteria would lead to a decreased event rate in the prolonged study arm and thus, in our opinion, invalidates the conclusion drawn by the authors. The fact that the cumulative incidence rates shown differ primarily during the first 10- 12 months and become parallel later on is indicative for such an effect.
Second, although mentioned in the statistical analysis section, the authors do not provide adequate statistics (i.e. p-values) for their primary results and did not perform log-rank tests to assure that the Kaplan-Meier analysis shown does reach the required significance level. The reader is thus required to validate the results from the number of events presented in Table 2, which does not provide evidence for a significant difference between flexible and fixed-duration using Fisher's exact test statistics (p=0.08 for unprovoked DVT, p=0.81 for secondary DVT, p=0.09 for both combined).
Even though information for guidance for anticoagulation duration is of outmost interest, we have serious doubts that the study, due to the above mentioned shortcomings in design and presentation, will allow for clarification on this issue and help guiding us in treating DVT patients.
References
(1)Prandoni P, Prins MH, Lensing AWA, Ghirarduzzi A, Ageno W, Imberti D, Scannapieco G, Ambrosio GB, Pesavento R and Cuppini S: Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis. Ann Intern Med 150:577-585, 2009
(2)Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE and Comerota AJ: Antithrombotic Therapy for Venous Thromboembolic Disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 133:454-545, 2009
(3)Kearon C, Gent M, Hirsh J, et al.: A Comparison of Three Months of Anticoagulation with Extended Anticoagulation for a First Episode of Idiopathic Venous Thromboembolism. N Engl J Med 340:901-907, 1999
(4)Douketis JD, Gu CS, Schulman S, Ghirarduzzi A, Pengo V and Prandoni P: The Risk for Fatal Pulmonary Embolism after Discontinuing Anticoagulant Therapy for Venous Thromboembolism. Ann Intern Med 147:766- 774, 2007
Conflict of Interest:
None declared
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Too Prevalent Residual Thrombus
Submit responsePrandoni et al. showed that tailored duration of anticoagulation depending on ultrasonography findings can provide better outcomes (1). However, the study subjects had surprisingly high rate of residual thrombus after finishing recommended duration of anticoagulation: 29.4% of subjects on fixed OAT (oral anticoagulant therapy) had residual thrombus and 53.0% of subjects on flexible OAT received treatment longer than recommended because of non-recanalized ultrasonography findings. In comparison, 1.6% and 2.6% of the subjects who received anticoagulation for three and six months respectively had treatment failure in a recent study (2). In fact, residual thrombus after treatment of DVT is shown to be a risk factor of recurrent DVT (3). Therefore, better outcomes in flexible OAT may have resulted from high rate of residual thrombus in the study population and may not be applicable to other populations.
References
(1) Prandoni P, Prins MH, Lensing AWA, Ghirarduzzi A, Ageno W, Imberti D, Scannapieco G, Ambrosio GB, Pesavento R and Cuppini S: Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis. Ann Intern Med 150:577-585, 2009
(2) Campbell IA, Bentley DP, Prescott RJ and Routledge PA: Shetty, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 334:674, 2007
(3) Young L, Ockelford P, Milne D, Rolfe-Vyson V, McKelvie S and Harper P: Post-treatment residual thrombus increases the risk of recurrent deep vein thrombosis and mortality. Journal of Thrombosis and Haemostasis 4:1919-1924, 2006
Conflict of Interest:
None declared
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Risky jobs and personalized protocols
Submit responseIn fields such as law enforcement, homeland security and firefighting physicians may be asked to consider whether a patient can take risks associated with his job. Anticoagulation poses certain risks and risk of recurrent VTE is also a consideration. Unemployment is also hazardous to a person's health. Perhaps such tools as ultrasound and D-Dimer can offer more precision in advising individual patients than population based protocols when issues of employability and job safety are also important parameters.
Conflict of Interest:
None declared