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Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis: A Randomized Trial

Paolo Prandoni, MD, PhD; Martin H. Prins, MD, PhD; Anthonie W.A. Lensing, MD, PhD; Angelo Ghirarduzzi, MD; Walter Ageno, MD; Davide Imberti, MD; Gianluigi Scannapieco, MD; Giovanni B. Ambrosio, MD; Raffaele Pesavento, MD; Stefano Cuppini, MD; Roberto Quintavalla, MD; Giancarlo Agnelli, MD, AESOPUS Investigators
[+] Article and Author Information

ClinicalTrials.gov registration number: NCT00380120.

For additional AESOPUS investigators, see the Appendix.


From University of Padua, Padua, Italy; University of Maastricht, Maastricht, and University of Amsterdam, Amsterdam, the Netherlands; and Santa Maria Nuova Hospital, Reggio Emilia, University of Insubria, Varese, Hospital of Piacenza, Piacenza, Treviso Healthcare Trust, Treviso, Civic Hospital of Venice, Venice, Civic Hospital, Castelfranco Veneto, Civic Hospital, Rovigo, Civic Hospital of Parma, Parma, and University of Perugia, Perugia, Italy.


Acknowledgment: The authors thank all of their patients, without whom this study would not have been possible.

Potential Financial Conflicts of Interest: None disclosed.

Reproducible Research Statement:Study protocol: Available from Dr. Prandoni (e-mail, paoloprandoni@tin.it). Statistical code and data set: Available from Dr. Prins (e-mail, mh.prins@epid.unimaas.nl).

Requests for Single Reprints: Paolo Prandoni, MD, PhD, Department of Cardiothoracic and Vascular Sciences, Clinica Medica II, Thromboembolism Unit, University of Padua, Via Giustiniani 2, 35128 Padua, Italy; e-mail, paoloprandoni@tin.it.

Current Author Addresses: Dr. Prandoni: Department of Cardiothoracic and Vascular Sciences, Clinica Medica II, Thromboembolism Unit, University of Padua, Via Giustiniani 2, 35128 Padua, Italy.

Dr. Prins: Department of Clinical Epidemiology and Technology Assessment, University of Maastricht, PO Box 616, NL-6200 MD Maastricht, the Netherlands.

Dr. Lensing: Center for Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Box 22660, Amsterdam, the Netherlands.

Dr. Ghirarduzzi: Department of Internal Medicine, Angiology Unit, Arcispedale Santa Maria Nuova, Viale Risorgimento 80, I-42100 Reggio Emilia, Italy.

Dr. Ageno: Department of Clinical Medicine, University of Insubria, Viale Borri 57, 21100 Varese, Italy.

Dr. Imberti: Thrombosis and Haemostasis Center, Emergency Department, Hospital of Piacenza, Ospedale Civile, Via Taverna 49, I-29100 Piacenza, Italy.

Dr. Scannapieco: Committee for Thromboembolic Disease, Treviso Healthcare Trust, 31100 Treviso, Italy.

Dr. Ambrosio: Department of Internal Medicine, Civic Hospital of Venice, Venice, Italy.

Dr. Pesavento: Department of Angiology, Civic Hospital, Castelfranco Veneto, Italy.

Dr. Cuppini: Department of Internal Medicine, Civic Hospital, SOC of Medicine, ULSS 18-Rovigo, Viale Tre Martyrdoms 89, 45100 Rovigo, Italy.

Dr. Quintavalla: Azienda Ospedaliera-Universitaria di Parma, Via Gramsci 14, 43100 Parma, Italy.

Dr. Agnelli: Division of Internal and Cardiovascular Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Via Dottori 1, 06129 Perugia, Italy.

Author Contributions: Conception and design: P. Prandoni, G. Agnelli.

Analysis and interpretation of the data: M.H. Prins, A.W.A. Lensing.

Drafting of the article: P. Prandoni, M.H. Prins, A.W.A. Lensing, G. Scannapieco, G.B. Ambrosio.

Critical revision of the article for important intellectual content: A.W.A. Lensing, A. Ghirarduzzi, W. Ageno, D. Imberti, G. Scannapieco, G.B. Ambrosio, R. Pesavento, S. Cuppini, R. Quintavalla, G. Agnelli.

Final approval of the article: P. Prandoni, M.H. Prins, A.W.A. Lensing, A. Ghirarduzzi, W. Ageno, D. Imberti, R. Pesavento, S. Cuppini, R. Quintavalla, G. Agnelli.

Provision of study materials or patients: P. Prandoni, A. Ghirarduzzi, W. Ageno, D. Imberti, G. Scannapieco, G.B. Ambrosio, R. Pesavento, S. Cuppini, R. Quintavalla.

Statistical expertise: M.H. Prins.

Administrative, technical, or logistic support: P. Prandoni.

Collection and assembly of data: P. Prandoni, A. Ghirarduzzi, W. Ageno, D. Imberti.


Ann Intern Med. 2009;150(9):577-585. doi:10.7326/0003-4819-150-9-200905050-00003
Text Size: A A A

Background: The optimal duration of oral anticoagulant therapy in patients with deep venous thrombosis (DVT) of the lower extremities remains uncertain.

Objective: To assess whether tailoring the duration of anticoagulation on the basis of the persistence of residual thrombi on ultrasonography reduces the rate of recurrent venous thromboembolism (VTE) compared with the administration of conventional fixed-duration treatment in adults with proximal DVT.

Design: Parallel, randomized trial from 1999 to 2006. Trained physicians who assessed outcomes were blinded to patient assignment status, but patients and providers were not.

Setting: 9 university or hospital centers in Italy.

Patients: 538 consecutive outpatients with a first episode of acute proximal DVT at completion of an uneventful 3-month period of anticoagulation.

Intervention: Patients were randomly assigned (stratified by center and secondary vs. unprovoked DVT by using a computer-generated list that was accessible only to a trial nurse) to fixed-duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial.

Measurements: The rate of confirmed recurrent VTE during 33 months of follow-up.

Results: Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67).

Limitations: The trial lacked a double-blind design. The sample size was not powered to detect differences in bleeding between groups and to detect effectiveness of the intervention in the subgroups of patients with unprovoked and secondary DVT. Patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded.

Conclusion: Tailoring the duration of anticoagulation on the basis of ultrasonography findings reduces the rate of recurrent VTE in adults with proximal DVT.

Primary Funding Source: None.

Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

DVT = deep venous thrombosis; OAT = oral anticoagulant therapy; VTE = venous thromboembolism.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Cumulative incidence of recurrent thromboembolism.

OAT = oral anticoagulant therapy; VTE = venous thromboembolism.

Grahic Jump Location

Tables

References

Letters

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Comments

Submit a Comment
Risky jobs and personalized protocols
Posted on May 21, 2009
Linda D Green
Prince George's Hospital Center
Conflict of Interest: None Declared

In 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

Too Prevalent Residual Thrombus
Posted on May 26, 2009
Jongoh Kim
Albert Einstein Medical Center
Conflict of Interest: None Declared

Prandoni 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

Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients with DVT
Posted on June 4, 2009
Stephan Imfeld
University Hospital, Basel, Switzerland
Conflict of Interest: None Declared

TO 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

Residual thrombosis and recurrent thromboembolism
Posted on June 22, 2009
Paolo Prandoni
Department of Cardiothoracic and Vascular Sciences, University of Padua, Italy
Conflict of Interest: None Declared

In 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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Summary for Patients

Residual Thrombosis to Guide the Duration of Anticoagulation

The summary below is from the full report titled “Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis. A Randomized Trial.” It is in the 5 May 2009 issue of Annals of Internal Medicine (volume 150, pages 577-585). The authors are P. Prandoni, M.H. Prins, A.W.A. Lensing, A. Ghirarduzzi, W. Ageno, D. Imberti, G. Scannapieco, G.B. Ambrosio, R. Pesavento, S. Cuppini, R. Quintavalla, and G. Agnelli, for the AESOPUS Investigators.

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