SEARCH

SEARCH BY CITATION

Keywords:

  • deep vein thrombosis;
  • pulmonary embolism;
  • recurrence;
  • residual vein thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

See also Watson HG. RVO – Real value obscure. This issue, pp 1116–8; Carrier M, Rodger MA, Wells PS, Righini M, Le Gal G. Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis. This issue, pp 1119–25.

Summary. Objectives: There is growing interest in using residual vein obstruction (RVO) to guide the duration of oral anticoagulant therapy (OAT) for unprovoked deep vein thrombosis (DVT). We sought to determine if RVO as determined by compression ultrasonography (CUS) after completion of 5–7 months of anticoagulation for unprovoked DVT is associated with an increased risk of recurrent venous thromboembolism (VTE). Materials and Methods: This was a multicentre multinational prospective cohort study undertaken in tertiary care centers. Patients with a first ‘unprovoked’ major VTE were enrolled over a 4-year period and completed a mean 18-month follow-up in September 2006. All 452 patients with DVT had baseline CUS at inclusion to assess any RVO before stopping OAT at 5–7 months. During follow-up off OAT, all episodes of suspected recurrent VTE were independently adjudicated with reference to baseline imaging. Results: Forty-five out of 231 patients with abnormal CUS (19.5%) had recurrent VTE during follow-up, as compared with 32 out of 220 patients with normal CUS (14.6%), and one patient had inadequate CUS. There was no significant association between an abnormal CUS at inclusion and the risk of recurrent VTE: hazard ratio 1.4 (95% confidence interval, 0.9–2.1), P = 0.19. None of the different degrees of clot resolution on baseline CUS was statistically significantly associated with the risk of recurrent VTE. Conclusion: In our study, the presence of RVO at the time of OAT withdrawal was not associated with a statistically significant higher risk of recurrent VTE. RVO assessment may not be useful to guide duration of anticoagulation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

The duration of oral anticoagulant therapy (OAT) in patients after a first episode of venous thromboembolism (VTE) that is not provoked by a major risk factor is controversial. In patients with unprovoked VTE, the risk of recurrence after OAT withdrawal is high [1–4]. On the other hand, OAT is very effective at reducing the risk of recurrence as long as the treatment is continued, but this benefit appears to be reduced after discontinuation [1,5]. Moreover, the benefits while on OAT need to be balanced against the main adverse event of OAT: major bleeding [1,2,4,6]. The risk of major bleeding appears lower than the risk of recurrent VTE. However, the estimation of the risk-benefit balance is further complicated by the fact that the case fatality rate of a major bleed is 3-fold higher than that of a recurrent VTE following anticoagulation, 11.3% vs. 3.6%, respectively [7]. Overall, the risk benefit balance of indefinite anticoagulation is unknown in patients with a first unprovoked VTE.

Among patients with unprovoked VTE, the benefits of prolonged OAT may clearly outweigh risks in some subgroups at high risk of recurrent VTE, but may be completely offset by the risk of bleeding in subgroups at lower risk of recurrent VTE. Ongoing research attempts to identify such subgroups, based on individual risk factor assessment, which could be useful in helping to tailor clinical decision making [8]. Several risk factors have been studied, including characteristics of the index event (location of VTE), demographic characteristics of patients (age, gender and ethnicity), and parameters related to hemostasis (thrombophilia, D-dimer and thrombin generation assays) [9]. Also, much attention has been paid to patients with persistent residual thrombi in lower limb veins after an initial 3–6 months OAT course [10–17]. Indeed, residual lower limb venous obstruction (RVO) could be associated with an increased risk of recurrent VTE, possibly because RVO either might impair ipsilateral venous outflow and be a possible trigger for coagulation activation and therefore for recurrent VTE, or reflect an underlying generalized hypercoagulable state [13]. Reported relative risks of recurrent VTE in patients with RVO as compared with patients with no RVO range from 0.6 (95% confidence interval (CI), 0.1–2.7) [18] to 24.9 (95% CI, 3.4–183.6) [16]. Differences in estimates of association between RVO and recurrent VTE might be due to heterogeneity in included patient populations (unprovoked-only vs. unselected VTE patients, or first VTE episode vs. first and recurrent VTE), in inter-operator reliability, and in definitions of RVO.

Therefore, we sought to examine among patients included in the REVERSE study – a prospective cohort study that had a primary aim of developing a clinical prediction rule for recurrent VTE after a first unprovoked episode – the relationship between RVO and the risk of recurrent VTE in patients with unprovoked deep vein thrombosis (DVT).

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

The REVERSE study

The REVERSE study was a prospective cohort study designed to derive a clinical decision rule to identify patients at low risk for recurrent VTE after completion of 5–7 months of anticoagulant therapy for a first unprovoked VTE [8]. Institutional research ethics board approval was obtained at all participating centers. All consecutive unselected patients seen in clinics by participating physicians for VTE follow-up at 12 tertiary care centers in four countries were asked to participate if they had: (i) a first episode of unprovoked objectively proven VTE 5–7 months prior to enrollment initially treated with > 5 days of heparin, followed by 5–7 months of oral anticoagulants (target International Normalized Ratio 2–3); and (ii) no recurrent VTE during the treatment period. At the time the REVERSE study was performed, all participating centers treated patients with a first unprovoked VTE for at least 6 months, and none of them used compression ultrasonography (CUS) at 3 months to decide on treatment duration. Diagnosis of DVT required a non-compressible segment on CUS of lower limb proximal veins. Diagnosis of pulmonary embolism (PE) required a high probability ventilation-perfusion (V/Q) scan or a segmental or larger artery filling defect on chest computed tomography (CT) scan. A first unprovoked VTE was defined as VTE occurring in the absence of a leg fracture or lower extremity plaster cast, immobilization for more than 3 days, or surgery using a general anesthetic in the 3 months prior to the index VTE event, and without diagnosis of malignancy in the prior 5 years at the time of enrollment. Patients were excluded if they were unable or unwilling to consent, were under the age of 18 years, had already discontinued anticoagulant therapy, required ongoing anticoagulation for reasons other than VTE, were geographically inaccessible for follow-up, or were being treated for a recurrent unprovoked VTE or a previously known high-risk thrombophilia, defined as known deficiency of protein S, protein C or antithrombin, known persistently positive anticardiolipin antibodies (> 30 U mL−1), a known persistently positive lupus anticoagulant or two or more known defects (e.g. homozygous for factor V Leiden (FVL) or prothrombin gene mutation (PGM), or compound heterozygous for FVL and PGM). Thrombophilia testing was not systematically conducted prior to enrollment; patients were only excluded if their high risk thrombophilias were known (i.e. identified prior to enrollment).

Baseline imaging assessment

After obtaining written informed consent, all patients underwent standardized data collection including demographic characteristics, non-major risk factors (pregnancy or post-partum period, current medications, history of myocardial infarction, stroke or heart failure, varicose veins, obesity, family history of VTE, history of previous secondary VTE, and IVC filter insertion) for venous thromboembolism at the time of index event, and imaging reports confirming the index (i.e. initial) venous thromboembolic event (5–7 months earlier). All patients then underwent baseline imaging: CUS of the leg(s) if the patient had DVT signs or symptoms at the time of the index event, and/or V/Q scan if the patient had PE signs or symptoms at the time of index event. CUS consisted of a real-time B-mode examination of the proximal veins over their entire length from the iliac vein to the trifurcation of the popliteal vein, in the leg that was symptomatic at the time of the index event. A standardized CUS report form was used at all centers. Ultrasonographers were asked to classify the patient as having a normal, abnormal or inadequate CUS. In the case of abnormal CUS, they were also asked to specify whether they observed a minimal wall thickening (≤ 5% of maximum vein diameter compressible), a partial resolution (≥ 40% of maximum diameter compressible), a minimal resolution (< 40% of maximum diameter compressible), no resolution (compressible diameter same as previous findings), or worsened thrombus (new thrombus in area where there was no previous thrombus). Finally, for each residual thrombus seen at CUS, its location (distance in centimeters between the thrombus proximal termination and the sapheno-femoral junction), its length (in centimeters) and the diameter of the vein under compression as well as when not compressed were recorded and drawn on a chart of the lower limb venous system.

Follow-up

After baseline imaging was obtained, patients were instructed to stop their anticoagulant treatment and to contact study personnel if they developed symptoms of recurrent VTE during follow-up. They were also seen in clinic at least every 6 months and asked about signs and symptoms of recurrent VTE. No systematic screening test for VTE was performed during follow-up. Patients with symptoms suggestive of recurrent VTE underwent a standardized diagnostic strategy that included comparison of imaging tests at the time of suspected recurrent event with baseline imaging conducted at the time of study enrollment, as previously described [19]. A case report form was completed for all suspected recurrent VTE during follow-up. All documents related to suspected recurrent VTE (clinical notes, laboratory results and imaging tests) were collected and sent along with the local decision to the coordinating center. All suspected symptomatic VTE events and deaths during follow-up were independently adjudicated by two physicians.

Data analysis

Participants were withdrawn and censored at the time they withdrew consent, were started on anticoagulants for a reason other than VTE or were lost to follow-up. Observation time was defined as the time at risk from the end of the anticoagulant treatment for the index VTE to the first recurrent VTE or withdrawal date. Incidence rates of recurrent VTE were calculated as the number of recurrent VTEs over the number of person-years of follow-up. The Cox proportional hazards model was used to compare risks between groups. For analyses relating the degree of RVO to recurrent VTE, the most significant residual thrombus was used in patients with more than one anatomical site involved.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Between October 2001 and March 2006, 646 participants were enrolled. The median age of participants was 53 years (range 18–95), 49% were female and the majority (92.4%) were Caucasians. After a median follow-up of 16 months (range, 1–47 months; interquartile range, 6–25 months), 91 patients (14.1%) had an adjudicated recurrent VTE. The annual risk of recurrent VTE was 9.3% (95% CI, 7.7–11.3%). Index events included 194 (30%) isolated PE, 339 (52.5%) isolated DVT and 113 (17.5%) cases of both DVT and PE. The study flow-chart is displayed in Fig. 1.

image

Figure 1.  Study flow-chart.

Download figure to PowerPoint

General characteristics of the 452 patients with either an isolated DVT or a DVT associated with PE are shown in Table 1. After a mean follow-up of 17 months (interquartile range, 6–24 months), 77 out of these 452 patients with index DVT (17.0%) had an adjudicated recurrent VTE: annual risk 12.1% (95% CI, 9.4–14.8%). Recurrent VTE occurred after a mean period of 10 months (range, 1–39 months; interquartile range, 3–16 months). All had baseline CUS at inclusion. CUS was normal in 220 patients (48.7%), abnormal in 231 patients (51.1%) and inadequate in one (0.2%) (low-quality image not allowing patient’s classification). Forty-five out of 231 patients with abnormal CUS (19.5%) had recurrent VTE during follow-up, as compared with 32 out of 220 patients with normal CUS (14.6%). There was no significant association between an abnormal CUS at inclusion and the risk of recurrent VTE: hazard ratio 1.4 (95% CI, 0.9–2.1), P = 0.19. A Kaplan–Meier survival curve is displayed in Fig. 2. Of note, in all patients diagnosed with ipsilateral recurrent DVT and in whom RVO had been seen at baseline, the diagnosis of recurrent DVT was made on the basis of the presence of a thrombus in a previously free vein segment.

Table 1.   General characteristics of the 452 patients with DVT at initial presentation
Characteristicsn (%) or mean (SD)
  1. SD, standard deviation.

Female gender203 (44.9)
Age, years54 (17)
Weight, kg89 (22)
Height, cm172 (11)
Body mass index, kg m229.5 (6.8)
D-dimer, ng mL−1 (Vidas D-dimer)312 (421)
Any hyperpigmentation, edema or redness in either leg184 (46)
image

Figure 2.  Cumulative incidence of recurrent VTE according to baseline CUS results.

Download figure to PowerPoint

Of the 231 patients with abnormal CUS, 11 (5.0%) had minimal wall thickening, 78 (35.3%) had a partial thrombus resolution (40% or more of the vein diameter compressible), 52 (23.5%) had minimal resolution (< 40% of the vein diameter compressible), and 23 (10.4%) had stable (n = 19) or worsened thrombus (n = 4). In 57 patients, the initial CUS performed at the time of index DVT diagnosis was not available for comparison. Finally, information was missing in the 10 remaining patients, in whom the examiner quoted the CUS as ‘abnormal’ but didn’t specify the degree of thrombus improvement. Corresponding cumulative risks of recurrent VTE and hazard ratios are presented in Table 2. None of the different degrees of clot resolution at baseline CUS was statistically significantly associated with the risk of recurrent VTE (Fig. 3). Combining patients with minimal thrombus resolution and stable or worsened thrombus did not change the results (data not shown).

Table 2.   Cumulative risks of recurrent VTE and hazard-ratio for recurrent VTE for patients with different degrees of CUS abnormality as compared with patients with normal CUS at baseline
CUS resultnCumulative risk of recurrent VTEHazard-ratio (95% CI), P
  1. *Results of CUS at the time of index DVT unavailable for comparison (n = 57); missing information (n = 10).

Normal22032/220 (14.6%)1
Abnormal CUS231  
 Minimal wall thickening112/11 (18.2%)1.0 (0.2–4.1), 0.97
 Partial thrombus resolution789/78 (11.5%)0.7 (0.3–1.5), 0.41
 Minimal thrombus resolution529/52 (17.3%)1.4 (0.7–2.9), 0.41
 Stable/worsened thrombus235/23 (21.7%)1.6 (0.6–4.1), 0.33
 Missing data*6720/67 (29.8%) 
image

Figure 3.  Cumulative risk of recurrent VTE according to the degree of clot resolution at baseline CUS.

Download figure to PowerPoint

Presence of RVO according to the criteria used by Prandoni and Cosmi (i.e. RVO deemed absent if the vein diameter was 2.0 mm or less under compression) could be assessed in all but 50 patients for whom vein diameter data under compression were missing. One hundred and seventy-eight out of 402 (44.3%) evaluable patients had RVO. Of these 35/178 (19.7%) had a recurrent VTE, as compared with 32/224 (14.3%) of patients without RVO (log-rank P-value, 0.20). Presence of RVO according to the criteria described by Piovella and Siragusa (i.e. no RVO if the residual thrombus occupies 40% or less of the vein diameter) could not be assessed in 58 patients. One hundred and forty-nine out of 394 (37.8%) evaluable patients had RVO. The risk of recurrent VTE was 28/149 (18.8%) in patients with RVO, as compared with 37/245 (15.1%) in patients with no RVO (log-rank P-value, 0.47).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

In patients included in the REVERSE cohort study after a first episode of unprovoked VTE, among those with a DVT at index event, we found no statistically significant association between residual vein obstruction on compression ultrasonography at baseline (i.e. when enrolled 5–7 months after the index [or initial] DVT) and the risk of recurrent VTE during follow-up. Patients with an abnormal baseline CUS (minimal wall thickening, and partial and minimal resolution) had no significantly increased risk of recurrent VTE as compared with patients with normal CUS at baseline.

This study presents an important negative finding. As detailed below, there is increasing enthusiasm for using RVO to guide duration of anticoagulation [14]. These approaches, if adopted, will be cumbersome for patients and clinicians and resource-intensive for health care systems and as such must be thoroughly investigated prior to adoption.

Previous studies examining the association between RVO and subsequent recurrent VTE have yielded discrepant results. However, comparison between studies is difficult because of differences in study design, definition of RVO and patient’s characteristics. Firstly, different definitions have been used to characterize RVO. Piovella et al. [12] chose to define RVO as residual thrombus occupying, at maximum compressibility, more than 40% of the vein area calculated in the absence of compression. This definition was later used in the DACUS study by Siragusa et al. [16]. In studies performed by Prandoni et al. [13,14] and Cosmi et al. [10,17], veins were considered recanalized if the diameter under compression was equal to or < 2.0 mm in a single measurement, or equal to or < 3.0 mm on two consecutive examinations at least 3 months apart. Other studies provided no clear definition [2,6,18,20]. Notably, we found no significant association between residual vein obstruction as defined by any of these criteria and the risk of recurrent VTE. Secondly, some studies evaluated patients for RVO at the time of OAT withdrawal, whereas others performed repeated ultrasonography every 3–6 months during follow-up. However, the risk of recurrent VTE is maximal at the time of OAT withdrawal and then decreases over time [21]. Moreover, vein recanalization improves over time even after the first 3–6 months of OAT [13]. Thus, categorizing patients as having RVO or not on the basis of the last performed ultrasound rather than on the ultrasound performed at the time of OAT withdrawal might lead to different conclusions. Thirdly, clinical characteristics of included patients differed widely across studies. Some studies included patients with either proximal or distal DVT [11,18,20] whereas others only included patients with proximal DVT [2,6,10,14,16]. Duration of initial anticoagulant treatment also varied, with some studies recruiting patients after a fixed duration of anticoagulation [16] and others recruiting patients after variable durations of anticoagulation [11–13]. Given that RVO is time dependant and that duration of anticoagulation might influence the risk of recurrent VTE, evaluation after a fixed duration of anticoagulation would be likely to result in more robust estimates of association. In one study, 15% of patients underwent catheter-directed or systemic thrombolysis [20], which may influence RVO at the time of OAT withdrawal. Definition of recurrent VTE differed, and suspected outcomes were not independently adjudicated in all studies. Provoked and/or unprovoked DVT patients were included in some studies [11,16]. Presence of a major risk factor for DVT (active malignancy, surgery, immobilization or leg fracture/cast) is recognized as one of the most powerful predictors of recurrent VTE. This could be an important confounding factor, should an association exist between the presence of such major risk factors and RVO.

Clinical management studies have also been conducted examining approaches that use RVO as a guide to duration of anticoagulation. Siragusa et al. [16] reported on a combined cohort study and randomized trial where patients with DVT (provoked and unprovoked) had RVO assessment after 3 months of anticoagulation. In the cohort of 78 patients whose veins had recanalized (< 40% residual venous obstruction), anticoagulation was discontinued, and the risk of recurrent VTE was 1.3% (95% CI, 1–7%). However, 77% of patients with RVO had unprovoked VTE whereas this proportion was only 36% in patients without RVO. Indeed, in the cohort of patients with < 40% RVO, only 28 patients had unprovoked DVT and one developed recurrent VTE (3.6%; 95% CI, 0–19%). Therefore it remains unknown whether this approach is safe in unprovoked DVT patients, the group for whom the optimal duration of anticoagulation remains unclear. Prandoni et al. [14] recently reported a randomized trial comparing the risk of recurrent VTE in DVT patients (provoked and unprovoked) with a fixed duration of anticoagulation vs. duration of anticoagulation guided by RVO. In the latter group, anticoagulation was stopped when vein recanalization (< 2 mm residual obstruction on one measurement or < 3 mm obstruction on two measurements) was documented on repeat compression ultrasound imaging at 3, 9, 15 and 21 months. Patients remaining on anticoagulation at 21 months then discontinued therapy and all study patients were then followed for an additional year (total 33 months after enrollment). Cumulative recurrent VTE in the unprovoked DVT patients at 33 months was not statistically significantly different in the CUS-guided group (24/155, 15%; 95% CI, 10–22%) compared with the fixed duration group (36/151, 24%; 95% CI, 17–31%). Hence, again, it remains unknown whether this approach is safe in unprovoked DVT patients, the group for whom the clinical decision regarding duration of anticoagulation is unclear.

Also of critical importance, prior to adopting a clinical diagnostic or prognostic test in clinical practise, its interobserver reliability must be demonstrated in real world settings to ensure generalizability. Linkins et al. [22] have demonstrated that interobserver reliability of residual CUS measurements is poor, with a mean difference of 2 mm (95th centile for the difference, 8 mm) between two experienced expert observers in a tertiary care center. This poor reproducibility is a significant limitation necessitating more standardized measurement approaches prior to adoption.

It is important to note the limitations of our study. First, although data were captured prospectively and RVO assessment was part of a priori defined potential candidate predictors for recurrent VTE, this study is a post-hoc analysis of the REVERSE cohort study. Second, as noted above, compression ultrasonography results are operator dependent. Ultrasonography, while performed with an a priori standardized approach, was performed by multiple technologists in multiple centers, and therefore while our findings may represent the ‘real world’ lack of association between RVO and recurrent VTE, it is possible that more precisely measured RVO and recurrent VTE are associated. Finally, despite a relatively large sample size, the upper bound of the 95% confidence interval around the hazard ratio estimate was 2.1. Therefore, we can not exclude that a larger sample size would not detect a statistically significant difference.

In conclusion, in the REVERSE study, presence of RVO at the time of OAT withdrawal was not associated with a statistically significant higher risk of recurrent VTE. RVO assessment alone may not be discriminant enough to guide clinicians on the duration of anticoagulant therapy in patients with a first unprovoked proximal deep vein thrombosis.

Addendum

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

Conception and design: M. Rodger, G. Le Gal, M. J. Kovacs, S. R. Kahn, P. S. Wells, D. A. Anderson. Administrative support: P. S. Wells, M. Rodger, R. White. Grant funding: M. J. Kovacs, S. R. Kahn, M. Rodger. Data acquisition: all authors. Data analysis: G. Le Gal, M. Carrier, M. Rodger. Drafting of the paper: G. Le Gal, M. Carrier, M. Rodger. Critical revision for important intellectual content: M. J. Kovacs, S. R. Kahn, M. Righini, M. T. Betancourt. Final approval of the manuscript: all authors.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

M. Carrier is a recipient of a Canadian Institute for Health Research RCT mentoring award. S. R. Kahn is a recipient of a Clinical Investigator Award from the Fonds de la Recherche en Santé du Québec. P. S. Wells is a recipient of a Canada Research Chair. M. Crowther holds a Career Investigator Award from the Heart and Stroke Foundation. M. Rodger was the recipient of the Maureen Andrew New Investigator Award and a Career Investigator Award from the Heart and Stroke Foundation of Canada. We thank the staff and patients from the thrombosis clinics that participated in the study. This study was funded by the Canadian Institutes of Health Research (Grant # MOP 64319) and BioMerieux (through an unrestricted research grant). G. Le Gal and M. Rodger had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References

BioMerieux had no role in the: design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. The Canadian Institutes of Health Research reviewed the design of the study but had no role in the: conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  • 1
    Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Moia M, Guazzaloca G, Bertoldi A, Tomasi C, Scannapieco G, Ascani A, Villalta S, Frulla M, Mosena L, Girolami A, Vaccarino A, Alatri A, Palareti G, Marchesi M, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001; 345: 1659.
  • 2
    Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA, Johnston M, Douketis J, Roberts R, van Nguyen P, Kassis J, Dolan S, Demers C, Desjardins L, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 9017.
  • 3
    Prandoni P, Noventa F, Ghirarduzzi A, Pengo V, Bernardi E, Pesavento R, Iotti M, Tormene D, Simioni P, Pagnan A. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92: 199205.
  • 4
    Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 142534.
  • 5
    Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M, Imberti D, Poggio R, Ageno W, Pogliani E, Porro F, Zonzin P. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003; 139: 1925.
  • 6
    Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, MacKinnon B, Weitz JI, Crowther MA, Dolan S, Turpie AG, Geerts W, Solymoss S, van Nguyen P, Demers C, Kahn SR, Kassis J, Rodger M, Hambleton J, Gent M. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003; 349: 6319.
  • 7
    Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152: 57889.
  • 8
    Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179: 41726.
  • 9
    Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol 2009; 29: 298310.
  • 10
    Cosmi B, Legnani C, Iorio A, Pengo V, Ghirarduzzi A, Testa S, Poli D, Tripodi A, Palareti G. Residual venous obstruction, alone and in combination with D-dimer, as a risk factor for recurrence after anticoagulation withdrawal following a first idiopathic deep vein thrombosis in the prolong study. Eur J Vasc Endovasc Surg 2010; 39: 35665.
  • 11
    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: 191924.
  • 12
    Piovella F, Crippa L, Barone M, Vigano D’Angelo S, Serafini S, Galli L, Beltrametti C, D’Angelo A. 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: 51522.
  • 13
    Prandoni P, Lensing AW, Prins MH, Bernardi E, Marchiori A, Bagatella P, Frulla M, Mosena L, Tormene D, Piccioli A, Simioni P, Girolami A. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137: 95560.
  • 14
    Prandoni P, Prins MH, Lensing AW, Ghirarduzzi A, Ageno W, Imberti D, Scannapieco G, Ambrosio GB, Pesavento R, Cuppini S, Quintavalla R, Agnelli G. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med 2009; 150: 57785.
  • 15
    Poli D, Antonucci E, Ciuti G, Abbate R, Prisco D. Combination of D-dimer, F1 + 2 and residual vein obstruction as predictors of VTE recurrence in patients with first VTE episode after OAT withdrawal. J Thromb Haemost 2008; 6: 70810.
  • 16
    Siragusa S, Malato A, Anastasio R, Cigna V, Milio G, Amato C, Bellisi M, Attanzio MT, Cormaci O, Pellegrino M, Dolce A, Casuccio A, Bajardi G, Mariani G. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the “DACUS” study. Blood 2008; 112: 5115.
  • 17
    Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G. D-dimer levels in combination with residual venous obstruction and the risk of recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis. Thromb Haemost 2005; 94: 96974.
  • 18
    Kearon C, Ginsberg JS, Anderson DR, Kovacs MJ, Wells P, Julian JA, Mackinnon B, Demers C, Douketis J, Turpie AG, van Nguyen P, Green D, Kassis J, Kahn SR, Solymoss S, Desjardins L, Geerts W, Johnston M, Weitz JI, Hirsh J, et al. Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor. J Thromb Haemost 2004; 2: 7439.
  • 19
    Le Gal G, Kovacs MJ, Carrier M, Do K, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Perrier A, White RH, Vickars L, Rodger M. Validation of a diagnostic approach to exclude recurrent venous thromboembolism. J Thromb Haemost 2009; 7: 7529.
  • 20
    Kim TM, Kim JS, Han SW, Hong YS, Kim I, Ha J, Kim SJ, Chung JW, Park JH, Lee D, Park S, Kim BK, Kim NK, Yoon SS. Clinical predictors of recurrent venous thromboembolism: a single institute experience in Korea. Thromb Res 2009; 123: 43643.
  • 21
    Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 17.
  • 22
    Linkins LA, Stretton R, Probyn L, Kearon C. Interobserver agreement on ultrasound measurements of residual vein diameter, thrombus echogenicity and Doppler venous flow in patients with previous venous thrombosis. Thromb Res 2006; 117: 2417.