- Email: [email protected]
Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment
Eur J Vasc Endovasc Surg (2016)
-,
1e7
Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment M. Sartori
a,*
, G. Lessiani b, E. Favaretto a, L. Migliaccio a, M. Iotti c, L. Giusto d, A. Ghirarduzzi c, G. Palareti e, B. Cosmi
a
a
Department of Angiology and Blood Coagulation, University Hospital S. Orsola-Malpighi, Bologna, Italy Angiology Unit, Medicine and Geriatric Department, “Villa Serena” Hospital, Città Sant’Angelo, Pescara, Italy Angiology Unit, Arcispedale S. Maria Nuova, Reggio Emilia, Italy d Non-invasive Vascular Diagnostic Unit, University Hospital S. Anna, Ferrara, Italy e Cardiovascular Diseases, University of Bologna, Bologna, Italy b c
WHAT THIS PAPER ADDS Calf deep vein thrombosis (CDVT) ultrasound diagnostic criteria are still debated. A clot 3.5 mm may be an appropriate threshold for CDVT diagnosis. Six week heparin treatment is associated with recanalization in half of patients with CDVT.
Objective/Background: Calf deep vein thrombosis (CDVT) is frequently found in symptomatic outpatients, but CDVT ultrasound diagnostic criteria are still debated. It has been proposed that only clots with 5 mm maximum diameter can be considered as CDVT. Aims: To assess clot diameters and characteristics of CDVT, and to assess the recanalization rate of CDVT after anticoagulant treatment. Methods: In a prospective, multicenter cohort study symptomatic outpatients in whom CDVT was diagnosed by ultrasound were enrolled. Posterior tibial, fibular, medial and lateral gastrocnemius, and soleal veins were compressed transversally over their entire length. Clot diameter was measured during maximum compression and ultrasound was repeated after 6 weeks of low molecular weight heparin treatment. Results: In 172 patients (age 70 1 y, male 32%) CDVT was detected in 132 (76.7%) muscle veins only, and in 24 (14%) axial veins only, while 16 (9.3%) patients had both muscular and axial CDVT. A total of 212 clots were found with a diameter of 5.8 1.8 mm (IQR 4.5e6.8 mm) with the 10th percentile being 3.5 mm. A cut off value of 5 mm had a sensitivity of 0.76 (95% CI 0.69e0.82), whereas a value of 3.5 mm had a sensitivity of 0.94 (95% CI 0.89e0.97). Recanalization (i.e. residual vein obstruction 2 mm) was found in 51% of patients and the recanalization rate was not correlated with clot diameter at enrolment (rho 0.128 p ¼ 0.93) or with type of CDVT (axial vs. muscular thrombosis). Patients with significantly reduced mobility had lower probability of CDVT recanalization. Conclusion: A clot diameter 5 mm is found in only 76% of CDVT patients and a clot diameter 3.5 mm may be more appropriate as a threshold for CDVT. After 6 weeks of anticoagulant treatment, half of CDVT patients had recanalization and recanalization was not correlated with clot characteristics at enrolment, but with mobility of the patients. Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 17 January 2016, Accepted 19 July 2016, Available online XXX Keywords: Calf deep vein thrombosis, Clot diameter, Heparin, Isolated distal deep vein thrombosis, Residual venous obstruction, Whole leg ultrasound
INTRODUCTION Calf deep vein thrombosis (CDVT), defined as thrombosis confined to the infrapopliteal veins of the lower limbs, is a frequent finding in symptomatic outpatients.1 Compression * Corresponding author. Angiology and Haemostasis Unit, University Hospital of Bologna, Policlinico Sant’Orsola Malpighi, Via Albertoni, 15, 40138 Bologna, Italy. E-mail address: [email protected] (M. Sartori). 1078-5884/Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2016.07.022
ultrasound has been widely investigated for the diagnosis of iliofemoral and femoropopliteal deep vein thrombosis (DVT) of the lower limbs.2 In contrast, the sensitivity of ultrasound for CDVT diagnosis, even in symptomatic patients, is significantly lower than that for femoropopliteal diagnosis.1e3 Ultrasound criteria for CDVT diagnosis are not yet standardized. On the basis of a single French study, in which CDVT clots <5 mm in diameter were rarely observed under compression,4 a threshold diameter of 5 mm for CDVT diagnosis was proposed.4 This threshold has been adopted for CDVT diagnosis in some,5e8 but not all, studies.9e11
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
2
CDVT may be a heterogeneous entity affecting two different populations according to the kind of DVT (axial vs. muscular thrombosis). It has been shown that muscular and axial DVT exhibit different clinical symptoms at presentation but affect the same patient population.7 However, the distribution and characteristics of axial versus muscle CDVT needs further clarification and, so far, the recanalization rate of CDVT remains to be determined. It was hypothesized that several CDVT could have been missed by adopting a cut off of 5 mm. Moreover, it was hypothesized that the characteristics of axial and muscle vein thrombosis were similar and did not have an impact on CDVT recanalization. The aim of the present study was to assess (i) CDVT clot diameters and characteristics; (ii) the recanalization rate of CDVT after anticoagulant treatment; and (iii) the clinical factors affecting the lysis of the CDVT clot. METHODS Study design A prospective cohort study was conducted including symptomatic outpatients referred for suspected acute DVT of the lower limbs by general practitioners or the emergency department to the vascular emergency room of four angiology units (Bologna, Reggio Emilia, Pescara, and Ferrara, Italy) for the following symptoms: acute calf pain, acute calf swelling, calf cramps, acute calf redness, acute calf warmth. The physician in charge, who also performed a physical examination of the patients in the supine position, elicited a personal and family history from each patient. Patients with a previous CDVT in the symptomatic leg were excluded from the study. Patients then underwent whole leg duplex ultrasound (DUS) investigation of both lower limbs. Patients with CDVT were enrolled, whereas patients with iliofemoral and femoropopliteal DVT and/or pulmonary embolism were excluded from the study. Moreover, patients were excluded if they were younger than 18 years of age, if they had renal insufficiency with a creatinine clearance <30 mL/min, if they were receiving vitamin K antagonists, or low molecular weight heparin or fondaparinux for >24 h, or were pregnant or in the puerperium. The study was approved by the institutional ethical board of the coordinating centre (Bologna), and all patients gave their informed consent for study participation. Whole leg DUS investigation Patients underwent DUS examination of both legs by a vascular medicine physician with at least 4 years of experience of DUS of the lower leg venous system, as previously described.12 The iliac, femoral, and popliteal veins were examined first, then, in patients with normal findings, the calf veins were evaluated with the patient seated and their legs vertical. Calf veins were studied using various views: anteromedial, posterior, and posterolateral. The following veins were scanned in the transverse plane over their entire length: posterior tibial and fibular (axial veins), medial and
M. Sartori et al.
lateral gastrocnemius, and soleal veins (muscular veins).13 The anterior tibial veins were not investigated in the majority of the patients as anterior tibial veins are rarely affected by DVT.14 DVT diagnosis was confirmed if there was the presence of endoluminal material combined with lack of compression of the vein. Clot diameter was measured in the transverse plane during maximal compression. Results were registered on a chart according to clot location and diameter and used to compare diameters during follow up. For each patient, a “thrombotic score” was calculated as the sum of clot diameters in the following veins: posterior tibial, fibular, medial and lateral gastrocnemius, and soleal veins. Treatment and follow up Study observation started at the time of CDVT diagnosis and patients were followed up at the outpatient service of the participating angiology units. Patients were treated with enoxaparin 1 mg/kg subcutaneously twice a day for 2 weeks followed by 1 mg/kg subcutaneously once a day for 4 weeks. All patients were encouraged to wear knee high European class II graduated elastic stockings with 30e 40 mmHg compression at the ankle. At the end of enoxaparin treatment (6 weeks after diagnosis of CDVT), DUS was repeated. The residual degree of obstruction at the site of the previous clot was measured at maximal compression and it was expressed in millimeters. As previously described, recanalization of CDVT was defined as complete absence of deep vein obstruction or a residual intraluminal obstruction of 2 mm.15 Recurrent or suspected DVT extension was diagnosed in case of either (i) lack of compressibility of a previously compressible vein, or (ii) at least a 3 mm increase in the diameter of a previously non-compressible vein (when thrombus diameter changed between 1.1 and 2.9 mm, the examination was repeated 5e7 days later). During the entire follow up, in the case of worsening symptoms and/or suspected DVT extension, patients were recommended to come to the outpatients service where they underwent a whole leg DUS, the results of which were compared with the previously available examination. In case of suspected recurrent femoropopliteal and iliofemoral DVT, recurrence was diagnosed, as previously described.16 Patients with symptoms of pulmonary embolism had diagnostic testing based on a multi-detector computed tomography scan. Length of follow up was 3 months. Follow up included a visit and DUS 6 weeks following enrolment and a visit or a phone call 12 weeks after enrolment. After the 6 week visit, the treatment decisions were left at the discretion of the treating physician. Statistical analysis Analysis was carried out using the SPSS (version 15.0; IBM, Armonk, NY, USA). It was estimated that a cut off of 5 mm for CDVT diagnosis could miss 15% of CDVT (i.e., a sensitivity of 0.85); to obtain a confidence interval of 5%, we calculated a total sample of a 195 patients with CDVT. Normality was tested using the KolmogoroveSmirnov test.
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
Calf Deep Vein Thrombosis Clot Characteristics
Age and body mass index distribution were significantly different from normal distribution and were expressed as median and interquartile range (IQR). Categorical variables were expressed as frequency and percentage (95% confidence interval [CI] is also reported). Relationships between variables were assessed using chi-square or Fisher exact tests for categorical variables. The KruskaleWallis test was used to compare differences in ages according the anatomical site of CDVT. The associations between clinical characteristics of the study population (sex, obesity, cancer, significantly reduced mobility, trauma during symptomatic leg surgery, history of vein thrombosis, oestrogen containing therapy) and the presence of axial CDVT or the outcome (CDVT recanalization) were tested by univariate analysis followed by multivariate analysis. A parsimony model with predictors associated with a p-value .1 was presented to improve precision and avoid overfitting. The significance level was set at .05. RESULTS Patients were enrolled from 15 September 2013 to 15 August 2015 and all of them completed the follow up. Characteristics of enrolled patient (n ¼ 172) are summarized in Table 1, which shows that the most frequent risk factors for thrombosis were surgery within the previous 4 weeks and significantly reduced mobility. Cancer was present in 16 patients (9.3%). The most frequent symptoms were leg pain (83.7%) and oedema (65.7%), while redness and/or rash were present in a minority of patients (16.2%). Thrombosis confined only to the muscle veins was detected in 132 patients (76.7%; 95% CI 69.9e82.4), to axial veins in 24 patients (14.0%; 95% CI 9.6e19.9), and to axial and muscular veins in 16 patients (9.3%; 95% CI 5.8e14.9). Age was lower in patients with both muscular and axial CDVT than in those with thrombosis confined only to the muscle veins and in those with only axial calf vein thrombosis (58.8 17.4 vs. 71.5 13.9 vs. 70.2 10.2 years, respectively; p ¼ .009). Thrombotic score was higher in patients with axial DVT associated with muscular DVT than in those with either muscular or axial DVT (12.1 4.6 vs. 6.5 2.9 vs. 6.3 2.6 mm, respectively; p ¼ .001). The clinical characteristics associated with the presence of the axial calf thrombosis are reported in Table 2: male sex, the presence of cancer, and the use of oestrogen containing Table 1. Characteristics of the study population (n ¼ 172). Median (IQR) age, years 75 (17) Male/female (%) 55/117 (68.0) Median (IQR) BMI, kg/m2 24.6 (4.58) Venous thromboembolism risk factors (%) Active cancer 9.3 Surgery 31.4 Mobility significantly reduced 29.1 Trauma at symptomatic leg 15.7 History of vein thrombosis 12.2 Obesity 12.1 Use of HRT/oestrogen containing therapy 2.9 Note. IQR ¼ interquartile range; BMI ¼ body mass index; HRT ¼ hormone replacement therapy.
3
therapy were associated with the presence of the axial calf thrombosis, whereas age, obesity, surgery, significantly reduced mobility, trauma during symptomatic leg surgery, and history of vein thrombosis were not. A total of 212 clots were found with a mean diameter of 5.8 1.8 mm (IQR 4.5e6.8 mm, median 5.6 mm). Clot diameter ranged from 2.4 mm to 15 mm, with 3.5 mm the tenth and 4.5 mm the 25th percentiles. As shown in Table 3, there were 150 clots with a diameter 5 mm (71.1%; 95% CI 64.6e76.8). Considering the tenth percentiles of clot diameter, 162 patients (94.2%; 95% CI 89.6e 96.8%) had at least one clot with a diameter 3.5 mm, whereas only 131 (76.2%; 95% CI 69.3e81.9%) patients had at least one clot with a diameter 5 mm. A cut off value of 5 mm had a sensitivity of 0.76 (95% CI 0.69e0.82), whereas a value of 3.5 mm had a sensitivity of 0.94 (95% CI 0.89e0.97). As shown in Fig. 1, no difference (p ¼ .540) was observed in clot diameter among posterior tibial (n ¼ 16), fibular (n ¼ 26), medial gastrocnemius (n ¼ 101), lateral gastrocnemius (n ¼ 13), and soleal veins (n ¼ 55); mean SD clot diameters were 6.4 1.8 mm (IQR 5.2e 8.0, median 6.4 mm) for posterior tibial, 6.0 1.8 mm (IQR 4.7e7.5, median 5.7 mm) for fibular, 5.7 1.8 mm (IQR 4.5e7.0, median 5.3 mm) for medial gastrocnemius, 5.4 1.3 mm (IQR 5.0e6.3, median 5.6 mm) for lateral gastrocnemius, and 5.7 2.0 mm (IQR 4.5e6.3, median 5.6 mm) for soleal veins. After enoxaparin treatment, a mean SD clot diameter reduction of 3.6 2.9 mm (from 5.8 1.8 to 2.1 2.1; p ¼ .001) was found. The mean SD clot diameters were 3.1 2.6 mm (IQR 1.9e4.3, median 2.0 mm) for posterior tibial, 1.6 2.0 mm (IQR 0e3.5, median 1 mm) for fibular, 1.9 2.0 mm (IQR 0e3.5, median 2.0 mm) for medial gastrocnemius, 2.6 1.9 mm (IQR 1.0e4.3, median 2.5 mm) for lateral gastrocnemius, and 2.4 2.4 mm (IQR 0e3.8, median 2.6 mm) for soleal veins. The recanalization (after 6 weeks from CDVT diagnosis) was observed in 49.5% of the 212 clots. The recanalization rate was not correlated with clot diameter at enrolment (rho 0.128; p ¼ .930) and clots <5 mm had the same recanalization rate than those 5 mm (54.9% vs. 45.4%; p ¼ .171). CDVT recanalization occurred in 50.6% of patients (95% CI 43.2e58.0). As shown in Table 4, patients with significantly reduced mobility had a lower probability of CDVT recanalization. However, during multivariate analysis the statistical significance was borderline. No other factor was associated with a higher probability of clot recanalization among sex, obesity, active cancer, surgery, oestrogen containing therapy, and the anatomical site of thrombosis (axial vs. muscular thrombosis). Patients with a thrombotic score above the median had a similar probability of CDVT recanalization versus patients with thrombotic score below the median (Table 4). After the 6 week visit, 48 (27.9%) patients continued enoxaparin treatment until the end of follow up. During follow up, no major bleeding was observed; one female patient with cancer had a pulmonary embolism 2 weeks after stopping heparin treatment. Two male patients had
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
4
M. Sartori et al.
Table 2. Factors associated with the presence of calf axial deep vein thrombosis (CDVT). Univariate analysis Multivariate analysis OR 95% CI p OR 95% CI p Sex (male vs. female) 2.10 1.01e4.36 .044 2.58 1.18e5.60 .017 Obesitya 1.52 0.45e5.18 .499 Active cancer 3.88 1.35e11.10 .008 4.48 1.50e13.30 .007 Surgery 0.56 0.25e1.28 .166 Mobility significantly reduced 0.78 0.34e1.71 .518 Trauma at symptomatic leg surgery 0.93 0.35e2.50 .890 History of vein thrombosis 1.36 0.67e4.79 .243 Oestrogen containing therapy 14.6 1.48e134 .011 25.4 2.66e243 .005 Note. Patients were divided into two groups: those with thrombosis confined only to the muscle veins (muscular CDVT), and patients with axial calf vein thrombosis, including patients with both muscular and axial CDVT. OR ¼ odds ratio; CI ¼ confidence interval. a Obesity defined as a body mass index 30 kg/m2. Table 3. Distribution of clot diameter in patients with calf deep vein thrombosis and rate of clot recanalization after 6 weeks of low molecular weight heparin treatment. Diameter (mm) <3 3e3.9 4e4.9 5e5.9 6e6.9 7e7.9 8e8.9 9e9.9 10
n 8 19 35 55 44 28 13 2 8
Frequency (%) 3.8 9.0 16.5 25.9 20.8 13.2 6.1 0.9 3.8
Cumulative frequency (%) 3.8 12.7 29.2 55.2 75.9 89.2 95.5 96.2 100
% Clot recanalization (n) 62.5 (5) 42.1 (8) 51.4 (18) 60.0 (33) 43.2 (19) 42.9 (12) 38.5 (5) 50.0 (1) 50.0 (4)
recurrence of CDVT: one event was symptomatic, and one was asymptomatic. The latter occurred in a patient with cancer and was diagnosed by DUS at 6 weeks. In summary, the cumulative 3 month venous thromboembolism (VTE) rate was 12.5% (95% CI 3.5e36.0) in patients with cancer and 0.64% (95% CI 0.1e3.5) in those without cancer. DISCUSSION The present study shows that CDVT clot diameters were similar between axial and muscular veins and were
extremely variable, ranging from 2.4 to 15 mm, with 3.5 mm being the tenth percentile. Recanalization was observed in half of the patients with CDVT at 6 weeks from diagnosis and the recanalization rate was not related to the clot diameter at diagnosis or to the anatomical site of CDVT. It has been suggested that only clots 5 mm in diameter under compression may be considered as DVT.4 This threshold value has been used in several subsequent French studies,6e8 but this threshold was calculated by pooling together all DVTs (CDVT, femoropopliteal, and iliofemoral thrombosis).4 In the present study, it was found that around a quarter of the patients with CDVT has a clot diameter < 5 mm. The current data suggest the threshold of 5 mm for CDVT diagnosis is arbitrary and not related to the characteristics of the calf clots. The tenth percentile of clot diameter, that is, diameter 3.5 mm, may be a more appropriate threshold value. The prognostic value of this threshold has not been determined. It was found that clot diameters were similar in patients with axial and muscular thrombosis, and this was not unexpected as the same results were found in a French study.4 Furthermore, an arbitrarily defined thrombotic score was calculated and was higher in the patients with both axial and muscular DVT than in those with thrombosis confined
Table 4. Factors associated with clot recanalization at 6 weeks from the diagnosis of calf deep vein thrombosis (CDVT). Univariate analysis OR 95% CI 1.14 0.60e2.16 0.84 0.30e2.34 0.98 0.35e2.72 1.34 0.70e2.56 0.49 0.25e0.95 0.75 0.33e2.71 1.09 0.44e4.79 4.05 0.44e37 1.43 0.70e2.94 0.57 0.31e1.04
p .700 .743 .961 .377 .035 .487 .860 .182 .318 .068
Multivariate analysis OR 95% CI
p Sex (male vs. female) Obesitya Active cancer Surgery Mobility significantly reduced 0.51 0.26e1.00 .050 Trauma at symptomatic leg surgery History of vein thrombosis Oestrogen containing therapy Axial vs. muscular CDVTb Thrombotic scorec 0.60 0.32e1.10 .099 Note. a Obesity defined as a body mass index equal to or higher than 30 kg/m. b Patients were divided into two groups: those with thrombosis confined only to the muscle veins (muscular CDVT), and those with axial calf vein thrombosis, including patients with both muscular and axial CDVT. c Patients with thrombotic score above the median vs. patients with thrombotic score below the median. Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
Calf Deep Vein Thrombosis Clot Characteristics
5
Figure 1. Clot diameters (mean SD) of posterior tibial (tibial), fibular (fibular), medial gastrocnemius (int gastr), lateral gastrocnemius (ext gastr), and soleal veins (sol) at enrolment (basal) and after 6 week low molecular weight heparin treatment.
only to the muscle veins or those with only axial calf vein thrombosis, and this mirrors what the authors recently found regarding D-dimer plasma levels in CDVT.12 Whether the higher thrombotic score in patients with both muscular and axial calf DVT is associated with a worse outcome is still an unresolved question. It has been reported that the risk of recurrent VTE was similar between muscular and axial calf DVT.8 Similarly, thrombosis limited to muscular veins was not associated with higher risk of recurrent VTE,16 nor to a higher probability of recanalization. According to such data both muscular and axial calf vein thrombosis seem to have similar outcomes, suggesting that the anatomical site of CDVT is not able to predict the outcome. In the present study, axial CDVT was more frequent in male patients, in patients with cancer, and in patients on oestrogen containing therapy, suggesting the risk factors for axial CDVT are not the same for muscular CDVT. Herein, patients were treated with enoxaparin for 6 weeks, although current guidelines suggest, in patients with CDVT who are managed with anticoagulation, a 3 month treatment period.17 It has to be underlined that the only trial that compared 3 month with 6 week vitamin K antagonist treatment for CDVT did not show a significant difference with regard to VTE recurrences.18 Moreover, a previous study in similar patients who received a full dose of low molecular weight heparin for 1 week followed by half therapeutic dose for 3 weeks,19 and a preliminary report on a randomized trial,20 showed that low molecular weight heparin at a therapeutic dose for 2 weeks, followed by half the dose for additional 4 weeks, was an effective and safe alternative to warfarin in patients with CDVT. Taking into account these results, it was decided to treat the patients with anticoagulant treatment only for 6 weeks. The results suggest the safety of the treatment protocol in all the patients except those with cancer. In fact, the present multicenter study confirms previous single centre data,16 which
show a higher 3 month VTE rate in the subgroup of patients with cancer than in those without. Similarly another longitudinal study reported that malignancy was associated with CDVT extension, whereas transient risk factors such as recent surgery and trauma were not,21 and the aforementioned trial that compared 3 month with 6 week vitamin K antagonist treatment for CDVT, found a higher rate of VTE recurrence in patients with CDVT with cancer.17 The recanalization rate of CDVT was around 50% at 6 weeks from diagnosis of CDVT and seems higher than that of iliofemoral and femoropopliteal DVT.22 Similarly, a study showed a recanalization rate of 50% for 115 muscular DVT at 4 weeks,6 and a study on both muscular and axial DVT showed a recanalization rate of 41% within 1e3 months.10 It has to be noted that guidelines suggest a 12 week treatment for CDVT,17 and an ultrasound at 12 weeks from CDVT diagnosis was not performed. The recanalization rate may be higher at 12 weeks and in one of the few randomized trials on therapy of symptomatic CDVT, thrombus recanalization at 3 months was seen in 66% of cases in the heparin group and in 60% of cases in the placebo group.23 Only one factor associated with recanalization was found: the “mobility” of the patient (i.e., patients with significant reduced mobility had lower probability of CDVT recanalization). Several limitations of the present study should be acknowledged. The patients investigated were not consecutive and a selection bias cannot be excluded. However, this was a multicentre study and most of the included patients were the first subjects who were referred in the morning with the aim of reducing this bias. Although the study population was unselected, the findings may not apply to specific subgroups of patients, such as pregnant women. The anterior tibial veins were not investigated in all patients. Haemodynamic data such as the presence of reflux were not registered, although it could give important
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
6
insight on clot recanalization. Thrombus length, along with the aspect of the proximal “head”, were not determined. Moreover, no inter-observer variability was assessed for CDVT diagnosis and clot measure, and some concern may exist regarding the homogeneity of the diagnostic procedure in the study. It has to be noted that all ultrasound tests were performed by board certified vascular medicine physicians using a standardized examination protocol, and previous studies have shown that compression ultrasound yields satisfactory inter-agreement.24 Validation studies revealed that ultrasound sensitivity for CDVT diagnosis, even in symptomatic patients, is significantly lower than that for iliofemoral and femoropopliteal DVT,2 leading to the possibility that some falsely positive recurrent CDVT may have been enrolled. It was attempted to minimize false positives by excluding patients with a previous CDVT in the symptomatic leg. Two CDVT recurrences were seen during follow up and no validated protocol exists for CDVT recurrence diagnosis. The criteria have been described previously and, although reasonable, they are still arbitrary. Finally, the subgroup of patients with cancer was small and larger studies are required in such patients with CDVT. In conclusion, the threshold of 5 mm for the diagnosis of CDVT seems to be arbitrary and a threshold of 3.5 mm, that is the tenth percentile, may be reasonable. At 6 weeks, half the patients with CDVT are characterized by the absence of residual vein obstruction. The recanalization rate is not related to clot diameter at CDVT diagnosis nor to the anatomical characteristics of CDVT. In patients with cancer, 6 week heparin treatment seems to be insufficient for CDVT. CONFLICT OF INTEREST None. FUNDING None. REFERENCES 1 Palareti G, Sartori M. Treatment of isolated below the knee deep vein thrombosis. Curr Atheroscler Rep 2016;18:37. 2 Goodacre S, Sampson F, Thomas S, van Beek E, Sutton A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging 2005;5:6. 3 Righini M, Bounameaux H. Clinical relevance of distal deep vein thrombosis. Curr Opin Pulm Med 2008;14:408e13. 4 Bosson JL, Riachi M, Pichot O, Michoud E, Carpentier PH, Franco A. Diameters of acute proximal and distal deep venous thrombosis of the lower limbs. Int Angiol 1998;17:260e7. 5 Righini M, Le Gal G, Aujesky D, Roy PM, Sanchez O, Verschuren F, et al. Complete venous ultrasound in outpatients with suspected pulmonary embolism. J Thromb Haemost 2009;7:406e12. 6 Gillet JL, Perrin MR, Allaert FA. Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis. J Vasc Surg 2007;46:513e9.
M. Sartori et al. 7 Galanaud JP, Sevestre MA, Genty C, Laroche JP, Zizka V, Quéré I, et al. Comparison of the clinical history of symptomatic isolated muscular calf vein thrombosis versus deep calf vein thrombosis. J Vasc Surg 2010;52:932e8. 8 Galanaud JP, Sevestre MA, Genty C, Kahn SR, Pernod G, Rolland C, et al. Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J Thromb Haemost 2014;12:436e43. 9 Mattos MA, Melendres G, Sumner DS, Hood DB, Barkmeier LD, Hodgson KJ, et al. Prevalence and distribution of calf vein thrombosis in patients with symptomatic deep venous thrombosis: a color-flow duplex study. J Vasc Surg 1996;24: 738e44. 10 Singh K, Yakoub D, Giangola P, DeCicca M, Patel CA, Marzouk F, et al. Early follow up and treatment recommendations for isolated calf deep venous thrombosis. J Vasc Surg 2012;55: 136e40. 11 Palareti G, Cosmi B, Lessiani G, Rodorigo G, Guazzaloca G, Brusi C, et al. Evolution of untreated calf deep vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study. Thromb Haemost 2010;104:1063e70. 12 Sartori M, Cosmi B, Legnani C, Favaretto E, Valdré L, Guazzaloca G, et al. The Wells rule and D-dimer for the diagnosis of isolated distal deep vein thrombosis. J Thromb Haemost 2012;10:2264e9. 13 Caggiati A, Bergan JJ, Gloviczki P, Eklof B, Allegra C, Partsch H. International Interdisciplinary Consensus Committee on Venous Anatomical Terminology. Nomenclature of the veins of the lower limb: extensions, refinements, and clinical application. J Vasc Surg 2005;41:719e24. 14 Elias A, Cadène A, Elias M, Puget J, Tricoire JL, Colin C, et al. Extended lower limb venous ultrasound for the diagnosis of proximal and distal vein thrombosis in asymptomatic patients after total hip replacement. Eur J Vasc Endovasc Surg 2004;27: 438e44. 15 Prandoni P, Lensing AW, 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;137:955e60. 16 Sartori M, Migliaccio L, Favaretto E, Palareti G, Cosmi B. Two years outcome of isolated distal deep vein thrombosis. Thromb Res 2014;134:36e40. 17 Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence based Clinical Practice Guidelines. Chest 2012;141(2 Suppl.):e419Se94S. 18 Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe Rague S, Durieu I, et al. Investigators of the “Duree Optimale du Traitement AntiVitamines K” (DOTAVK) Study. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001;103:2453e60. 19 Parisi R, Visonà A, Camporese G, Verlato F, Lessiani G, Antignani PL, et al. Isolated distal deep vein thrombosis: efficacy and safety of a protocol of treatment. Treatment of Isolated Calf Thrombosis (TICT) Study. Int Angiol 2009;28:68e72. 20 Ghirarduzzi A, Camporese G, Siragusa S, Imberti D, Bucherini E, Landini F, et al. A randomized, prospective, open-label study on distal vein thrombosis (low-molecularweight heparin vs.
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
Calf Deep Vein Thrombosis Clot Characteristics warfarin for 6 weeks): the Todi study. J Thromb Haemost 2009;7(suppl. 2):PP-WE-403. 21 MacDonald PS, Kahn SR, Miller N, Obrand D. Short-term natural history of isolated gastrocnemius and soleal vein thrombosis. J Vasc Surg 2003;37:523e7. 22 Sartori M, Favaretto E, Cini M, Legnani C, Palareti G, Cosmi B. D-dimer, FVIII and thrombotic burden in the acute phase of deep vein thrombosis in relation to the risk of post-thrombotic syndrome. Thromb Res 2014;134:320e5.
7 23 Schwarz T, Buschmann L, Beyer J, Halbritter K, Rastan A, Schellong S. Therapy of isolated calf muscle vein thrombosis: a randomized, controlled study. J Vasc Surg 2010;52:1246e50. 24 Schwarz T, Schmidt B, Schmidt B, Schellong SM. Interobserver agreement of complete compression ultrasound for clinically suspected deep vein thrombosis. Clin Appl Thromb Hemost 2002;8:45e9.
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
-,
1e7
Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment M. Sartori
a,*
, G. Lessiani b, E. Favaretto a, L. Migliaccio a, M. Iotti c, L. Giusto d, A. Ghirarduzzi c, G. Palareti e, B. Cosmi
a
a
Department of Angiology and Blood Coagulation, University Hospital S. Orsola-Malpighi, Bologna, Italy Angiology Unit, Medicine and Geriatric Department, “Villa Serena” Hospital, Città Sant’Angelo, Pescara, Italy Angiology Unit, Arcispedale S. Maria Nuova, Reggio Emilia, Italy d Non-invasive Vascular Diagnostic Unit, University Hospital S. Anna, Ferrara, Italy e Cardiovascular Diseases, University of Bologna, Bologna, Italy b c
WHAT THIS PAPER ADDS Calf deep vein thrombosis (CDVT) ultrasound diagnostic criteria are still debated. A clot 3.5 mm may be an appropriate threshold for CDVT diagnosis. Six week heparin treatment is associated with recanalization in half of patients with CDVT.
Objective/Background: Calf deep vein thrombosis (CDVT) is frequently found in symptomatic outpatients, but CDVT ultrasound diagnostic criteria are still debated. It has been proposed that only clots with 5 mm maximum diameter can be considered as CDVT. Aims: To assess clot diameters and characteristics of CDVT, and to assess the recanalization rate of CDVT after anticoagulant treatment. Methods: In a prospective, multicenter cohort study symptomatic outpatients in whom CDVT was diagnosed by ultrasound were enrolled. Posterior tibial, fibular, medial and lateral gastrocnemius, and soleal veins were compressed transversally over their entire length. Clot diameter was measured during maximum compression and ultrasound was repeated after 6 weeks of low molecular weight heparin treatment. Results: In 172 patients (age 70 1 y, male 32%) CDVT was detected in 132 (76.7%) muscle veins only, and in 24 (14%) axial veins only, while 16 (9.3%) patients had both muscular and axial CDVT. A total of 212 clots were found with a diameter of 5.8 1.8 mm (IQR 4.5e6.8 mm) with the 10th percentile being 3.5 mm. A cut off value of 5 mm had a sensitivity of 0.76 (95% CI 0.69e0.82), whereas a value of 3.5 mm had a sensitivity of 0.94 (95% CI 0.89e0.97). Recanalization (i.e. residual vein obstruction 2 mm) was found in 51% of patients and the recanalization rate was not correlated with clot diameter at enrolment (rho 0.128 p ¼ 0.93) or with type of CDVT (axial vs. muscular thrombosis). Patients with significantly reduced mobility had lower probability of CDVT recanalization. Conclusion: A clot diameter 5 mm is found in only 76% of CDVT patients and a clot diameter 3.5 mm may be more appropriate as a threshold for CDVT. After 6 weeks of anticoagulant treatment, half of CDVT patients had recanalization and recanalization was not correlated with clot characteristics at enrolment, but with mobility of the patients. Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 17 January 2016, Accepted 19 July 2016, Available online XXX Keywords: Calf deep vein thrombosis, Clot diameter, Heparin, Isolated distal deep vein thrombosis, Residual venous obstruction, Whole leg ultrasound
INTRODUCTION Calf deep vein thrombosis (CDVT), defined as thrombosis confined to the infrapopliteal veins of the lower limbs, is a frequent finding in symptomatic outpatients.1 Compression * Corresponding author. Angiology and Haemostasis Unit, University Hospital of Bologna, Policlinico Sant’Orsola Malpighi, Via Albertoni, 15, 40138 Bologna, Italy. E-mail address: [email protected] (M. Sartori). 1078-5884/Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2016.07.022
ultrasound has been widely investigated for the diagnosis of iliofemoral and femoropopliteal deep vein thrombosis (DVT) of the lower limbs.2 In contrast, the sensitivity of ultrasound for CDVT diagnosis, even in symptomatic patients, is significantly lower than that for femoropopliteal diagnosis.1e3 Ultrasound criteria for CDVT diagnosis are not yet standardized. On the basis of a single French study, in which CDVT clots <5 mm in diameter were rarely observed under compression,4 a threshold diameter of 5 mm for CDVT diagnosis was proposed.4 This threshold has been adopted for CDVT diagnosis in some,5e8 but not all, studies.9e11
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
2
CDVT may be a heterogeneous entity affecting two different populations according to the kind of DVT (axial vs. muscular thrombosis). It has been shown that muscular and axial DVT exhibit different clinical symptoms at presentation but affect the same patient population.7 However, the distribution and characteristics of axial versus muscle CDVT needs further clarification and, so far, the recanalization rate of CDVT remains to be determined. It was hypothesized that several CDVT could have been missed by adopting a cut off of 5 mm. Moreover, it was hypothesized that the characteristics of axial and muscle vein thrombosis were similar and did not have an impact on CDVT recanalization. The aim of the present study was to assess (i) CDVT clot diameters and characteristics; (ii) the recanalization rate of CDVT after anticoagulant treatment; and (iii) the clinical factors affecting the lysis of the CDVT clot. METHODS Study design A prospective cohort study was conducted including symptomatic outpatients referred for suspected acute DVT of the lower limbs by general practitioners or the emergency department to the vascular emergency room of four angiology units (Bologna, Reggio Emilia, Pescara, and Ferrara, Italy) for the following symptoms: acute calf pain, acute calf swelling, calf cramps, acute calf redness, acute calf warmth. The physician in charge, who also performed a physical examination of the patients in the supine position, elicited a personal and family history from each patient. Patients with a previous CDVT in the symptomatic leg were excluded from the study. Patients then underwent whole leg duplex ultrasound (DUS) investigation of both lower limbs. Patients with CDVT were enrolled, whereas patients with iliofemoral and femoropopliteal DVT and/or pulmonary embolism were excluded from the study. Moreover, patients were excluded if they were younger than 18 years of age, if they had renal insufficiency with a creatinine clearance <30 mL/min, if they were receiving vitamin K antagonists, or low molecular weight heparin or fondaparinux for >24 h, or were pregnant or in the puerperium. The study was approved by the institutional ethical board of the coordinating centre (Bologna), and all patients gave their informed consent for study participation. Whole leg DUS investigation Patients underwent DUS examination of both legs by a vascular medicine physician with at least 4 years of experience of DUS of the lower leg venous system, as previously described.12 The iliac, femoral, and popliteal veins were examined first, then, in patients with normal findings, the calf veins were evaluated with the patient seated and their legs vertical. Calf veins were studied using various views: anteromedial, posterior, and posterolateral. The following veins were scanned in the transverse plane over their entire length: posterior tibial and fibular (axial veins), medial and
M. Sartori et al.
lateral gastrocnemius, and soleal veins (muscular veins).13 The anterior tibial veins were not investigated in the majority of the patients as anterior tibial veins are rarely affected by DVT.14 DVT diagnosis was confirmed if there was the presence of endoluminal material combined with lack of compression of the vein. Clot diameter was measured in the transverse plane during maximal compression. Results were registered on a chart according to clot location and diameter and used to compare diameters during follow up. For each patient, a “thrombotic score” was calculated as the sum of clot diameters in the following veins: posterior tibial, fibular, medial and lateral gastrocnemius, and soleal veins. Treatment and follow up Study observation started at the time of CDVT diagnosis and patients were followed up at the outpatient service of the participating angiology units. Patients were treated with enoxaparin 1 mg/kg subcutaneously twice a day for 2 weeks followed by 1 mg/kg subcutaneously once a day for 4 weeks. All patients were encouraged to wear knee high European class II graduated elastic stockings with 30e 40 mmHg compression at the ankle. At the end of enoxaparin treatment (6 weeks after diagnosis of CDVT), DUS was repeated. The residual degree of obstruction at the site of the previous clot was measured at maximal compression and it was expressed in millimeters. As previously described, recanalization of CDVT was defined as complete absence of deep vein obstruction or a residual intraluminal obstruction of 2 mm.15 Recurrent or suspected DVT extension was diagnosed in case of either (i) lack of compressibility of a previously compressible vein, or (ii) at least a 3 mm increase in the diameter of a previously non-compressible vein (when thrombus diameter changed between 1.1 and 2.9 mm, the examination was repeated 5e7 days later). During the entire follow up, in the case of worsening symptoms and/or suspected DVT extension, patients were recommended to come to the outpatients service where they underwent a whole leg DUS, the results of which were compared with the previously available examination. In case of suspected recurrent femoropopliteal and iliofemoral DVT, recurrence was diagnosed, as previously described.16 Patients with symptoms of pulmonary embolism had diagnostic testing based on a multi-detector computed tomography scan. Length of follow up was 3 months. Follow up included a visit and DUS 6 weeks following enrolment and a visit or a phone call 12 weeks after enrolment. After the 6 week visit, the treatment decisions were left at the discretion of the treating physician. Statistical analysis Analysis was carried out using the SPSS (version 15.0; IBM, Armonk, NY, USA). It was estimated that a cut off of 5 mm for CDVT diagnosis could miss 15% of CDVT (i.e., a sensitivity of 0.85); to obtain a confidence interval of 5%, we calculated a total sample of a 195 patients with CDVT. Normality was tested using the KolmogoroveSmirnov test.
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
Calf Deep Vein Thrombosis Clot Characteristics
Age and body mass index distribution were significantly different from normal distribution and were expressed as median and interquartile range (IQR). Categorical variables were expressed as frequency and percentage (95% confidence interval [CI] is also reported). Relationships between variables were assessed using chi-square or Fisher exact tests for categorical variables. The KruskaleWallis test was used to compare differences in ages according the anatomical site of CDVT. The associations between clinical characteristics of the study population (sex, obesity, cancer, significantly reduced mobility, trauma during symptomatic leg surgery, history of vein thrombosis, oestrogen containing therapy) and the presence of axial CDVT or the outcome (CDVT recanalization) were tested by univariate analysis followed by multivariate analysis. A parsimony model with predictors associated with a p-value .1 was presented to improve precision and avoid overfitting. The significance level was set at .05. RESULTS Patients were enrolled from 15 September 2013 to 15 August 2015 and all of them completed the follow up. Characteristics of enrolled patient (n ¼ 172) are summarized in Table 1, which shows that the most frequent risk factors for thrombosis were surgery within the previous 4 weeks and significantly reduced mobility. Cancer was present in 16 patients (9.3%). The most frequent symptoms were leg pain (83.7%) and oedema (65.7%), while redness and/or rash were present in a minority of patients (16.2%). Thrombosis confined only to the muscle veins was detected in 132 patients (76.7%; 95% CI 69.9e82.4), to axial veins in 24 patients (14.0%; 95% CI 9.6e19.9), and to axial and muscular veins in 16 patients (9.3%; 95% CI 5.8e14.9). Age was lower in patients with both muscular and axial CDVT than in those with thrombosis confined only to the muscle veins and in those with only axial calf vein thrombosis (58.8 17.4 vs. 71.5 13.9 vs. 70.2 10.2 years, respectively; p ¼ .009). Thrombotic score was higher in patients with axial DVT associated with muscular DVT than in those with either muscular or axial DVT (12.1 4.6 vs. 6.5 2.9 vs. 6.3 2.6 mm, respectively; p ¼ .001). The clinical characteristics associated with the presence of the axial calf thrombosis are reported in Table 2: male sex, the presence of cancer, and the use of oestrogen containing Table 1. Characteristics of the study population (n ¼ 172). Median (IQR) age, years 75 (17) Male/female (%) 55/117 (68.0) Median (IQR) BMI, kg/m2 24.6 (4.58) Venous thromboembolism risk factors (%) Active cancer 9.3 Surgery 31.4 Mobility significantly reduced 29.1 Trauma at symptomatic leg 15.7 History of vein thrombosis 12.2 Obesity 12.1 Use of HRT/oestrogen containing therapy 2.9 Note. IQR ¼ interquartile range; BMI ¼ body mass index; HRT ¼ hormone replacement therapy.
3
therapy were associated with the presence of the axial calf thrombosis, whereas age, obesity, surgery, significantly reduced mobility, trauma during symptomatic leg surgery, and history of vein thrombosis were not. A total of 212 clots were found with a mean diameter of 5.8 1.8 mm (IQR 4.5e6.8 mm, median 5.6 mm). Clot diameter ranged from 2.4 mm to 15 mm, with 3.5 mm the tenth and 4.5 mm the 25th percentiles. As shown in Table 3, there were 150 clots with a diameter 5 mm (71.1%; 95% CI 64.6e76.8). Considering the tenth percentiles of clot diameter, 162 patients (94.2%; 95% CI 89.6e 96.8%) had at least one clot with a diameter 3.5 mm, whereas only 131 (76.2%; 95% CI 69.3e81.9%) patients had at least one clot with a diameter 5 mm. A cut off value of 5 mm had a sensitivity of 0.76 (95% CI 0.69e0.82), whereas a value of 3.5 mm had a sensitivity of 0.94 (95% CI 0.89e0.97). As shown in Fig. 1, no difference (p ¼ .540) was observed in clot diameter among posterior tibial (n ¼ 16), fibular (n ¼ 26), medial gastrocnemius (n ¼ 101), lateral gastrocnemius (n ¼ 13), and soleal veins (n ¼ 55); mean SD clot diameters were 6.4 1.8 mm (IQR 5.2e 8.0, median 6.4 mm) for posterior tibial, 6.0 1.8 mm (IQR 4.7e7.5, median 5.7 mm) for fibular, 5.7 1.8 mm (IQR 4.5e7.0, median 5.3 mm) for medial gastrocnemius, 5.4 1.3 mm (IQR 5.0e6.3, median 5.6 mm) for lateral gastrocnemius, and 5.7 2.0 mm (IQR 4.5e6.3, median 5.6 mm) for soleal veins. After enoxaparin treatment, a mean SD clot diameter reduction of 3.6 2.9 mm (from 5.8 1.8 to 2.1 2.1; p ¼ .001) was found. The mean SD clot diameters were 3.1 2.6 mm (IQR 1.9e4.3, median 2.0 mm) for posterior tibial, 1.6 2.0 mm (IQR 0e3.5, median 1 mm) for fibular, 1.9 2.0 mm (IQR 0e3.5, median 2.0 mm) for medial gastrocnemius, 2.6 1.9 mm (IQR 1.0e4.3, median 2.5 mm) for lateral gastrocnemius, and 2.4 2.4 mm (IQR 0e3.8, median 2.6 mm) for soleal veins. The recanalization (after 6 weeks from CDVT diagnosis) was observed in 49.5% of the 212 clots. The recanalization rate was not correlated with clot diameter at enrolment (rho 0.128; p ¼ .930) and clots <5 mm had the same recanalization rate than those 5 mm (54.9% vs. 45.4%; p ¼ .171). CDVT recanalization occurred in 50.6% of patients (95% CI 43.2e58.0). As shown in Table 4, patients with significantly reduced mobility had a lower probability of CDVT recanalization. However, during multivariate analysis the statistical significance was borderline. No other factor was associated with a higher probability of clot recanalization among sex, obesity, active cancer, surgery, oestrogen containing therapy, and the anatomical site of thrombosis (axial vs. muscular thrombosis). Patients with a thrombotic score above the median had a similar probability of CDVT recanalization versus patients with thrombotic score below the median (Table 4). After the 6 week visit, 48 (27.9%) patients continued enoxaparin treatment until the end of follow up. During follow up, no major bleeding was observed; one female patient with cancer had a pulmonary embolism 2 weeks after stopping heparin treatment. Two male patients had
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
4
M. Sartori et al.
Table 2. Factors associated with the presence of calf axial deep vein thrombosis (CDVT). Univariate analysis Multivariate analysis OR 95% CI p OR 95% CI p Sex (male vs. female) 2.10 1.01e4.36 .044 2.58 1.18e5.60 .017 Obesitya 1.52 0.45e5.18 .499 Active cancer 3.88 1.35e11.10 .008 4.48 1.50e13.30 .007 Surgery 0.56 0.25e1.28 .166 Mobility significantly reduced 0.78 0.34e1.71 .518 Trauma at symptomatic leg surgery 0.93 0.35e2.50 .890 History of vein thrombosis 1.36 0.67e4.79 .243 Oestrogen containing therapy 14.6 1.48e134 .011 25.4 2.66e243 .005 Note. Patients were divided into two groups: those with thrombosis confined only to the muscle veins (muscular CDVT), and patients with axial calf vein thrombosis, including patients with both muscular and axial CDVT. OR ¼ odds ratio; CI ¼ confidence interval. a Obesity defined as a body mass index 30 kg/m2. Table 3. Distribution of clot diameter in patients with calf deep vein thrombosis and rate of clot recanalization after 6 weeks of low molecular weight heparin treatment. Diameter (mm) <3 3e3.9 4e4.9 5e5.9 6e6.9 7e7.9 8e8.9 9e9.9 10
n 8 19 35 55 44 28 13 2 8
Frequency (%) 3.8 9.0 16.5 25.9 20.8 13.2 6.1 0.9 3.8
Cumulative frequency (%) 3.8 12.7 29.2 55.2 75.9 89.2 95.5 96.2 100
% Clot recanalization (n) 62.5 (5) 42.1 (8) 51.4 (18) 60.0 (33) 43.2 (19) 42.9 (12) 38.5 (5) 50.0 (1) 50.0 (4)
recurrence of CDVT: one event was symptomatic, and one was asymptomatic. The latter occurred in a patient with cancer and was diagnosed by DUS at 6 weeks. In summary, the cumulative 3 month venous thromboembolism (VTE) rate was 12.5% (95% CI 3.5e36.0) in patients with cancer and 0.64% (95% CI 0.1e3.5) in those without cancer. DISCUSSION The present study shows that CDVT clot diameters were similar between axial and muscular veins and were
extremely variable, ranging from 2.4 to 15 mm, with 3.5 mm being the tenth percentile. Recanalization was observed in half of the patients with CDVT at 6 weeks from diagnosis and the recanalization rate was not related to the clot diameter at diagnosis or to the anatomical site of CDVT. It has been suggested that only clots 5 mm in diameter under compression may be considered as DVT.4 This threshold value has been used in several subsequent French studies,6e8 but this threshold was calculated by pooling together all DVTs (CDVT, femoropopliteal, and iliofemoral thrombosis).4 In the present study, it was found that around a quarter of the patients with CDVT has a clot diameter < 5 mm. The current data suggest the threshold of 5 mm for CDVT diagnosis is arbitrary and not related to the characteristics of the calf clots. The tenth percentile of clot diameter, that is, diameter 3.5 mm, may be a more appropriate threshold value. The prognostic value of this threshold has not been determined. It was found that clot diameters were similar in patients with axial and muscular thrombosis, and this was not unexpected as the same results were found in a French study.4 Furthermore, an arbitrarily defined thrombotic score was calculated and was higher in the patients with both axial and muscular DVT than in those with thrombosis confined
Table 4. Factors associated with clot recanalization at 6 weeks from the diagnosis of calf deep vein thrombosis (CDVT). Univariate analysis OR 95% CI 1.14 0.60e2.16 0.84 0.30e2.34 0.98 0.35e2.72 1.34 0.70e2.56 0.49 0.25e0.95 0.75 0.33e2.71 1.09 0.44e4.79 4.05 0.44e37 1.43 0.70e2.94 0.57 0.31e1.04
p .700 .743 .961 .377 .035 .487 .860 .182 .318 .068
Multivariate analysis OR 95% CI
p Sex (male vs. female) Obesitya Active cancer Surgery Mobility significantly reduced 0.51 0.26e1.00 .050 Trauma at symptomatic leg surgery History of vein thrombosis Oestrogen containing therapy Axial vs. muscular CDVTb Thrombotic scorec 0.60 0.32e1.10 .099 Note. a Obesity defined as a body mass index equal to or higher than 30 kg/m. b Patients were divided into two groups: those with thrombosis confined only to the muscle veins (muscular CDVT), and those with axial calf vein thrombosis, including patients with both muscular and axial CDVT. c Patients with thrombotic score above the median vs. patients with thrombotic score below the median. Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
Calf Deep Vein Thrombosis Clot Characteristics
5
Figure 1. Clot diameters (mean SD) of posterior tibial (tibial), fibular (fibular), medial gastrocnemius (int gastr), lateral gastrocnemius (ext gastr), and soleal veins (sol) at enrolment (basal) and after 6 week low molecular weight heparin treatment.
only to the muscle veins or those with only axial calf vein thrombosis, and this mirrors what the authors recently found regarding D-dimer plasma levels in CDVT.12 Whether the higher thrombotic score in patients with both muscular and axial calf DVT is associated with a worse outcome is still an unresolved question. It has been reported that the risk of recurrent VTE was similar between muscular and axial calf DVT.8 Similarly, thrombosis limited to muscular veins was not associated with higher risk of recurrent VTE,16 nor to a higher probability of recanalization. According to such data both muscular and axial calf vein thrombosis seem to have similar outcomes, suggesting that the anatomical site of CDVT is not able to predict the outcome. In the present study, axial CDVT was more frequent in male patients, in patients with cancer, and in patients on oestrogen containing therapy, suggesting the risk factors for axial CDVT are not the same for muscular CDVT. Herein, patients were treated with enoxaparin for 6 weeks, although current guidelines suggest, in patients with CDVT who are managed with anticoagulation, a 3 month treatment period.17 It has to be underlined that the only trial that compared 3 month with 6 week vitamin K antagonist treatment for CDVT did not show a significant difference with regard to VTE recurrences.18 Moreover, a previous study in similar patients who received a full dose of low molecular weight heparin for 1 week followed by half therapeutic dose for 3 weeks,19 and a preliminary report on a randomized trial,20 showed that low molecular weight heparin at a therapeutic dose for 2 weeks, followed by half the dose for additional 4 weeks, was an effective and safe alternative to warfarin in patients with CDVT. Taking into account these results, it was decided to treat the patients with anticoagulant treatment only for 6 weeks. The results suggest the safety of the treatment protocol in all the patients except those with cancer. In fact, the present multicenter study confirms previous single centre data,16 which
show a higher 3 month VTE rate in the subgroup of patients with cancer than in those without. Similarly another longitudinal study reported that malignancy was associated with CDVT extension, whereas transient risk factors such as recent surgery and trauma were not,21 and the aforementioned trial that compared 3 month with 6 week vitamin K antagonist treatment for CDVT, found a higher rate of VTE recurrence in patients with CDVT with cancer.17 The recanalization rate of CDVT was around 50% at 6 weeks from diagnosis of CDVT and seems higher than that of iliofemoral and femoropopliteal DVT.22 Similarly, a study showed a recanalization rate of 50% for 115 muscular DVT at 4 weeks,6 and a study on both muscular and axial DVT showed a recanalization rate of 41% within 1e3 months.10 It has to be noted that guidelines suggest a 12 week treatment for CDVT,17 and an ultrasound at 12 weeks from CDVT diagnosis was not performed. The recanalization rate may be higher at 12 weeks and in one of the few randomized trials on therapy of symptomatic CDVT, thrombus recanalization at 3 months was seen in 66% of cases in the heparin group and in 60% of cases in the placebo group.23 Only one factor associated with recanalization was found: the “mobility” of the patient (i.e., patients with significant reduced mobility had lower probability of CDVT recanalization). Several limitations of the present study should be acknowledged. The patients investigated were not consecutive and a selection bias cannot be excluded. However, this was a multicentre study and most of the included patients were the first subjects who were referred in the morning with the aim of reducing this bias. Although the study population was unselected, the findings may not apply to specific subgroups of patients, such as pregnant women. The anterior tibial veins were not investigated in all patients. Haemodynamic data such as the presence of reflux were not registered, although it could give important
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
6
insight on clot recanalization. Thrombus length, along with the aspect of the proximal “head”, were not determined. Moreover, no inter-observer variability was assessed for CDVT diagnosis and clot measure, and some concern may exist regarding the homogeneity of the diagnostic procedure in the study. It has to be noted that all ultrasound tests were performed by board certified vascular medicine physicians using a standardized examination protocol, and previous studies have shown that compression ultrasound yields satisfactory inter-agreement.24 Validation studies revealed that ultrasound sensitivity for CDVT diagnosis, even in symptomatic patients, is significantly lower than that for iliofemoral and femoropopliteal DVT,2 leading to the possibility that some falsely positive recurrent CDVT may have been enrolled. It was attempted to minimize false positives by excluding patients with a previous CDVT in the symptomatic leg. Two CDVT recurrences were seen during follow up and no validated protocol exists for CDVT recurrence diagnosis. The criteria have been described previously and, although reasonable, they are still arbitrary. Finally, the subgroup of patients with cancer was small and larger studies are required in such patients with CDVT. In conclusion, the threshold of 5 mm for the diagnosis of CDVT seems to be arbitrary and a threshold of 3.5 mm, that is the tenth percentile, may be reasonable. At 6 weeks, half the patients with CDVT are characterized by the absence of residual vein obstruction. The recanalization rate is not related to clot diameter at CDVT diagnosis nor to the anatomical characteristics of CDVT. In patients with cancer, 6 week heparin treatment seems to be insufficient for CDVT. CONFLICT OF INTEREST None. FUNDING None. REFERENCES 1 Palareti G, Sartori M. Treatment of isolated below the knee deep vein thrombosis. Curr Atheroscler Rep 2016;18:37. 2 Goodacre S, Sampson F, Thomas S, van Beek E, Sutton A. Systematic review and meta-analysis of the diagnostic accuracy of ultrasonography for deep vein thrombosis. BMC Med Imaging 2005;5:6. 3 Righini M, Bounameaux H. Clinical relevance of distal deep vein thrombosis. Curr Opin Pulm Med 2008;14:408e13. 4 Bosson JL, Riachi M, Pichot O, Michoud E, Carpentier PH, Franco A. Diameters of acute proximal and distal deep venous thrombosis of the lower limbs. Int Angiol 1998;17:260e7. 5 Righini M, Le Gal G, Aujesky D, Roy PM, Sanchez O, Verschuren F, et al. Complete venous ultrasound in outpatients with suspected pulmonary embolism. J Thromb Haemost 2009;7:406e12. 6 Gillet JL, Perrin MR, Allaert FA. Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis. J Vasc Surg 2007;46:513e9.
M. Sartori et al. 7 Galanaud JP, Sevestre MA, Genty C, Laroche JP, Zizka V, Quéré I, et al. Comparison of the clinical history of symptomatic isolated muscular calf vein thrombosis versus deep calf vein thrombosis. J Vasc Surg 2010;52:932e8. 8 Galanaud JP, Sevestre MA, Genty C, Kahn SR, Pernod G, Rolland C, et al. Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J Thromb Haemost 2014;12:436e43. 9 Mattos MA, Melendres G, Sumner DS, Hood DB, Barkmeier LD, Hodgson KJ, et al. Prevalence and distribution of calf vein thrombosis in patients with symptomatic deep venous thrombosis: a color-flow duplex study. J Vasc Surg 1996;24: 738e44. 10 Singh K, Yakoub D, Giangola P, DeCicca M, Patel CA, Marzouk F, et al. Early follow up and treatment recommendations for isolated calf deep venous thrombosis. J Vasc Surg 2012;55: 136e40. 11 Palareti G, Cosmi B, Lessiani G, Rodorigo G, Guazzaloca G, Brusi C, et al. Evolution of untreated calf deep vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study. Thromb Haemost 2010;104:1063e70. 12 Sartori M, Cosmi B, Legnani C, Favaretto E, Valdré L, Guazzaloca G, et al. The Wells rule and D-dimer for the diagnosis of isolated distal deep vein thrombosis. J Thromb Haemost 2012;10:2264e9. 13 Caggiati A, Bergan JJ, Gloviczki P, Eklof B, Allegra C, Partsch H. International Interdisciplinary Consensus Committee on Venous Anatomical Terminology. Nomenclature of the veins of the lower limb: extensions, refinements, and clinical application. J Vasc Surg 2005;41:719e24. 14 Elias A, Cadène A, Elias M, Puget J, Tricoire JL, Colin C, et al. Extended lower limb venous ultrasound for the diagnosis of proximal and distal vein thrombosis in asymptomatic patients after total hip replacement. Eur J Vasc Endovasc Surg 2004;27: 438e44. 15 Prandoni P, Lensing AW, 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;137:955e60. 16 Sartori M, Migliaccio L, Favaretto E, Palareti G, Cosmi B. Two years outcome of isolated distal deep vein thrombosis. Thromb Res 2014;134:36e40. 17 Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence based Clinical Practice Guidelines. Chest 2012;141(2 Suppl.):e419Se94S. 18 Pinede L, Ninet J, Duhaut P, Chabaud S, Demolombe Rague S, Durieu I, et al. Investigators of the “Duree Optimale du Traitement AntiVitamines K” (DOTAVK) Study. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001;103:2453e60. 19 Parisi R, Visonà A, Camporese G, Verlato F, Lessiani G, Antignani PL, et al. Isolated distal deep vein thrombosis: efficacy and safety of a protocol of treatment. Treatment of Isolated Calf Thrombosis (TICT) Study. Int Angiol 2009;28:68e72. 20 Ghirarduzzi A, Camporese G, Siragusa S, Imberti D, Bucherini E, Landini F, et al. A randomized, prospective, open-label study on distal vein thrombosis (low-molecularweight heparin vs.
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022
Calf Deep Vein Thrombosis Clot Characteristics warfarin for 6 weeks): the Todi study. J Thromb Haemost 2009;7(suppl. 2):PP-WE-403. 21 MacDonald PS, Kahn SR, Miller N, Obrand D. Short-term natural history of isolated gastrocnemius and soleal vein thrombosis. J Vasc Surg 2003;37:523e7. 22 Sartori M, Favaretto E, Cini M, Legnani C, Palareti G, Cosmi B. D-dimer, FVIII and thrombotic burden in the acute phase of deep vein thrombosis in relation to the risk of post-thrombotic syndrome. Thromb Res 2014;134:320e5.
7 23 Schwarz T, Buschmann L, Beyer J, Halbritter K, Rastan A, Schellong S. Therapy of isolated calf muscle vein thrombosis: a randomized, controlled study. J Vasc Surg 2010;52:1246e50. 24 Schwarz T, Schmidt B, Schmidt B, Schellong SM. Interobserver agreement of complete compression ultrasound for clinically suspected deep vein thrombosis. Clin Appl Thromb Hemost 2002;8:45e9.
Please cite this article in press as: Sartori M, et al., Ultrasound Characteristics of Calf Deep Vein Thrombosis and Residual Vein Obstruction After Low Molecular Weight Heparin Treatment, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.07.022