Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: The blind, prospective CALTHRO study

New Technologies, Diagnostic Tools and Drugs Schattauer 2010 1 Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: The blind, prospective CALTHRO study Gualtiero Palareti 1 ; Benilde Cosmi 1 ; Gianfranco Lessiani 2 ; Giuseppina Rodorigo 1 ; Giuliana Guazzaloca 1 ; Carlotta Brusi 1 ; Lelia Valdré 1 ; Eleonora Conti 1 ; Michelangelo Sartori 1 ; Cristina Legnani 1 1 Department of Angiology and Blood Coagulation Marino Golinelli, University Hospital S. Orsola-Malpighi, Bologna, Italy; 2 Fisiopatologia Vascolare, Casa di Cura Villa Serena, Città Sant'Angelo, Pescara, Italy Summary The natural history of calf deep-vein thrombosis (DVT) is still uncertain and it is debated whether it warrants to be diagnosed and treated. We aimed to investigate the complication rate of untreated isolated calf DVT (ICDVT). Symptomatic outpatients were prospectively managed with serial compression ultrasonography (SCUS). Those without proximal DVT and with likely pre-test clinical probability (PCP) or altered D-dimer received immediate subsequent complete examination of calf deep veins (CCUS) by a different operator. The result of CCUS was kept blind both to the managing doctor and the patient and disclosed after three months. Primary outcome was the rate of venous thromboembolism at three months. We examined 431 subjects (196 males; median age 68.0 years) in whom five outcomes were recorded (1.2%; 95% confidence intervals [CI]: 0.4 2.7). If CCUS results had been available, out- comes would have been recorded in 3/424 patients (0.7%; CI: 0.2 2.1) with two events in subjects negative at both serial and complete CUS. ICDVT was diagnosed in 65 subjects (15.3%; 95% CI: 12 19); of whom 59 remained uneventful (one was lost to follow-up). A significant higher rate of outcomes was recorded in subjects with than without ICDVT (5/64; 7.8%; 95% CI: 3 17 vs. 3/351; 0.8%; 95% CI: 0 2; p=0.003). However, after excluding two events picked at serial CUS in subjects with ICDVT, the difference became barely significant (3/64; 4.7%; 95% CI: 1 13; p=0.049). Thrombotic evolution of untreated ICDVT in high-risk subjects may be relevant. Larger studies are needed to address this issue. Keywords Calf, distal, DVT, vein thrombosis, diagnosis Correspondence to: Prof. Gualtiero Palareti Dept. Angiology and Blood Coagulation Marino Golinelli University Hospital S. Orsola-Malpighi Via Albertoni, 15 40138 Bologna, Italy Tel.: +39 051 6362483, Fax: +39 051 341642 E-mail: gualtiero.palareti@unibo.it Received: April 15, 2010 Accepted after de novo submission: June 21, 2010 Prepublished online: August 5, 2010 doi:10.1160/th10-06-0351 Thromb Haemost 2010; 104: Introduction It is estimated that only one of four outpatients suspected of having deep-vein thrombosis (DVT) actually has the disease. This ratio could be even lower due to the steady increase in the number of patients being referred for the greater awareness of DVT and its complications. Diagnostic procedures, allowing objective diagnosis/exclusion, should therefore be clinically safe, non-invasive and time- and cost-effective in consideration of the relatively large number of patients to be investigated. Management studies have shown that it is safe to withhold anticoagulation in outpatients with suspected DVT if compression ultrasonography (CUS) (1) limited to proximal deep veins yields normal results on presentation and when repeated within 7 days (2, 3). The addition of pre-test clinical probability (PCP) assessment (4), D-dimer assay (5 7) or both (8 13) can improve the cost-effectiveness of the diagnostic procedure by excluding patients with low clinical probability and normal D-dimer from repeated testing. This diagnostic procedure (serial CUS) is based on the premise that thrombi which remain confined to the calf do not need to be diagnosed and treated, unlike thrombi that extend to proximal veins. There is no general agreement, however, on whether non extending calf DVTs need to be diagnosed and treated. DVT limited to the calf is not free of embolic risk and can trigger post-thrombotic syndrome with rates that have ranged from 20% to 80% in prospective studies (14). They recommend, therefore, a single, complete ultrasound examination of all deep veins (complete CUS) in all symptomatic patients. Complete CUS -- implying that all diagnosed calf DVTs are treated with anticoagulants -- is largely followed in clinical practice and has also been advocated as the standard of care for assessment of lower extremity DVT (15). Recently, two randomised studies have shown that serial and complete CUS are similarly safe in the management of patients with suspected leg DVT (16, 17). Complete CUS is technically more demanding and needs extra time to be performed when compared with serial CUS. In some patients complete CUS may be impossible to be perfomed (e.g. plaster cast of the lower limbs) and also the exploration of deep calf veins may be inadequate in a number of patients (1 2%) as also reported in some studies (17). The amount of effort and resources that should be put into calf DVT diagnosis needs to be settled and will depend on assessing the Thrombosis and Haemostasis 104.4/2010

2 Palareti et al. Untreated calf DVT the CALTHRO study potential clinical damage caused by not diagnosing and not treating isolated calf DVTs (ICDVTs). The aim of the present study was to assess the clinical consequences of untreated ICDVTs. Suspected DVT was managed according to serial CUS strategy and complete CUS, involving the calf veins, was also performed but its results remained blind both to the patient and the treating doctor. Material and methods Design of the study and patients The study was performed between September 2006 and February 2009 in two clinical centres: a) Angiology and Blood Coagulation Unit, active in a tertiary care teaching hospital (University Hospital S. Orsola-Malpighi), Bologna, Italy and b) Servizio di Fisiopatologia Vascolare, Casa di Cura Villa Serena, Città Sant'Angelo, Pescara, Italy. Symptomatic outpatients referring to the vascular emergency room of the two centres for suspected acute DVT in a leg were potentially eligible for the study providing it was the first event in the involved leg, a proximal DVT was excluded and the clinical probability was likely or D-dimer assay abnormal. Patients were referred by general practitioners and they were not eligible if: < 18 years old, pregnant or in puerperium, with symptoms attributable to pulmonary embolism (PE) or with acute superficial vein thrombosis of the symptomatic leg. All patients were managed using serial CUS; thus, they received: a) assessment of pre-test clinical probability (PCP) according to Wells (13); b) CUS examination limited to proximal deep veins; c) D-dimer testing in cases of unlikely PCP. On the basis of this diagnostic work-up the following categories of subjects were identified: a) subjects with proximal DVT; they were treated with anticoagulants and excluded from the study; b) subjects with negative proximal CUS, unlikely PCP and normal D-dimer test; they were discharged and excluded from the study; c) subjects with negative proximal CUS, likely or unlikely PCP but associated with abnormal D-dimer test; these subjects were eligible and were invited to participate in the study. The design of the study was explained to eligible subjects. They would receive the standard diagnostic procedure, consisting in a second proximal CUS after 5 7 days (or earlier if symptoms or signs worsened); in the meantime they would wear an elastic, below-knee, class 2 compression stocking (to improve symptoms by reducing both edema and/or pain) and take non-steroidal antiinflammatory drugs (NSAIDS) if pain was present. As a rule, no anticoagulant drugs were to be prescribed. If they agreed to take part in the study, they would immediately receive a complete colour Doppler ultrasonography of the whole symptomatic leg (including deep calf veins) by a different experienced examiner. The results of this examination would not be communicated to the patient or to the first examining doctor, and would be recorded in a form kept in a sealed envelope. The envelope would be opened three months later, when all participating patients received a physical examination or a structured interview by phone call from a doctor or a nurse using a standardised questionnaire to assess their general health status, chest or leg complaints, and history of hospital admission for any cause. The envelope would also be opened after detection of proximal DVT at the CUS repeated after 5 7 days, or if the patient presented again for symptomatic complications within three months. During this interval time they were invited to refer urgently to the outpatient service whenever symptoms or signs of thromboembolic complications arose. In both participating centres, proximal US examinations were performed and interpreted by experienced vascular medicine physicians (6 in the Bologna centre, and 2 in the Pescara centre). All examiners had had supervised training for at least six months and had routinely worked in the in/outpatient vascular ultrasound examination services in both centres for at least two years. It was not possible to enroll all consecutive eligible patients but rather patients were included based on the availability of expert medical staff that could perform complete CUS (3 in the Bologna centre and 1 in the Pescara centre) on the day of their presentation. These physicians had supervised training to perform complete CUS for a minimum of six months. At least the first eligible patient of the day was included, to minimise selection bias. The study was approved by the Ethics Committee of the two participating centres. Ultrasound examination of deep leg veins and D-dimer assay Each patient underwent a first ultrasound examination of proximal deep veins, followed immediately by a subsequent complete ultrasound examination of the symptomatic leg, including deep calf veins, by a different operator, using a standardised examination protocol. High-resolution 5 to 7.5-MHz linear transducers were used. The proximal deep veins were examined with the patient in the supine position by moving the probe from the common femoral vein in the groin to the trifurcation of the popliteal vein and applying gentle compression along the deep venous system. The deep calf veins were examined down to ankle level with a similar ultrasound procedure, with the patient in the sitting position with the legs hanging down. The calf veins examined were the posterior tibial, the peroneal, the gastrocnemius muscular and soleal. The criterion to diagnose proximal DVT was non-compressibility of the vein in the transverse plane, with Doppler tests of iliac veins in case of suspected isolated iliac thrombosis. The criterion for calf DVT was incompressibility of the vein combined with the absence of venous flow after distal compression. For D-dimer testing the Sta-Liatest D-dimer reagent by Stago (Asnieres, France) (n.v. < 500 ng/ml) was used in the Bologna centre, and the Automated Latex Enhanced Immunoassay (HemoSil ) (Instrumentation Laboratory, Lexington, MA, USA) (n.v. < 500 ng/ml) in the Pescara centre. Thrombosis and Haemostasis 104.4/2010 Schattauer 2010

Palareti et al. Untreated calf DVT the CALTHRO study 3 Statistical analysis Primary outcome endpoints were the rate of symptomatic thromboembolic complications (proximal or ICDVT and PE) recorded over a three month follow-up in the whole group of subjects investigated according to the serial CUS. The incidence of symptomatic venous thromboembolic events during three month follow-up, after a normal workup with a serial CUS, was expected to be around 1.0%. A sample size of 400 patients was calculated, estimating 3% as the upper 95% confidence interval (CI) for thromboembolic complications at the three month follow-up. Secondary outcomes were the rate of thromboembolic complications over a three-month follow-up in those patients in whom ICDVTs would have been diagnosed if the results of the complete CUS had been immediately available in comparison with those patients in whom a ICDVT was excluded. Continuous variables are presented as median and range. Baseline differences between groups were assessed by the Fischer s or chi-square (Yates correction) tests, as appropriate, for categorical variables and Mann-Withney U test for continuous variables; p-values <0.05 were considered to be statistically significant. The data were analysed using the Prism statistical software package (Version 3.0, GraphPad Software Incorporated, San Diego, CA, USA) and the SPSS statistical package (Version 11.0, SPSS Inc., Chicago, IL, USA). Results Serial CUS Figure 1A shows the entire population of patients investigated for suspected DVT. Figure 1B shows a diagram of the study population managed according to serial CUS. A total of 431 subjects were included in the study after 18 subjects refused to participate. Table 1 shows the characteristics of the enrolled subjects. In all of them the presence of proximal DVT had been excluded at Figure 1: Flow charts of the study. A) Symptomatic outpatients with suspected leg DVT; B) Negative CUS, likely PCP or altered D-dimer invited to participate in the study. $ = including the 7 subjects who did not present at 2 nd CUS but had a complete followup. = in this subject (negative at complete CUS) calf DVT was tested and diagnosed at 2 nd CUS due to worsening of symptoms. & = this subject had worsening symptoms and calf DVT (present at complete CUS) was confirmed during follow-up. * = secondary outcome. ** = 3/64; 4.7% (95% CI:1 13) after exclusion of the 2 subjects in whom DVT was picked at the 2 nd CUS. A Schattauer 2010 Thrombosis and Haemostasis 104.4/2010

4 Palareti et al. Untreated calf DVT the CALTHRO study B Figure 1: Continued presentation by means of proximal CUS examination, and all had likely pre-test clinical probability or altered D-dimer assay. They received an appointment to return after 5 7 days (or before if symptoms worsened) for repeated proximal CUS examination. After the first negative proximal CUS and before the second control, all subjects were invited to wear below-knee elastic stockings and take NSAIDS for pain, while only seven subjects received LMWH prophylactic doses. At the 5 7 day control, proximal DVT was diagnosed in two subjects (0.5%;95% confidence intervals- CI: 0 2), in one subject calf DVT was diagnosed for worsening symptoms while superficial vein thrombosis was diagnosed in two subjects. These five subjects were appropriately treated with anticoagulants. Seven subjects did not return after the 5 7 days for repeated CUS. When investigated at end of follow-up, six of these did not report clinical problems. Nine subjects (out of 431) were lost to follow-up (2.1%). During the entire follow-up eight primary clinical endpoints were recorded in the whole study population. Three of them were detected at 2 nd proximal CUS examination and treated with anticoagulants. Five outcomes not detected by serial CUS were recorded at three months (1 PE, 2 proximal and 2 ICDVT; 1.2%; 95% CI: 0.4 2.7). Results if patients had been managed by complete CUS On the day of their first presentation all subjects received a complete CUS examination of calf deep veins of the symptomatic leg. In seven subjects the ultrasound examination of calf veins was considered technically inadequate and inconclusive by the examining doctor; these cases were excluded from further evaluation (1.6%; 95% CI:1 3%). No proximal DVT was detected. The mean du- Thrombosis and Haemostasis 104.4/2010 Schattauer 2010

Palareti et al. Untreated calf DVT the CALTHRO study 5 Table 1: Characteristics of the investigated subjects. Number of subjects included in the study 431 Age median, years (range) 68 (19 96) Sex male/female 196/235 Symptomatic leg Right Left Bilateral Clinical probability Likely Unlikely Risk factors for DVT according to the Wells score, no. (%) Active cancer Paralysis, paresis, or recent plaster immobilization of the lower extremities Recently bedridden for 3 days or more, or major surgery within the previous 3 months Previously documented DVT in the contralateral leg D-dimer assay (403 subjects tested) Altered (> 0.5 ng/ml) Normal ( 0.5 ng/ml) 186 240 5 234 197 22 (5.1) 31 (7.2) 43 (10.0) 29 (6.7) Duration of symptoms, days median (range) 5 (1 31) 237 166 ration of complete CUS examination was 8 minutes. Thrombosis in at least one deep calf vein was detected in 65/424 subjects (15.3%), and more than one deep vein was involved in 22 (33.8%) of them. In two subjects (3.1%) a calf DVT extended to proximal veins and it was then detected at 2 nd examination of serial CUS. Table 2 shows the characteristics of the subjects with or without calf DVT. Subjects with calf DVT had a significantly more frequent likely clinical probability (p= 0.014) while no difference was observed in the rates of altered D-dimer and of risk factors for DVT when compared with subjects without calf DVT. The results of complete CUS were kept blind to both patients and treating doctors; the patients with diagnosed calf DVT did not receive, therefore, different treatment from the others. In subjects in whom ICDVT was diagnosed at complete CUS, five complications were recorded. One subject was admitted with PE to a different hospital two days after his visit; three proximal DVTs occurred in subjects with diagnosed calf DVT at complete CUS (2 were picked at repeated CUS), and one calf DVT, present at complete CUS, was diagnosed for worsening symptoms after the initial serial CUS. One of the nine subjects lost-to follow-up had calf DVT at complete CUS. The remaining patients had an uneventful follow-up. Three thromboembolic events, however, occurred in subjects with negative results at complete CUS (1 proximal and 2 calf DVTs, one of which was negative at complete CUS and was detected for worsening symptoms at the 2 nd CUS; 3/424; (0.7%; CI: 0.2 2.1) (Fig. 1B). The two cases with superficial vein thrombosis were both detected at 2 nd examination of serial CUS (with negative complete CUS results and without calf DVT). At the end of three month follow-up the evolution of signs/symptoms in the affected leg did not differ in subjects with or without diagnosed calf DVT (see Table 2). Two subjects died of cancer and one started anticoagulation with vitamin K antagonists for atrial fibrillation. If complete CUS results had been available, 65 subjects would have received anticoagulant treatment after initial diagnosis of calf DVT, and hence five outcome events would have been prevented. When the actual outcomes were stratified according to the presence or absence of calf DVT diagnosed with complete CUS, there was a significant difference at three months in patients with untreated calf DVT (5/64: 7.8%, 95% CI:3 17) in comparison with patients without calf DVT (0.8%; 95% CI: 0 2) (p= 0.003). However, the difference became barely significant after the two calf DVTs, picked by repeated proximal CUS due to their proximal extension, were excluded from the group with ICDVT (3/64; 4.7% ; 95% CI:1 13; p=0.049). Discussion The natural history of isolated calf DVT is still uncertain, as a result, the need to test for calf DVT is a matter of debate and different choices are adopted in clinical practice (18). The need to test for and treat calf DVT should be related to the clinical risk associated with these thromboses. However, even if very few data are available on the natural history of calf DVT and the clinical risks, the need for treating it with anticoagulants when diagnosed is almost unanimously agreed upon and recommended by guidelines, including the recent ones of the American College of Chest Physicians (18). However, only one study, published by Lagerstedt et al. in 1985 (19) supports this practice. In that study, 28/51 patients with calf DVT diagnosed by venography were left without anticoagulation and eight of them had complications: one had a PE while the others had recurrences diagnosed by physical examination and serial isotopic tests (a diagnostic test that was later abandoned for this scope because of its insufficient perform- Schattauer 2010 Thrombosis and Haemostasis 104.4/2010

6 Palareti et al. Untreated calf DVT the CALTHRO study Age, years median (range) Sex (male/female) Symptomatic legs, no. Right Left Bilateral Clinical probability Likely, no. (%) Unlikely, no. (%) D-dimer assay (subjects tested) Altered, no. (%) Normal, no. (%) Sites of calf veins with thrombosis, no. Posterior tibial Peroneal Gastrocnemious medialis lateralis Soleal Subjects included = 431 Subjects with technically inadequate calf examination = 7 Subjects evaluated = 424 Calf DVT 65 (15.3%) 65 (27 96) 31/34 36 28 1 45 (69.2) 20 (30.8) (60) 38 (63.3) 22 (36.7) 25 21 33 5 19 No calf DVT 359 (84.7%) 68 (19 96) 161/198 147 208 4 186 (51.8) 173 (48.2) (337) 195 (57.9) 142 (42.1) P 0.187 0.773 0.014 0.515 Table 2: Results of comprehensive CUS examination and characteristics of subjects with diagnosed calf DVT. Subjects with > 1 calf vein with DVT, no. (%) Clinical evolution at 3 month follow-up, no. (%) Primary outcomes (DVT or PE) Secondary outcomes (SVT) Symptoms in the affected leg Improved or absent Stable Worsened (excluded subjects with thrombotic complications) Lost at follow-up * excluding the 2 subjects in whom DVT was picked at the 2nd CUS. 22 (33.8) 5 (7.8) 3 (4.7)* 54 (84.4) 5 (7.8) 0 1 3 (0.8) 3 (0.8) 321(91.5) 24 (6.8) 1 (0.3) 8 0.003 0.049 0.841 ance); no complications occurred in the 23 anticoagulated subjects. The need to diagnose and treat ICDVT seems to be contradicted by the results of more recent management studies of suspected DVT of the lower limbs in symptomatic outpatients employing serial CUS of proximal veins, in which ICDVTs are diagnosed only if extending proximally, but otherwise are left untreated. Serial CUS was shown to have a three-month rate of thromboembolic complications similar to that observed in management studies employing complete CUS, which can detect all DVTs (0.6% ;95% CI: 0.4 0.9% and 0.4%; 95% CI: 0.1 0.6%, respectively) in an analysis of pooled data of available management studies (21). More recently, the ERASMUS study was the first to randomise symptomatic outpatients with suspected DVT of the lower limbs to receive either serial CUS with D-dimer or complete CUS, regardless of PCP, and it also showed a similar failure rate of the two procedures (16). The similar safety of serial and complete CUS in both management and randomised studies suggests that the majority of ICDVTs have a benign evolution over a threemonth follow-up and therefore may not warrant diagnosis and treatment. It should be noted, however, that patients diagnosed with calf DVT received anticoagulant treatment in all the management studies analysed by Righini et al. (20), as well as in the ERAS- MUS randomised trial (16). This also implies that not all ICDVTs are diagnosed by complete CUS. If all ICDVTs were diagnosed and treated by complete CUS, the failure rate at three months should be expected to be significantly lower than that of serial CUS in managemnt studies. Serial and complete CUS differ in their advantages and disadvantages (21). Serial CUS is technically simpler than complete CUS, as it does not require sophisticated instrumentation or a high level of vascular examination expertise. However, repeated testing involves a greater use of health system resources and more discomfort for patients, some of whom are not willing to come back for the second examination (especially if symptoms are easing). Complete CUS detects all DVTs in a single session and is generally well accepted by patients, who can receive results immediately (positive Thrombosis and Haemostasis 104.4/2010 Schattauer 2010

Palareti et al. Untreated calf DVT the CALTHRO study 7 or negative). However, this procedure requires more sophisticated instrumentation, more skilled investigators and in some cases the investigation of calf deep veins can be technically inadequate. Complete CUS also requires more time to be performed. This can be the case in subjects with likely clinical probability and apparently negative CUS in whom the operators try to be as accurate as possible before excluding thrombosis, even in small veins. As a result, this could lead over-diagnosis of calf DVT (22). The most important clinical consequence of the complete CUS is that it leads to diagnosis of DVT in a significant percentage of investigated subjects who should then all be treated with anticoagulants, even though only very few will be at risk of clinically relevant complications. As a result, the use of complete CUS could limited only to those patients with a higher risk of DVT. More recently, Gibson et al.(17) randomised only symptomatic outpatients with likely PCP or unlikely PCP with altered D-dimer to receive either serial or single complete CUS. During follow-up, venous thromboembolism occurred in four patients (2.0%; 95% CI 0.6 5.1) in the serial CUS arm, and in two patients (1.2%;95% CI 0.2 4.3) in the complete CUS arm, indicating similar safety of the two procedures in high-risk patients. Our study design differed from that of previously published studies because our aim was to establish the natural history of calf DVT. Patients were enrolled only if they had likely clinical probability or altered D-dimer levels and they all underwent CUS to exclude proximal DVT. As a result, included patients were at higher risk of having ICDVT. These subjects were managed according to serial CUS but they also received a complete CUS, the results of which were kept blind and disclosed only after three months. The clinical results obtained at three months with serial CUS were compared with those that would have been obtained with complete CUS. All subjects diagnosed with calf DVTs would have received at least three months of anticoagulation and that all thrombotic events in these subjects would have been prevented. As expected, at the end of three months, the serial CUS failure rate was similar to that which would have been recorded if the results complete CUS had been available. The rate of calf DVT (15.3%) was consistent with that recorded in other studies where the frequency of diagnosed isolated distal DVT ranged from 4.7% to 18% (16, 23 26). At follow-up, thrombotic complications occurred in five out of the 64 subjects with diagnosed calf DVT (one case was lost to follow-up), two of them extending proximally and being detected at second CUS examination of the serial CUS procedure and one calf DVT diagnosed for worsening symptoms during the first week. This rate was significantly higher than that of subject in whom ICDVT was excluded by complete CUS. However when the two proximally extending ICDVT detected at the 2 nd CUS were excluded from the group with ICDVT, the difference in outcomes between subjects with and without ICDVT became barely significant. Although receiving no specific treatment except below-knee elastic stockings and NSAIDS in case of pain, 59 subjects out of 64 were free from thrombotic complications and signs/symptoms were markedly improved or completely absent in most of them. In contrast, the complete CUS procedure would not have prevented three outcomes that occurred in subjects with negative complete CUS. Conversely, 59 subejcts out of the 64 diagnosed with calf DVT that completed follow-up would have received, unnecessarily, anticoagulation for three months. These results indicate that most untreated calf DVTs have a benign clinical course and only some of them may have clinically relevant thrombotic outcome. Unfortunately, we do not have yet standardised criteria to single out those patients who are at higher risk of such outcomes and so all of them will be treated with anticoagulants for a period (usually three months) a treatment associated with bleeding risks and discomfort for patients. In our study subjects with calf DVT had likely PCP more frequently than those without calf DVT, while the proportion of subjects with altered D-dimer was similar in subjects with or without calf DVT. Furthermore, selection criteria of those who need a second examination are not well established in clinical practice. In the present study 30.8% and 36.7% of subjects with diagnosed calf DVT had unlikely clinical probability or normal D-dimer levels, respectively. In our study an extension of calf DVTs into proximal veins as picked by repeated CUS occurred in very few cases, with a rate (3.1%) much lower than that expected of 15 20% (27 29). The results of our study should be interpreted with caution. First, the study was performed in only two clinical centres, and this is a limit to its generalisability. Second the number of examined subjects was relatively small due to two factors: the need to exclude from a rather cumbersome investigation those subjects with very What is known about this topic? The natural history of a deep-vein thrombosis (DVT) located in the calf is still not well defined. Whether isolated calf DVT should be looked for, diagnosed and treated, remains unsettled. Recent clinical studies have shown that two different diagnostic strategies (1. the serial CUS that diagnoses and treat only proximal DVT, and 2. the single complete CUS that diagnoses also isolated calf DVT) have similar safety in the management of patients with suspected leg DVT. What does this paper add? After exclusion of a proximal DVT, isolated calf DVTs were detected in 15.3% of symptomatic out-patients who had likely clinical probability or altered D-dimer. Untreated Isolated calf DVTs had an uneventful clinical course at three month follow-up in most subjects and extended into proximal veins in only 3.1% of cases. However, the rate of complications at three months was significantly higher in subjects with than without calf DVT (7.8% vs. 0.8%, p= 0.003), although the difference became barely significant after excluding two subjects with proximally extending calf DVT picked at the 2 nd serial CUS (4.7% vs. 0.8%; p=0.049). There is a need for clinical studies focused on trying to identify those symptomatic out-patients deserving investigation and treatment for isolated calf DVT. Schattauer 2010 Thrombosis and Haemostasis 104.4/2010

8 Palareti et al. Untreated calf DVT the CALTHRO study low probability of calf DVT (with both low pre/test clinical probability and negative D-dimer assay) and the rather limited resources available (one vascular doctor free on call for the complete CUS examination). Third, the patients investigated were not all consecutive patients referring to the vascular outpatient service of the two clinical centres and a bias of selection cannot be excluded. However, with the aim of reducing this bias, most of the patients included were eligible subjects who presented first in the morning. Fourth, the complete CUS did not involve the exploration of the anterior tibial veins. However, this is a very rare location of thrombi which is not usually evaluated, as also done by other investigators (16, 24, 26). Fifth, no inter-observer variability was assessed for complete CUS. Sixth, the use of elastic stockings and NSAIDS may be considered as a treatment of calf DVT and in itself may change the evolution of isolated calf DVT in some cases, although the number of subjects actually taking NSAIDS for pain was not recorded. Finally, the total number of thromboembolic complications (n=8) observed at three month follow-up was small and produced quite large confidence intervals when the events were considered according to the presence of ICDVT at complete CUS. As a result, the estimates of the outcomes may be imprecise indicating that specifically designed, multicentre, prospective studies with larger samples are needed for definite conclusion about the clinical relevance of ICDVT. Acknowledgements We thank Stephen Jewkes for his correction of English. References 1. Lensing AWA, Prandoni P, Brandjes D, et al. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med 1989; 320: 342 345. 2. Cogo A, Lensing AWA, Koopman MMW, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. Br Med J 1998; 316: 17 20. 3. Birdwell BG, Raskob GE, Whitsett TL, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998; 128: 1 7. 4. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997; 350: 1795 1798. 5. Bernardi E, Prandoni P, Lensing AW, et al. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. The Multicentre Italian D-dimer Ultrasound Study Investigators Group. Br Med J 1998; 317: 1037 1040. 6. Perrier A, Desmarais S, Miron MJ, et al. Non-invasive diagnosis of venous thromboembolism in outpatients. Lancet 1999; 353: 190 195. 7. Stein PD, Hull RD, Patel KC, et al. 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