Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome

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1 Journal of Thrombosis and Haemostasis, 7: DOI: /j x REVIEW ARTICLE Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome S. R. KAHN Division of Internal Medicine and Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, McGill University, Montréal, Canada To cite this article: Kahn SR. Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome. J Thromb Haemost 2009; 7: See also Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C, on behalf of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. This issue, pp Summary. The post-thrombotic syndrome (PTS) is a frequent and important complication of deep venous thrombosis (DVT). The diagnosis of PTS is based primarily on the presence of typical symptoms and clinical signs. In the 1990s, a clinical scale known as the Villalta scale was proposed as a measure that could be used to diagnose and classify the severity of PTS. The objective of the present paper was to review the published evidence on the measurement properties of the Villalta scale. Results of the review demonstrate that the Villalta scale is a reliable and valid measure of PTS in patients with previous, objectively confirmed DVT. The scale is acceptable to research subjects and research personnel, and shows responsiveness to clinical change in PTS. Aspects of the Villalta scale that merit further evaluation include test retest reliability, more detailed assessment of ulcer severity and assessment of responsiveness across the full range of PTS severity. Research aimed at improving the measurement of PTS will also help to improve the overall validity of findings generated by clinical studies of PTS. Keywords: clinical scale, diagnosis, measurement, post-thrombotic syndrome, reliability, validity, venous thrombosis. Introduction The post-thrombotic syndrome (PTS) is a frequent complication of deep venous thrombosis (DVT) that is costly, potentially disabling and leads to reduced quality of life [1 3]. In clinical practise, PTS is diagnosed on the basis of the Correspondence: Susan R. Kahn, Division of Internal Medicine and Centre for Clinical Epidemiology and Community Studies, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Rm. A-114, Montréal, PQ H3T 1E2, Canada. Tel.: ; fax: susan.kahn@mcgill.ca presence of typical symptoms and clinical signs. This approach is logical because PTS manifests clinically as a range of symptoms and signs that can differ in character and severity among patients [4]. In 1992, Prandoni and colleagues [5] proposed a clinical scale to diagnose and classify the severity of PTS that has come to be known as the Villalta scale, based on its description in an abstract published in 1994 [6]. During the last years, the Villalta scale has been used in a number of studies of the incidence, risk factors, prevention and treatment of PTS [1,3,7 11]. While not their primary focus, these studies have generated important ancillary data on the measurement properties of the scale. The objective of this report is to review published evidence on the reliability, validity, acceptability and responsiveness of the Villalta scale as a measure of PTS. Methods A computerized search of the MEDLINE and EMBASE electronic databases (1990-present) was performed to identify published papers that described the use of the Villalta scale to measure PTS in patients with DVT. The references of papers identified by the search were also examined to detect additional relevant abstracts or papers. Papers that provided information pertaining to descriptive elements, reliability, validity, acceptability or responsiveness of the Villalta scale were retrieved, and the information obtained is described and synthesized below. Results Description of the Villalta scale The Villalta scale was initially developed in a cross-sectional study of 100 consecutive patients who were evaluated 6 36 months following venography-confirmed DVT [6]. The scale consists of five patient-rated venous symptoms (pain, cramps, heaviness, paresthesia, pruritus) and six clinician-rated

2 Villalta scale to measure the post-thrombotic syndrome 885 physical signs (pretibial edema, skin induration, hyperpigmentation, pain during calf compression, venous ectasia, redness), which are each rated on a four-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Points are summed to produce a total score (range: 0 33). Subjects are classified as having PTS if the score is 5, or if a venous ulcer is present, in a leg with previous DVT. In the original report [6] and in some subsequent studies [7 12], the severity of PTS was categorized as mild/moderate if the score was 5 14, and as severe if the score was 15 or if a venous ulcer was present, regardless of the total score. In recent studies, the mild/moderate category has been subcategorized as mild if the score is 5 9 and moderate if the score is [1,3]. While in some studies two consecutive assessments that corresponded to PTS (i.e. Villalta score 5) were required to diagnose PTS [7,8,10], in other studies PTS has been diagnosed based on a single assessment [1,11]. Reliability of the Villalta scale The reliability, or reproducibility, of a measure refers to the extent to which measurements yield consistent results if repeated over time or by different raters, assuming that the aspect being measured has remained constant [13]. The inter-rater reliability of the Villalta scale has been evaluated in two studies. As described in the original abstract, the inter-rater (physician physician) agreement, measured by the weighted kappa statistic, was good to excellent for the total score (j = 0.78; 95% CI 0.59, 0.98), sum of signs score (j = 0.77; 95% CI 0.58, 0.95), sum of symptoms score (j = 0.80; 95% CI 0.57, 1.00), and PTS severity category (i.e. none, mild/moderate, severe) (j = 0.75; 95% CI 0.51, 0.99) [6]. The reliability of the Villalta scale was also assessed in a substudy to the REVERSE Study, a multicenter, prospective cohort study of 646 patients with a first, unprovoked venous thromboembolism [14]. Study nurses received a 1-h training session on assessing the physical signs components of the Villalta scale. Subsequently, independent duplicate ratings of physical signs were performed at four study centers by pairs of raters (study nurses) in 125 patients in total; the symptoms components of the scale were rated by the patient only once. The total Villalta score showed excellent correlation between raters (SpearmanÕs coefficient 0.89). The inter-rater reliability for the cut-point Ôany vs. no PTSÕ was good (j = 0.71; 95% CI ) and for Ômoderate or severe vs. no or mild PTSÕ was excellent (j = 1.00) [15]. The studyõs strengths include its prospective, multicenter design and a sample size that was large enough to provide precise estimates of reliability. However, reliability is likely to have been overestimated because the same symptoms ratings were used for both assessments. Other measures of reproducibility of the Villalta scale such as intra-rater and test retest reliability have not been reported. To assess intra-rater reliability, single raters perform two ratings on the same subject on separate occasions. As the inter-rater reliability of the Villalta scale has been shown to be good to excellent, it is anticipated that intra-rater reliability would be similar or better. Test retest reliability is particularly relevant for patient-based measures such as self-completed questionnaires. An indicator of the stability of a measure over time, test retest reliability is assessed by administering the measure on two occasions separated by an interval of time that is short enough to ensure that clinical changes are unlikely to have occurred but sufficiently long to ensure that patients do not recall their responses from the first assessment [13]. Assessment of the test retest reliability of the patient-completed symptoms component of the Villalta scale has not been reported in the published literature. Validity of the Villalta scale In broad terms, the validity of a scale is assessed by considering whether there is evidence that the scale is measuring what it is intended to measure. Because there is no Ôgold standardõ, objective, diagnostic test for PTS to which the Villalta scale could be compared, assessing the validity of the Villalta scale relies on showing that the scaleõs scores and proposed cutpoints correlate with (i) relevant health outcomes, such as generic and disease-specific quality of life (QOL) and (ii) known anatomic or physiologic correlates of PTS. Several lines of evidence support the validity of the Villalta scale for the measurement of PTS. Correlation with relevant health outcomes Patient-perceived health burden: As reported in the original abstract, a physician who was not involved in performing ratings of the individual components of the Villalta scale independently assessed the overall degree to which venous symptoms and signs interfered with the patientõs daily life (interference was classified as none, light, moderate or severe). Using degree of interference with daily life as the Ôgold standardõ, optimal cut-points for PTS and for PTS severity were determined with receiver-operator characteristic curve (ROC) analysis [6]. Total Villalta score (rather than symptoms alone, or signs alone) was the best predictor of degree of interference with daily life, and weighting of individual symptoms or signs did not improve these results. Among patients with no interference (67% of patients), mean (SD) Villalta score was 1.7 (2.0), while in patients with light (22%), moderate (7%) and severe (4%) interference, mean scores were 5.1 (1.7), 8.8 (2.3) and 18.5 (3.4), respectively. The scale showed good ability to discriminate disease severity, as measured by area under the ROC curve (AUC). For none vs. light interference, AUC was 0.93 ± 0.027; for light vs. moderate interference, AUC was 0.98 ± 0.016; and for moderate vs. severe interference, AUC was Based on the results obtained, a score of 5 was selected to indicate the presence of PTS, a score of 5 14 to indicate mild to moderate PTS, and a score 15 to indicate severe PTS. Quality of life: A number of studies have demonstrated that PTS measured with the Villalta scale correlates strongly with patient-reported QOL, measured using validated QOL instru-

3 886 S. R. Kahn ments. For the QOL measures described below, lower scores indicate poorer QOL and differences of 3 4 points are considered to be clinically relevant [16,17]. In a cross-sectional, single-center study of 41 outpatients with a previous episode of objectively confirmed DVT, the presence of PTS (i.e. Villalta score 5), higher Villalta score, andgreatercategoryofptsseverityeachcorrelatedstrongly with poorer venous disease-specific QOL, measured with the VEINES-QOL questionnaire [17] (P < for each comparison) [9]. For example, patients with severe PTS had VEINES-QOL scores that were, on average, 21 points lower than patients without PTS (P < 0.001). In a 145-patient substudy to a large multicenter trial that compared two intensities of warfarin for the long-term treatment of unprovoked venous thromboembolism (ELATE Study) [18], the presence of PTS, ascertained at a mean follow-up of 2.2 years, strongly correlated with poorer venous disease-specific QOL (decrease of 6.9 points on the VEINES-QOL measure, P < ) and poorer generic physical QOL (decrease of 7.4 points on SF-36 Physical Component Score (PCS), P = ) [18]. In a prospective multicenter cohort study of 387 patients with acute DVT who were followed for 2 years, patients who developed PTS had significantly poorer QOL at all follow-up visits compared with patients who did not develop PTS [3]. At 2 years, PTS was the most important independent predictor of generic physical QOL (adjusted average SF-36 PCS score, 7.1 points lower than in patients without PTS; P < ) and disease-specific QOL (adjusted average VEINES-QOL score, 4.4 points lower than in patients without PTS; P < ), and showed evidence of a dose-response effect, such that patients with more severe PTS had correspondingly poorer QOL [3]. Furthermore, in the same study, among 233 study patients who underwent Duplex ultrasound evaluation at the 1-year visit, having PTS was strongly associated with statistically and clinically significant poorer generic physical and mental QOL (mean difference of 9.4 points on SF-36 PCS and 4.7 points on SF-36 mental component score (MCS)) as well as poorer venous-disease specific QOL (mean difference of 7.6 points on VEINES-QOL measure), whereas the presence of venous valvular reflux was not [19]. Finally, correlations between Villalta scores and generic physical QOL in the above-noted studies were stronger than correlations with generic mental QOL, which would be expected for a physical condition such as PTS. Associations with anatomic or physiologic correlates of PTS: Additional support for the validity of the Villalta scale is provided by studies that have shown associations between Villalta score results and known anatomic or physiologic abnormalities associated with chronic venous disease. In a study of the utility of non-invasive tests, including clinical assessment, to detect prior proximal vein thrombosis in 100 patients who had previously had venography for suspected DVT, a low Villalta score alone successfully identified 93% of patients who did not have previous DVT, whereas a high Villalta score alone identified 33% of patients who had previous DVT [20]. Among 180 patients who were prospectively evaluated 3 and 6 months after a first episode of proximal DVT, those with PTS, defined by a Villalta score of 5, had a higher frequency of venous abnormalities on Duplex ultrasound, including residual vein thrombosis, popliteal valvular reflux or both (P < 0.001) [21]. Finally, in 124 patients with previous DVT, mean ambulatory venous pressure (AVP) (measured by intravenous cannulation of a foot vein) increased in a graded fashion with greater Villalta PTS severity category (AVP 29 mmhg for no PTS, 41 mmhg for mild/ moderate PTS, and 66 mmhg for severe PTS; P <0.001for trend) [22]. It is acknowledged that the symptoms and signs assessed by the Villalta PTS scale are non-specific and may have causes other than PTS; the same holds true for other scales that have been developed to measure or classify PTS or chronic venous disease [23]. However, in a study that applied six different classification schema for PTS to both the DVT-affected and control legs of 124 patients, PTS as measured by the Villalta scale had a high absolute difference (37%) in prevalence between affected and control legs, with an odds ratio of 5.0 for affected vs. control legs [22]. Acceptability of the Villalta scale The acceptability of a measure refers to whether research personnel and subjects are willing and able to administer and complete the measure, with a low proportion of missing data. The Villalta scaleõs symptoms component can be completed by patients in 5 min, and the signs component can be completed by research staff in 10 min. To help administer the scale, a visual guide for grading the severity of signs has been developed [23] and is being used in a large multicenter trial of elastic compression stockings to prevent PTS [24]. Missing data on the scale are rare, occurring in < 1% of assessments at five timepoints in a 387-patient prospective cohort study [1]. Various groups of investigators in a number of countries have used the Villalta scale to measure PTS, further demonstrating its acceptability. The scale has been used in crosssectional studies [9,20,22], cohort studies [1,7,10,25], singlecenter trials [8,26 28] and multicenter trials [18], including an ongoing randomized trial that is comparing the effectiveness of catheter-directed venous thrombolysis with conventional treatment with anticoagulants to prevent PTS after acute iliofemoral DVT [29]. Responsiveness of the Villalta scale to clinical change in PTS severity AscaleÕs responsiveness refers to whether it is able to detect (i.e. is sensitive to) clinically important change over time in the condition that it is measuring. Responsiveness is assessed by comparing the concordance between change in the measure of interest and change in an alternative measure of the same condition [13]. Two studies have provided direct evidence that the Villalta scale is responsive to change in the clinical severity of PTS.

4 Villalta scale to measure the post-thrombotic syndrome 887 First, within a multicenter prospective cohort study noted above [3], an analysis of 359 patients that focused on the first few months of follow-up found that worsening of the Villalta score during the 4 months following an acute episode of DVT was associated with clinically and statistically significant deterioration in generic physical quality of life (P < 0.001) and venous disease-specific quality of life (P < 0.001) [12]. Second, in a randomized controlled cross-over trial that evaluated a novel lower-limb venous return assist device for the treatment of severe PTS in 32 patients, use of the active device led to a mean 3.1 point improvement in the Villalta score over study follow-up, compared with use of the control device (P = 0.004). This effect was paralleled by greater patientreported benefit and significant improvement in venous-disease specific quality of life in the active device group over the same time period [11]. Conclusions The Villalta scale was proposed in the 1990s as a clinical scale to diagnose and classify the severity of PTS. In this paper, published studies that have provided data on the measurement properties of the scale were reviewed. These data are consistent in supporting that the Villalta scale is a reliable, valid, acceptable and responsive measure of PTS in patients with previous, objectively confirmed DVT. This review also highlights that information on the following aspects of the Villalta scale is lacking and would be worth evaluating: (i) assessing the reliability of the symptoms components of the scale; (ii) determining if assigning numeric points for ÔulcerÕ based on increasing ulcer severity (e.g. no ulcer, healed ulcer, one open ulcer, > 1 open ulcer) would refine the scaleõs ability to discriminate among severe forms of PTS, compared with the current binary approach of scoring ÔulcerÕ as present or absent; and (iii) further assessing responsiveness to clinical change in groups of patients who initially have different severity categories of PTS (e.g. mild, moderate or severe). This review was developed by the author as a companion paper to the ISTH Scientific and Standardization Committee publication on standardizing the definition of PTS for use in clinical investigations [23]. In that publication, it is recommended that the Villalta scale be used to define the presence and severity of PTS after objectively diagnosed DVT. While other clinical scales and classification schema for chronic venous disease generally, or for PTS specifically, have been described, discussion of these scales is beyond the scope of this paper, but is provided in recent reviews [22,30,31]. Acknowledgements S. R. Kahn is a recipient of a Senior Clinical Research Scientist Award from the Fonds de la Recherche en Sante du Que bec. Disclosure of Conflict of Interests The author states that she has no conflict of interest. References 1 Kahn SR, Shrier I, Julian JA, Ducruet T, Arsenault L, Miron MJ, LampingDL,JohriM,GinsbergJ.Determinantsandtimecourseof the post-thrombotic syndrome after acute deep venous thrombosis. AnnInternMed2008; 149: Caprini JA, Botteman MF, Stephens JM, Nadipelli V, Ewing MM, Brandt S, Pashos CL, Cohen AT. 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