International Psychometric Validation of the CIVIQ, a specific Quality of Life Questionnaire in Patients suffering from Chronic Venous Insufficiency:

results of the RELIEF study, a Large International Quality of Life Investigation

B. Arnould(1), G. Jantet(2), P. Marquis(1), P. Aussage(3), R. Launois(4)

(1) MAPI Values, 27, rue de la Villette, 69003, Lyon, France. barnould@mapi.fr (B. Arnould, P. Marquis); (2) Vascular Surgeon, 14, rue Duroc, 75007 Paris, France (G. Jantet, on behalf of the RELIEF Study Group [Reflux assessment and quality of life improvement with micronized flavonoids]); (3) MDS Pharma-Services, 6, avenue de la Cristallerie 92316 SEVRES CEDEX France (P. Aussage); (4) Professor, Rseau dEvaluation et dEconomie de la Sant, 28, rue dAssas, 75006 Paris France. launois.rees@wanadoo.fr (R. Launois) Address correspondence to: Benoit Arnould, MAPI Values, 27 rue de la Villette, 69003 Lyon, France. Tel: +33.(0).4.72.13.66.62; Fax: +33.(0).4.72.13.51.40; email:barnould@mapi.fr

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Abstract The ChronIc Venous Insufficiency Quality of Life Questionnaire (CIVIQ) is the first international quality of life (QoL) questionnaire specific to chronic venous insufficiency (CVI). This 20-item questionnaire providing a Global Index and a profile on four QoL dimensions (Psychological, Pain, Physical, Social) was initially developed in French and then translated into English. It was then translated before subsequent use in a prospective, multicenter, international study (the RELIEF* study) assessing QoL in CVI patients (with and without venous reflux) treated with flavonoid fractions. A total of 4,048 adult patients (46.6% with venous reflux) from 18 countries completed the questionnaire at D-15, D0, D60, D120, and D180. The psychometric evaluation demonstrated that the CIVIQ was a valid, reliable, stable and sensitive scale (coefficients: Cronbach's alpha > 0.7; item-scale correlation > 0.4; intra-class and concordance correlation > 0.8; effect sizes > 0.4). Pain had a major impact on QoL scores, and clinical improvement was a major factor of QoL improvement. A general trend for QoL improvement was found during the whole study period, whatever the change in symptoms or clinical status. The patients without venous reflux always had a better QoL than those with venous reflux. In conclusion, the properties of the CIVIQ Global Index fulfill all requirements and can be recommended in further international evaluations of QoL in CVI patients.

Key-words Quality of life; Venous Insufficiency, Chronic Venous Insufficiency; Chronic Venous Insufficiency Questionnaire; micronized purified flavonoid fraction; Reflux assessment and quality of life improvement with micronized flavonoids study.

Abbreviations CEAP: clinical classification of chronic venous insufficiency; CIVIQ: Chronic Venous Insufficiency Questionnaire; CVI: Chronic Venous Insufficiency; MAP: multi-trait analysis; MFA: multiple factor analysis; MPFF: Micronized Purified Flavonoid Fraction; PAF: principal axis factoring; QoL: quality of life; RELIEF study: *Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids study; VAS: Visual Analog Scale.

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Introduction Chronic Venous Insufficiency (CVI), the clinical signs and symptoms of which are well known (edema, varicose veins, pain, heaviness, discomfort and cramp), is a major health problem, especially in industrialized countries, affecting approximately 5% of the adult population and consuming 1 to 2% of health-care budgets in European countries [1]. The importance of using quality of life (QoL) tools to evaluate patient perception of disease has been underlined [2], and instruments have been developed to assess QoL for conditions such as angina pectoris, hypertension or, more recently, CVI [3, 4, 5, 6, 7]. All of the studies conducted in CVI patients support the assumption of a significant impairment of QoL by CVI [8, 9, 10, 11, 12]. Nevertheless, until recently, in the absence of a specific multilingual QoL questionnaire, no large-scale cross-cultural studies of QoL in CVI patients have been performed. The RELIEF study (Reflux assessment and quality of life improvement with micronized flavonoids) was a prospective, clinico-epidemiological, multicenter, international study [13, 14]. Its main objective was to internationally validate the QoL instrument specific to CVI (ChronIc Venous Insufficiency quality of life Questionnaire: CIVIQ) [3] in different languages and countries. Its second objective was to assess the course of QoL in CVI patients (with or without venous reflux) treated with micronized, purified flavonoid fraction (MPFF*) for 6 months; it additionally set out to collect international epidemiological data on CVI and to assess the progression of signs and symptoms in treated patients. The present paper focuses on the psychometric validation of the CIVIQ, and gives references for the interpretation of the QoL in CVI patients.
* Daflon 500 mg, Alvenor, Ardium, Arvenum 500, Capiven, Detralex, Elatec, Variton, Venitol, (Laboratoires SERVIER).

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Patients and methods

Patients and study plan

The RELIEF study was conducted in accordance with the principles set out in the Declaration of Helsinki (1964) as revised in Hong Kong (1989). As regards quality of life assessment, 4,048 patients belonging to 18 countries worldwide (Argentina, Brazil, Brunei, Czech Republic, Egypt, Hong Kong, Hungary, India, Malaysia, Philippines, Poland, Russia, Singapore, Slovakia, Spain, Sri Lanka, Turkey and Venezuela) were included in the RELIEF study from February 1997 to February 1999. All the patients enrolled by the examining physician had to sign an informed consent form before being included. Only patients aged over 18 years, wearing compression stockings or not, having a CEAP [15] clinical stage between 0 and 4 (Table 1), able to complete the QoL questionnaire, and judged psychologically stable and well-motivated were included. Patients presenting with concomitant active disease, history of venous surgery, or with a CEAP clinical stage higher than 4 were excluded. At selection visit (D-15), the patients completed the QoL questionnaire; their sociodemographic and clinical characteristics were collected. On D0 (baseline), after a washout period of 15 days, patients were divided into two groups: one group with and one without venous reflux. Venous reflux was detected by hand-held pocket Doppler (MicroDop8) and photoplethysmography (PPG) (Vasotest) [13]. Both groups were treated with 1,000 mg daily of MPFF for six months. Patients were instructed not to change their habits as to wearing compression stockings or not. Control visits were scheduled every 2 months (D60, D120 and D180). The following parameters were assessed at each visit: (a) QoL, using the CIVIQ; (b) CEAP clinical stage [15]; (c) symptoms (sensations of swelling, cramps, leg heaviness) using a 4-point scale (0 = absent, 1 = mild, 2 = significant and 3 = severe); (d) pain using a 10 cm visual analog scale (VAS), (e) edema by measuring leg circumferences with the Leg-O4

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Meter (this device provides the measurement itself and the height at which the measurement is taken) [16].

MicroDop8, Vasotest: SonoMed France, 14, rue de Moronval F-28100 Dreux Leg-O-Meter: BTL Communication, 18, avenue du Recteur Poincar75016 Paris

Quality of Life questionnaire

The revised CIVIQ, based on a specific questionnaire developed and validated for CVI in France in 1994 [5], was used to measure patients' QoL. It was a 20-item self-administered questionnaire, rated twice: once regarding the perceived severity level of impairment, and the second time regarding the importance of the question for the patient. From the original French version, the questionnaire was translated for international use. This process requires the identification of cross-cultural equivalence of the concepts or constructs measured so that comparisons may be made between populations of different cultures [17]. Thus the content of the questionnaire was first submitted to the opinion of the different countries involved. The linguistic validation was therefore performed in two steps: first, confirmation of the cultural relevance of the questionnaires content; second, the translation process. Cultural adaptations into English, Italian, Polish, Portuguese and Spanish were carried out. Additional versions were then made available in Arabic, Czech, Hungarian, Russian and Slovakian (Table 2). During this process some conceptual changes were made to refine the content validity of the Social dimension of the CIVIQ. In all, 10 versions were used in the RELIEF study. The scoring rules used for the construction of the CIVIQ dimensions were those defined by the questionnaires author: the 20 severity items of the CIVIQ (each scored on a 5-point ordinal scale [18]) were assigned to four dimensions, with 3 to 9 items each: Psychological (9 items), Pain (4 items), Physical (4 items) and Social (3 items) repercussions (Appendix 1). The score 5

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for each dimension was obtained by adding scores for each constituent item and the Global Index was obtained by summing the 20 items. Absolute scores were then converted into an index following the authors instructions [3]. In order to facilitate the interpretation of the results, the scores presented in this paper were linearly transformed into a scale ranging from 0 to 100, the highest score indicating the best QoL.
Measurement properties and statistics

Statistical analysis was carried out by MAPI Values (Lyon, France) on an IBM-compatible computer using SAS software release 6.12 (SAS Institute, CARY, NC, USA). Sociodemographic and clinical data were described. The psychometric properties of the questionnaire were analyzed in the manner reported by the authors of the questionnaire at the time of initial development [3, 5]. Face validity (acceptability) was described in terms of quality of completion on an item basis. The questionnaire structure was assessed using principal axis factoring (PAF) analysis with Promax rotation and multi-trait analysis (MAP). Based on item-scale correlations, this analysis evaluates the hypothesized scale structure of the questionnaire. Item-convergent validity was accepted when items were significantly correlated with their own dimension (Pearson's correlation coefficients >0.40) and item-discriminant validity was accepted when items were more strongly correlated with their own dimension than with the other dimensions (results are expressed as the percentage of scaling success). In order to counteract discrepancies in country sample sizes when running the PAF, data for each country were weighted using a coefficient equal to 1 divided by the number of observations in the country. This resulted in a balanced weight of each country sub-sample in the construct validity of the international version of the CIVIQ. In addition, a non-weighted PAF was performed to assess the robustness of the results. The internal consistency reliability was assessed using Cronbach's alpha coefficient. This coefficient indicates, for each multi-item scale, the 6

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proportion of variance due to the true score as compared to that due to measurement error. The maximum value of the coefficient is 1 and the minimum recommended value to ensure acceptable reliability is 0.7 [19]. Clinical validity explores logical relationships that could exist between the questionnaire and clinical measures such as CEAP stage, or symptoms such as pain. Clinical validity was assessed by Spearman's correlation coefficients calculated at baseline. The hypothesis was that the more severely CVI was rated the lower the patient's quality of life. In addition, a Generalized Linear Model was performed to determine the sociodemographic and clinical parameters influencing baseline QoL. Specific attention was given to the seasonal factor. As countries from different climatic areas were included, the month of inclusion was not a relevant indicator of the season and thus a combined variable was created combining the month and climatic area. Three core climatic areas were defined: above the northern tropic, below the southern tropic and inter-tropical. The reproducibility of the questionnaire was tested using QoL results obtained at D-15 and D0 (Test - Retest procedure). The aim was to check the stability of the scores in clinically stable patients. It was assessed using intraclass (ICC) and concordance (CCC) correlation coefficients. The recommended minimum value for the coefficients is 0.8 [20]. Sensitivity (responsiveness to change over time) for scores in each dimension and the Global Index was assessed by means of standardized response mean (SRM) and effect sizes (ES). The aim was to check the ability of the questionnaire scores to respond when changes were observed in clinical status as well as symptoms. Effect sizes were considered acceptable when their absolute values were above 0.40 and large when over 0.8 [21]. In addition to these classical analyses a sub-group analysis was performed in patients that could be considered as patients with stable pain levels. First, a group of patients with a slight change in pain measured by VAS (change in pain score between -2.5 and 2.5 cm) was selected. Since the global trend in the study population was an improvement in pain the

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distribution of the change in pain over time was not centered on zero. Thus a sub-group of patients from the slightly improved population was selected to match the slightly impaired patients (i.e. 280 patients) in terms of their absolute pain, venous reflux, gender, age and country. This procedure resulted in the selection of a population of 544 patients experiencing a null mean change in VAS pain - all patients experiencing either a slight decrease (between2.5 and 0, n = 264) or a slight increase (between 0 and +2.5, n = 280). The subgroup of patients experiencing a slight decrease were comparable to the subgroup of patients experiencing a slight increase as regards factors other than change in VAS pain.

Results
Patient characteristics

At baseline (N = 3,995), the majority of patients were of Caucasian ethnic origin (77.9%), women (81.1%), professionally active (61.8% were employed full-time and 7.4% part-time), and aged 45.6 12.3 years (mean SD). They had experienced CVI with (46.6%) or without (53.4%) venous reflux for 12.4 9.8 years (mean SD), and were classified in CEAP clinical stage 2 (39.3%) or above (CEAP stages 3 or 4: 39.4%). Using the 4-point scale, swelling and cramps were usually present and of mild intensity (only 22.1% and 30.8% of the patients did not experience swelling or cramps respectively) while heaviness was usually present and significant (only 5.9% of the patients did not experience heaviness). As regards pain, the mean value at baseline was 3.8 2.5 cm (10 cm VAS) (Table 3).

Acceptability of the questionnaire

Out of the 4,048 patients having completed the CIVIQ at least once, 53 were excluded from analysis as they had no evaluable QoL assessment at baseline. Out of the 3,995 patients with

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an evaluable baseline CIVIQ questionnaire 91.5% (n = 3,656) had 5 evaluable QoL assessments (one assessment at each of the 5 planned visits), and 99.0% (n = 3,956) had at least one other evaluable CIVIQ questionnaire after baseline and could therefore be included in the longitudinal analyses. As regards the responses of the 4,048 patients that had completed the CIVIQ at least once, the following results were obtained: 8.0% (D0) and 12.6% (D180) of the questionnaires had at least one missing data, and the average percentages of missing data by item were 1.67% (D0) and 7.34% (D180).

Cross-sectional psychometric analyses

Score distributions and reliability of the scale Score distributions and scale reliability are both presented in Table 4. The internal consistency reliability was good with all the Cronbach's alpha coefficients being over 0.70. Moreover, the percentages of patients having the lowest (floor effect) or highest (ceiling effect) possible scores were low (floor effect: between 0.9% and 8.5%; ceiling effect: between 0.0% and 0.3%), indicating the good coverage of the underlying concepts.

Scale structure The convergent validity, measured by the correlation of each item with its own dimension, was very good with all the item-scale coefficients being higher than 0.40. The percentage of items correlating more strongly with their own dimension than with the other dimensions (scaling success) was excellent for the Psychological dimension (100.0%), good for the Pain dimension (91.7%), acceptable for the Physical dimension (75.0%), and not stable for the Social dimension (55.6%).

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Factorial structure To confirm the scaling hypothesis and scoring a principal axis factoring (PAF) analysis with Promax rotation was performed, the number of factors being limited to 4 which was the number of dimensions in the CIVIQ. The levels of variance explained by each factor (after rotation) were 8.0, 7.0, 6.9 and 5.5, respectively. The first factor could be clearly interpreted as a physical factor despite not being very consistent with the original definition. The second factor was a psychological factor and contained 7 of the 9 items from the original Psychological dimension. The third factor was a pain factor with 3 of the 4 items from the original Pain dimension; However, in the non-weighted PAF analysis the third factor contained all 4 items of the Pain dimension. The fourth factor was a mixed factor (one item from each of the original dimensions). One item (get tired quickly) was highly correlated with several factors resulting in some instability and three items (must take precautions, to do housework, to travel) did not clearly fit a dimension. In summary, the PAF provided a strong confirmation of the structure of three QoL domains in the international CIVIQ: Physical, Pain, and Psychological.

Clinical validity Clinical validity was good; the better the clinical status of the patients the better their QoL, as measured by the CIVIQ Global Index, for all clinical parameters analyzed (Table 5, Figure 1). All the correlation coefficients were associated with high significance levels (p = 0.0001). Results were similar when considering each dimension of the CIVIQ although pain was the dimension for which the highest correlations were found. As regards the CIVIQ Global Index, the highest correlation coefficient (r = 0.46400) was observed with the VAS-pain parameter. As regards the separate CIVIQ dimensions the clinical parameters were always more correlated with the CIVIQ Pain dimension than with the other dimensions except for CEAP

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clinical stage which was more correlated (r = 0.20430) with the Psychological dimension. The highest correlation coefficient was observed between the VAS-pain parameter and the pain QoL dimension (r = 0.51609). The relationship between clinical and socio-demographic variables and QoL was studied using a Generalized Linear Model (Table 6). After adjustment on other factors, all the symptoms (cramps, heaviness, swelling and pain) still had a significant and consistent effect on QoL, as well as sex, age and season. Conversely, the venous reflux, edema (leg circumference) or CEAP stage had no significant effect on QoL scores after adjustment.
Longitudinal psychometric analyses

Reproducibility Reproducibility was assessed over the D-15 and D0 screening period in stable patients. The reproducibility of the CIVIQ-scores was tested according to various definitions of patient stability based on unchanged clinical stage of CVI (CEAP) or unchanged symptom scores (Swelling, Heaviness, Cramps, and Pain). The number of patients qualified as stable ranged from 3,749 (unchanged CEAP clinical stage) to 3,147 patients (unchanged Heaviness score). When selecting the patients qualified as stable, according to all these parameters together, 2,406 patients qualified as stable over the screening period regarding their disease. High correlation coefficients (ICC and CCC all over 0.80) were found both for the Global Index (Table 7) and for all dimension scores (data not shown) indicating a very good reproducibility for the CIVIQ.

Change over time and responsiveness to change between baseline and end of study The Global Index (mean SD) was 64.1 18.5 at baseline (D0), 73.1 17.2 at D60, 78.2 16.3 at D120 and 82.1 15.7 at D180 (end of study) showing an improvement in QoL over the study period as a whole. Thus the greatest improvement in QoL was noted after the first 2

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month period but further improvements were noted after 4 months and 6 months. At each time period QoL Global Index differed significantly between groups with or without venous reflux (p = 0.0001). Patients who experienced venous reflux were more impaired in their QoL than the other patients (Figure 2). When considering changes between baseline and D60, D120 or D180 significant changes were observed for all dimensions and for the Global Index with high statistical significance levels (p < 0.0001) (Figure 3). These changes were particularly high for the Pain dimension. No significant difference in the change over time between groups with or without venous reflux was observed except for the Pain dimension at D120 (p = 0.0058), and D180 (p = 0.005): the improvement in Pain scores were higher in patients without reflux than in those with reflux. The sensitivity to change over time was assessed over the D0-D180 study period in improved as well as worsened sub-groups of patients. Various definitions of improved and worsened patients were used: according to the change in clinical status (CEAP classification) or in each of the symptom scores (Swelling, Heaviness, Cramps, VAS-Pain). As regards the VAS-Pain parameter, as no real worsened class could be defined because all the patients tended to be stable or improve over the D0-D180 study period, patients were classified as improved [D180-D0 < -2.5 cm] or much improved [D180-D0 < -5 cm]. In improved patients the QoL always significantly improved. All measures of effect size (ES) were large, greater than 0.8 with a range from 1.09 (for the improved patients according to the Heaviness symptom) to 1.73 (for the much improved patients according to VAS-Pain). In worsened patients (according to clinical classification and symptoms) the QoL tended to improve as well. Nevertheless, the effect sizes in worsened patients were also positive yet lower ranging from 0.31 (for the worsened patients according to Heaviness symptom) to 0.70 (for the worsened patients according to Swelling symptom) (Table 8).

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Analysis of QoL in a subgroup of patients with VAS-Pain stability during the study period A sub-sample of subjects, who could be considered to have stable pain levels, was selected from the core study population. In all 544 patients stable in pain were selected (stability defined as a change from D0 to D180 [D180-D0] in VAS-Pain score ranging from a 2.5 cm decrease to a 2.5 cm increase). In this subgroup the mean change in pain (0.36 cm) between D0 and D180 was not significantly different from 0 (Student t test, p = 0.3562). Comparison between the sub-group of 280 patients who were slightly impaired (change ranging from 0 cm to +2.5 cm) and the sub-group of 264 patients who were slightly improved (change ranging from -2.5 cm to 0 cm) did not show any significant difference in age, gender, country, ethnic origin, season, smoking habits, alcohol habits, weight, duration of disease, complications, family history, CVI clinical stage, edema, heaviness or cramp severity. Differences (p <0.05) between the slightly improved sub-group and the slightly impaired sub-group were observed on occupation (full-time employment 61.4% versus 51.8% respectively), Swelling score at D0 (mild or absent swelling in 77.3% versus 71.5% respectively), and VAS-Pain at D0 (2.06 versus 2.51 cm respectively). The QoL Global Index and the QoL Pain score increased in this population of stable patients, in both slightly impaired and slightly improved patient subgroups, indicating a general trend for an improvement in QoL scores. The mean change in Global Index was 10.63 (9.46 and 11.85 in the subgroups of slightly impaired patients and slightly improved patients respectively). The mean change in the QoL Pain score was 14.64 (11.47 and 17.93 in the subgroups of slightly impaired patients and slightly improved patients respectively). These figures provide evidence of a consistent response of the CIVIQ QoL scores to change in VAS-pain (Figure 4): the greater the magnitude in pain relief as measured by the change in VAS-pain, the greater the improvement in QoL scores. In this population of

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patients stable in pain severity level, the responsiveness to change according to other symptoms and CEAP is described in Table 9.

Discussion The cross-cultural equivalence of instruments is recognized as a main issue in the assessment of QoL in large international studies [22]. The CIVIQ was administered to patients from 18 countries belonging to Southern America, Central, Southern and Eastern Europe, Northern Africa, Northern, Southern and Eastern Asia. Unfortunately no standard methodology is yet available to assess conceptual equivalence of a questionnaire between languages and cultures. However, the analyses performed on pooled data demonstrated the robustness of the core structure of the questionnaire. The PAF was run twice on pooled data, once with each patient being given a weight of 1, and once with each country being given the same weight. Both analyses delivered similar results. It is therefore considered that the results observed on pooled data were not misleadingly influenced by the countries where large numbers of patients had been recruited and were actually reflecting the cross-cultural common construct of the CIVIQ. If the proposed grouping of items had no cross-cultural validity it would not have been possible to find such a clear confirmation of the validity of the construct. The MAP analysis confirmed the results obtained from exploratory PAF: while the constructs were excellent for the Psychological dimension and good for the Pain dimension (scaling success: 100.0% and 91.7% respectively), they were acceptable for the Physical dimension (scaling success: 75.0%) and to be stabilized for the Social dimension (scaling success: 55.6%). On the other hand relatively high item-scale correlations were found for most of the items. Moreover, the Global Index, which was uni-dimensional, was confirmed as a good measure (good internal consistency reliability, no ceiling and no floor effects) of the core QoL of the patients suffering from CVI. The strongest dimensions regarding the international construct

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validity were the Pain and the Psychological QoL dimensions, while the weakest was the Social QoL dimension. This result, combined with the examination of the item content of these dimensions, suggested that the impact of CVI on pain in daily activities, as well as on the psychological well-being of the patients, would be captured by concepts presenting a high cross-cultural validity, while the impact of CVI on social functioning would be captured by concepts which were more sensitive to the specific cultural context. This should be taken into consideration for further adaptations of the CIVIQ into other languages. The history of the CIVIQ may help to understand some apparent discrepancies between the initial definition of the dimensions and the structure of the international version of the CIVIQ: item #13 get tired easily is correlated with all factors, which is a reason for instability from one sample to the other. Item #11 to practice a sport was translated in order to reflect a physical concept more than a social concept. This explains why it tends to group with the Physical dimension in the international sample. The same choice was made for the item #10 to go out in the evening with similar results. Items #8 to travel (car, bus, plane), #9 to do the housework and #15 must take precautions faced specific translation problems which result here in a questionable cross-cultural conceptual equivalence. Nevertheless, all items had a good convergent validity, and at least satisfactory internal consistency reliability was found for all dimension scores. In addition, the good test-retest reproducibility added evidence to the reliability of all the dimensions of the CIVIQ. In summary, the present international version of the CIVIQ had a valid construct allowing for the calculation of reliable Global Index and dimension scores, and permitting its use on pooled data from international studies. The clinical validity was good, the more impaired patients having the poorer QoL, whichever clinical parameter or self-reported symptom was being analyzed. The relationship between the clinical parameters and the QoL dimensions was highly consistent. The highest correlation

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coefficient was observed between the VAS-Pain symptom scale and the Pain QoL dimension. While symptoms such as pain, heaviness, and cramps were more correlated with the Pain QoL dimension, the CEAP clinical stage, evaluated by the physician, was more correlated with the Psychological than with the Pain QoL dimension. These results provided evidence that these two dimensions, which had good construct properties, actually capture two different concepts, the Pain dimension being more influenced by the perceived symptoms, and the Psychological dimension being more influenced by the perceived severity of the disease. Other parameters influencing baseline QoL have been identified: QoL was lower in older patients, women, and patients included in the study during warm seasons, than in the other patients. As observed in other QoL studies [26, 27] all the QoL scores except the Pain dimension score were significantly lower in women than in men. Age appeared to have a highly significant effect on Global Index and the score of the Physical dimension, indicating that age enhanced the disease-related physical problems. All the symptoms (cramps, heaviness, swelling and pain) had a significant and consistent effect on QoL. A surprising finding was the absence of any significant effect (after adjustment) of the venous reflux, edema (leg circumference) or CEAP stage on QoL scores. This result demonstrated that these parameters, which are translations of clinical signs by the investigators, did not have a direct impact on patients' QoL while, on the other hand, the symptoms (in particular pain) had a direct and independent impact on QoL scores. One of the findings from the Generalized Linear Model was the negative prognosis regarding QoL associated with the severity of the symptoms at baseline. A majority of the patients improved, during the study period, according to clinical and symptoms parameters: 661 improved and 64 worsened according to the CEAP classification; according to the symptom scores of swelling, heaviness and cramps more than 50% of patients improved during the study period while less than 5% worsened. Moreover, almost all

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of the patients improved during the study period according to pain symptom analysis. The QoL results for the improved patients were in the expected direction with high magnitude this demonstrated the responsiveness of the questionnaire. Conversely, impairment in QoL was expected in worsened patients and yet a slight QoL improvement was observed. Several hypotheses could contribute to explain this result. The first one was the role of non-specific effects. As described by Bouchet et al. [23] the variation in the QoL measures in longitudinal studies is due to several factors including not only treatment efficacy but also placebo effect, Hawthorne effect (defined as the tendency for people to change their behavior because they are the target of special interest and attention during the study) or natural history effect (which refers to all effects related to time including disease natural history and regression to the mean [24]). Similar effects were reported in other QoL studies [25]. As Bouchet et al. reported, their study was specifically designed, with four groups of patients, to measure the part of non-specific effects in the overall change. Therefore, it is evident that they may exist, but could generally not be measured in studies designed for another purpose. Finally, it is noteworthy that no patient clearly worsened with respect to pain (VAS evaluation), and that pain was the clinical parameter most closely correlated with the Global Index. Pain was also the parameter to which the CIVIQ was the most responsive. Thus, as pain had more impact on QoL than any other clinical parameters and symptoms, it could be hypothesized that, in the absence of any real worsening of pain in treated patients, QoL of all the patients tended to improve, whatever the change observed in other symptoms. This is the reason why a specific descriptive analysis was performed in a subgroup of stable patients with regards to pain. This subgroup consisted of patients with a low increase or decrease in VAS score from D0 to D180. In this subgroup of patients (for which the mean change in the pain symptoms was nil over the study period) a significant improvement in QoL was found over the same period. However, as hypothesized, change in perceived pain levels

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induced a proportional change in QoL: the more the pain improved the better the QoL became. The improvement in stable patients could be interpreted as an estimate of nonspecific effects, and the additional difference in QoL scores according to the magnitude of pain relief as the true response of the CIVIQ scores to pain relief. The mean change in Global Index observed in the 1,560 patients whose VAS-Pain score decreased was more than twice that of the sub-group of 544 VAS-Pain stable patients (respectively 23.8 and 10.6). The trend for improvement during the wash-out period could also be interpreted as an estimate of the impact of non-specific factors on the patients QoL: this marginal effect (less than 1 point on the Global Index over a two-week period) was less than half the overall trend for improvement after treatment initiation (more than 8 points on the scale, over the first eight-week period). These consistent results provided the evidence of the responsiveness of the CIVIQ to symptom relief in CVI and, moreover, the magnitude of the response in QoL reflected the magnitude of the symptom relief: the better the relief, the greater the response.

Conclusion The main purpose of this international prospective study was to measure the psychometric properties of the first quality of life questionnaire specific to Chronic Venous Insufficiency (CIVIQ) in different languages and cultures. Results demonstrated that the questionnaire was very well accepted. Its clinical validity was excellent. The internal consistency reliability of all dimensions was good, yet the initial assumptions regarding the aggregations of the items in the Physical and Social dimensions were not fully validated. However, there was a high concordance between the content of the CIVIQ and its construct suggesting that the weakness of the construct of the Social dimension was a direct consequence of the on-going process of conceptual refinement of the items of this dimension. All scores were valid and reliable yet

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the Social score should not be interpreted as a specific dimension. The longitudinal properties of the CIVIQ were good: the reproducibility was found to be excellent in all dimensions and the responsiveness to change over time was also found to be excellent, specifically toward pain relief. The responsiveness to impairment could not be assessed because the study design (in the absence of a placebo group) did not allow for observing a significant population of impaired patients. The conclusion drawn from the analysis of these data is that the CIVIQ is a valid and reliable questionnaire and can be recommended in further international evaluations of QoL in CVI patients.

Acknowledgements The authors gratefully acknowledge Les Laboratoires SERVIER for their support for this study. The authors also acknowledge all the participants in the study, particularly the scientific advisor, G. Jantet, the international coordinators, J.P. Jimenez Cossio and J. Ulloa, and the national coordinators: J.R. Baron, S. Batktiroglu, S. Cheng, Y. Abd Wahab, D. Dhobb, F. Ibanes, A. Iman Nassef, M. Lagos, F. Lozano Sanchez, T. Ming Keng, C. Maduro, W. Noszczyk, E.T. Ona, M. Paramo Diaz, H. Partsch, P. Ramakrishna, V.S. Saveljev, R. Simkin, A.H. Sherifdeen, J. Strejcek, V. Stvrtinova, D. Vogelfang.

Correspondence for conditions of use of the CIVIQ should be addressed to webmaster@servier.com. Any use or translation of the CIVIQ is subject to the following conditions: 1) Provide SERVIER and Professor Launois with information on the study objective and database at D0

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for validation purpose. 2) Provide SERVIER and Professor Launois with a copy of any publication where the CIVIQ instrument is mentioned. Any publication involving the CIVIQ should include the following note: This questionnaire was developed by Professor Launois with an educational grant from Les Laboratoires SERVIER. Any person who wishes to use the questionnaire should contact Professor Launois on the site www.rees-france.com or SERVIER on the site: www.servier.com.or at the e-mail address webmaster@servier.com. 3) Make no commercial use of the questionnaire. No copyright on the original questionnaire nor the newly linguistically validated translations is authorised. No reproduction (even partial) of the CIVIQ can be performed without the author's agreement.

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References 1. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology 1997; 48: 67-9. 2. Fitzpatrick R, Fletcher A, Gore S, Jones D, Spiegelhalter D, Cox D. Quality of life measures in health care. I: Applications and issues in assessment. BMJ 1992; 305: 1074-7. 3. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual Life Res 1996; 5: 539-54. 4. Launois R. At the crossroads of venous insufficiency and hemorrhoidal disease: Daflon 500 mg repercusions of venous insufficiency on everyday life. Angiology 1994; 45: 495504. 5. Launois R, Reboul-Marty J, Henry B. [Construction and validation of a quality of life specific questionnaire: example of chronic venous insufficiency of the leg] (French). J Econ Md. 1994; 12: 109-126. 6. Klyscz T, Jnger M, Schanz S, Janz M, Rassner G, Kohnen R. [Quality of life in chronic venous insufficiency (CVI). Results of a study with the newly developed Tubingen Questionnaire for measuring quality of life of patients with chronic venous insufficiency] (German) Hautarzt 1998; 49: 372-81. 7. Augustin M, Dieterle W, Zschocke I, Brill C, Trefzer D, Peschen M, Schpf E, Vanscheidt W. Development and validation of a disease-specific questionnaire on the quality of life of patients with chronic venous insufficiency. Vasa 1997; 26: 291-301. 8. Lindholm C, Bjellerup M, Christensen O, et al. Quality of Life in chronic leg ulcer patients. Acta Derm Venereol 1993; 73: 440-443. 9. Franks P, Wright D, Fletcher A, et al. A questionnaire to assess risk factors, quality of life,

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and use of health resources in patients with venous disease. Eur J Surg 1992; 158: 149155. 10. Franks P, Moffatt C, Connolly M, et al. Community leg ulcer clinics: effect on quality of life. Phlebology 1994; 9: 83-86. 11. Arratt A, Mac Donald L, Ruta , et al. Towards measurement of outcome for patients with varicose veins. Qual Assur Health Care 1993; 2: 5-10. 12. Hyland M, Thomson B. Quality of life of leg ulcer patients: questionnaire and preliminary findings. J Wound Care 1994; 3: 294-298. 13. Jantet G. RELIEF Study: First consolidated European Data. Angiology 2000; 51(1): 31-7. 14. Jantet G and the RELIEF Study Group. Chronic Venous Insufficiency Worldwide results of the RELIEF Study. Angiology. In press. 15. Porter JM, Moneta GL, et al. International Consensus Committee on chronic venous insufficiency. Reporting standards in venous disease: an update. J Vasc Surg 1995; 21: 635-45. 16. Berard A, Kurz X, Zuccarelli F, et al. Reliability study of the Leg-O-Meter, an improved tape measure device in patients with chronic venous insufficiency of the leg. Angiology 1998; 49: 169-73. 17. Bullinger M, Anderson R, Cella D, Aaronson N. Developing and evaluating cross-cultural instruments from minimum requirements to optimal models. Qual Life Res 1993;2: 451459. 18. McDowell I, Newell C. Glossary of Technical Terms in Measuring health: A guide to rating scales and questionnaires. New York: Oxford University Press 1987; 327-331. 19. Nunnally JC. Psychometric theory, 2nd ed. New York: Mc Graw-Hill 1978. 20. Hays RD, Anderson R, Revicki DA. Psychometric evaluation and interpretation of health related quality of life data. Rapid Communications of Oxford Ltd 1995.

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21. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care 1989; 27(3, suppl): S179-S189. 22. Acquadro C, Jambon B, Ellis D, Marquis P. Language and translation issues. In Spilker B ed. Quality of life and pharmacoeconomics in clinical trials. Philadelphia: Lippincott Raven 1996, 575-585. 23. Bouchet C, Guillemin F, Brianon S. Non specific effects in longitudinal studies: impact on quality of life measures. Epidemiology 1996; 49: 15-20. 24. Davis CE. The effect of regression to the mean in epidemiologic and clinical studies. Am J Epidemiol 1976; 104:493-8. 25. Goggin T. Quality of life in hypertension- The effect of "care" versus "therapy". Drug Inf J 1994; 28: 115-21. 26. Deshotels A, Planchock N, Dech Z, Prevost S. Gender differences in perceptions of quality of life in cardiac rehabilitation patients. J Cardiopulm Rehabil 1995; 15: 143-8. 27. Dowdy SW, Dwyer KA, Smith CA, Wallston KA. Gender and psychological well-being of persons with rheumatoid arthritis. Arthritis Care Res 1996; 9: 449-56.

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Table 1: CEAP clinical classification [15] (Patients suffering from CVI classed at levels 0 to 4 were to be included in the study) Class 0 1 2 3 4 5 6 Contents No visible or palpable signs of venous disease Telangectasia, reticular veins, malleolar flare Varicose veins Edema without skin changes Skin changes due to venous disease (pigmentation, eczema, lipodermatosis) Skin changes as defined above with healed ulceration Skin changes as defined above with active ulceration

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Table 2: Countries and versions of the CIVIQ Country Argentina Brazil Brunei Czech Republic Egypt Hong Kong Hungary India Malaysia Philippines Poland Russia Singapore Slovakia Spain Sri Lanka Turkey Venezuela CIVIQ language version Spanish Portuguese English Czech Arabic English Hungarian English English English Polish Russian English Slovakian Spanish English Turkish Spanish

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Table 3: Patients characteristics (N = 3,995) Variables Sex (women) Age (years) Ethnic group (Caucasian) Occupation: Employed full-time Occupation: White-collar Weight (kg): Duration of CVI (years): CEAP (class 2): CEAP (classes 3 and 4): With venous reflux: Edema measurement (cm): Sensation of Lower Limb Swelling*: Heaviness*: Cramps*: Pain (VAS in cm):
* presence of the symptom

N; % mean SD N; % N; % N; % mean SD mean SD N; % N; % N; % mean SD N; % N; % N; % mean SD

3,239; 81.1% 45.6 12.3 3,112; 77.9% 2,468; 61.8% 1,297; 34.3% 71.0 14.3 12.4 9.8 1571; 39.3% 1572; 39.4% 1,860; 46.6% 27.2 5.7 3 102; 77.7% 3 749; 93.8% 2 755; 68.9% 3.8 2.5

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Table 4: Scores distributions at baseline and scales reliability Dimensions Scores (mean SD) % at floor* (N = 3,956) Psychological Pain Physical Social Global Index 69.0 19.9 55.4 19.3 62.7 22.6 66.0 22.5 64.6 18.5 1.5% 0.9% 4.5% 8.5% 0.3% 0.1% 0.3% 0.3% 0.3% 0.0 % at ceiling* Cronbach's alpha coefficient** 0.89 0.83 0.86 0.76 0.94

* % of respondents at the lowest (floor) or the highest (ceiling) possible score; ** measurement of internal consistency reliability

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Table 5: Clinical validity of the CIVIQ. Clinical parameter Global Index (mean SD) in patients suffering from CVI of Mild intensity* CEAP Swelling Heaviness Cramps 70.1 19.1 73.8 15.1 77.9 15.4 71.5 16.7 Severe intensity** 57.9 19.9 45.7 19.4 47.8 19.1 52.2 20.5 Spearmans correlation coefficient 0.22032 0.38561 0.41706 0.33244 0.0001 0.0001 0.0001 0.0001 p-value

* mild intensity was defined as follows: CEAP clinical stage = class 0; swelling, heaviness, cramps = absent; venous reflux = without; ** severe intensity was defined as follows: CEAP clinical stage = class 4; swelling, heaviness, cramps = severe; venous reflux = with.

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Table 6: Generalized Linear Model. Ability of each parameter to explain Global Index at baseline. Global Index Socio-professional status Sex Age Body mass index Season Duration of the disease Venous reflux CEAP stage Edema (Leg-O-meter) Cramps Swelling Heaviness Pain O X X O X O O O O X X X X

O: indicated a significant effect before adjustment for the other parameters; X: indicated a significant effect after adjustment for the other parameters.

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Table 7: Test-Retest reproducibility of the CIVIQ. Global Index according to the clinical parameters Clinical parameter (N = number of stable patients) CEAP (N = 3749) Swelling (N = 3250) Heaviness (N = 3147) Cramps (N = 3075) Pain (N = 3714) All parameters together (N = 2406) Change* in Global Index (mean SD) n (MD) 3,635 (114) 3,153 (97) 3,050 (97) 3,069 (96) 3,605 (109) 2,339 (67) Difference 0.59 6.74 0.64 6.40 0.62 6.10 0.43 6.20 0.57 6.47 0.54 5.38 0.9319 0.9385 0.9441 0.9427 0.9376 0.9561 0.9319 0.9385 0.9440 0.9427 0.9376 0.9560 0.0001 0.0001 0.0001 0.0001 0.0001 0.0001 ICC CCC p- value

* change was expressed by the difference between selection and baseline (D-15 to D0); MD: missing data; SD: standard deviation; ICC: intra-class correlation coefficient; CCC: concordance correlation coefficient

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Table 8: Responsiveness of the Global Index to change over time Clinical parameter Clinical evolution Number of patients Change in Global Index: D180-D0 (mean SD) CEAP* Improved* Worsened** Swelling* Improved Worsened Heaviness* Improved Worsened Cramps* Improved Worsened Pain** Very improved Improved

Effect sizes ES1 1.31 0.52 1.13 0.53 1.09 0.31 1.14 0.38 1.57 1.31 ES2 1.37 0.60 1.26 0.70 1.24 0.41 1.29 0.45 1.73 1.46

661 64 2,134 82 2,778 68 2,189 88 442 1,560

23.7 17.3 10.1 16.8 21.1 16.8 9.53 13.6 20.1 16.2 5.8 14.2 21.1 16.4 7.1 15.8 29.2 16.9 23.8 16.2

improvement was defined as a decrease of one class for CEAP clinical stage, swelling, heaviness and cramps; worsening was defined as an increase of one class for CEAP clinical stage, swelling, heaviness and cramps; ** improvement or impairment were defined according to change in score (10 cm visual analogue scale): much improved = decrease of 5 cm or more, improved = decrease of 2.5 to 5 cm; ES1 = Effect Size as defined by Kazis; ES2 = Standardized Response Mean

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Table 9: Responsiveness of the Global Index to change over time in the sub-sample of 544 patients stable in VAS-pain Clinical evolution Number of patients Change in Global Index: D180-D0 (mean SD) Effect sizes ES1 1.18 0.28 0.79 0.32 0.82 0.14 0.84 0.07 NA NA ES2 1.13 0.49 0.88 0.57 0.91 0.17 0.99 0.06 NA NA

Clinical parameter

CEAP*

Improved* Worsened**

79 19 231 32 299 25 229 30 0 0

21.318.9 5.611.5 14.916.8 5.810.3 14.316.7 2.917.4 15.615.8 0.814.6 NA NA

Swelling*

Improved Worsened

Heaviness*

Improved Worsened

Cramps*

Improved Worsened

Pain**

Very improved Improved

* improvement was defined as a decrease of one class for CEAP clinical stage, swelling, heaviness and cramps; worsening was defined as an increase of one class for CEAP clinical stage, swelling, heaviness and cramps; ** improvement or impairment were defined according to change in score (10 cm visual analogue scale): much improved = decrease of 5 cm or more, improved = decrease of 2.5 to 5 cm; ES1 = Effect Size as defined by Kazis; ES2 = Standardized Response Mean

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Figure 1: Baseline Global Index and QoL score for the pain dimension according to VAS pain Figure 1a. x-axis: pain evaluated by means of a 10 cm visual analogue scale (the higher VAS, the more severe pain). y-axis: Global Index (the higher QoL score, the better the QoL). n indicates the number of patients per group.

Figure 1b. x-axis: pain evaluated by means of a 10 cm visual analogue scale (the higher VAS, the more severe pain). y-axis: pain QoL score (the higher QoL score, the better the QoL). n indicates the number of patients per group.

Figure 2: Change in QoL scores between D-15 to D180 in patients with and without venous reflux For the Global Index (Figure a) and each dimension of the questionnaire (Figures b to e) time is on the x-axis and QoL score on the y-axis (a high value indicates a good QoL).

Figure 3: Change in QoL scores between D0 and D180 Dimensions are on the x-axis and the difference in QoL scores between D0 and D180 (D180 D0) are on the y-axis. A high value indicates an increase in the score of the dimension, and thus a relevant improvement in QoL.

Figure 4: Change in pain QoL score according to change in VAS pain Time is on the x-axis and Global Index (Figure 4a) or QoL score for the pain dimension (Figure 4b) on the y-axis (a high value indicates good QoL).

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