ART-2538_CIVIQ

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Abstract

The C hron I c V enous I nsufficiency 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 li fe 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 ass Essment and qua Lity

of l I fe improv Ement 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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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 Poincaré75016 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 questionnaire’s 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

questionnaire’s 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

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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). Socio-

demographic 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

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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 socio-

demographic 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 (between-

2.5 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 sub-

groups, 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 non-

specific 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

[email protected].

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 [email protected]. 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

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and use of health resources in patients with venous disease. Eur J Surg 1992; 158: 149-

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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.

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22. Acquadro C, Jambon B, Ellis D, Marquis P. Language and translation issues. In Spilker B

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23. Bouchet C, Guillemin F, Briançon S. Non specific effects in longitudinal studies: impact

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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.

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quality of life in cardiac rehabilitation patients. J Cardiopulm Rehabil 1995; 15: 143-8.

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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 Contents

0 No visible or palpable signs of venous disease

1 Telangectasia, reticular veins, malleolar flare

2 Varicose veins

3 Edema without skin changes

4 Skin changes due to venous disease (pigmentation, eczema, lipodermatosis)

5 Skin changes as defined above with healed ulceration

6 Skin changes as defined above with active ulceration

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Table 2: Countries and versions of the CIVIQ

Country CIVIQ language version

Argentina Spanish

Brazil Portuguese

Brunei English

Czech Republic Czech

Egypt Arabic

Hong Kong English

Hungary Hungarian

India English

Malaysia English

Philippines English

Poland Polish

Russia Russian

Singapore English

Slovakia Slovakian

Spain Spanish

Sri Lanka English

Turkey Turkish

Venezuela Spanish

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Table 3: Patients characteristics (N = 3,995)

Variables

Sex (women) N; % 3,239; 81.1%

Age (years) mean ± SD 45.6 ± 12.3

Ethnic group (Caucasian) N; % 3,112; 77.9%

Occupation: Employed full-time

Occupation: White-collar

N; %

N; %

2,468;

1,297;

61.8%

34.3%

Weight (kg): mean ± SD 71.0 ± 14.3

Duration of CVI (years): mean ± SD 12.4 ± 9.8

CEAP (class 2): N; % 1571; 39.3%

CEAP (classes 3 and 4): N; % 1572; 39.4%

With venous reflux: N; % 1,860; 46.6%

Edema measurement (cm): mean ± SD 27.2 ± 5.7

Sensation of Lower Limb Swelling*: N; % 3 102; 77.7%

Heaviness*: N; % 3 749; 93.8%

Cramps*: N; % 2 755; 68.9%

Pain (VAS in cm): mean ± SD 3.8 ± 2.5

* presence of the symptom

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Table 5: Clinical validity of the CIVIQ.

Global Index (mean ±±±± SD) in

patients suffering from CVI of

Clinical parameter

Mild intensity* Severe intensity**

Spearman’s

correlation

coefficient

p-value

CEAP 70.1 ± 19.1 57.9 ±19.9 0.22032 0.0001

Swelling 73.8 ± 15.1 45.7 ± 19.4 0.38561 0.0001

Heaviness 77.9 ± 15.4 47.8 ± 19.1 0.41706 0.0001

Cramps 71.5 ± 16.7 52.2 ± 20.5 0.33244 0.0001

* 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 O

Sex X

Age X

Body mass index O

Season X

Duration of the disease O

Venous reflux O

CEAP stage O

Edema (Leg-O-meter®) O

Cramps X

Swelling X

Heaviness X

Pain 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 Change* in Global Index (mean ±±±± SD) ICC CCC

(N = number of stable patients) n (MD) Difference

CEAP (N = 3749) 3,635 (114) 0.59 ± 6.74 0.9319 0.931

Swelling (N = 3250) 3,153 (97) 0.64 ± 6.40 0.9385 0.938

Heaviness (N = 3147) 3,050 (97) 0.62 ± 6.10 0.9441 0.944

Cramps (N = 3075) 3,069 (96) 0.43 ± 6.20 0.9427 0.942

Pain (N = 3714) 3,605 (109) 0.57 ± 6.47 0.9376 0.937

All parameters together (N = 2406) 2,339 (67) 0.54 ± 5.38 0.9561 0.956

* change was expressed by the difference between selection and baseline (D-15 to D0); MD: missing data; SD: standard deviatio

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* 661 23.7 ± 17.3

Worsened** 64 10.1 ± 16.8

Swelling* Improved 2,134 21.1 ± 16.8

Worsened 82 9.53 ± 13.6

Heaviness* Improved 2,778 20.1 ± 16.2

Worsened 68 5.8 ± 14.2

Cramps* Improved 2,189 21.1 ± 16.4

Worsened 88 7.1 ± 15.8

Pain** Very improved 442 29.2 ± 16.9

Improved 1,560 23.8 ±16.2

• improvement was defined as a decrease of one class for CEAP clinical stage, swelling, heaviness and cramps; wor

class for CEAP clinical stage, swelling, heaviness and cramps; ** improvement or impairment were defined acc

analogue scale): much improved = decrease of 5 cm or more, improved = decrease of 2.5 to 5 cm; ES1 = E

Standardized Response Mean

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• Table 9: Responsiveness of the Global Index to change over time in the sub-sample of 544 patie

Clinical parameter Clinical evolution Number of patients Change in Global Index:

D180-D0 (mean ±±±± SD)

CEAP* Improved* 79 21.3±18.9

Worsened** 19 5.6±11.5

Swelling* Improved 231 14.9±16.8

Worsened 32 5.8±10.3

Heaviness* Improved 299 14.3±16.7


Cramps* Improved 229 15.6±15.8


Pain** Very improved 0 NA

Improved 0 NA

* improvement was defined as a decrease of one class for CEAP clinical stage, swelling, heaviness and cramps; worsening

CEAP clinical stage, swelling, heaviness and cramps; ** improvement or impairment were defined according to change in

improved = decrease of 5 cm or more, improved = decrease of 2.5 to 5 cm; ES1 = Effect Size as defined by Kazis; ES2 = Stan

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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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