Relevant change in radiological progression in patients with hip osteoarthritis. I. Determination using predictive validity for total hip arthroplasty

Transcription

1 Rheumatology 2002;41: Relevant change in radiological progression in patients with hip osteoarthritis. I. Determination using predictive validity for total hip arthroplasty J. F. Maillefert 1,4,A.Gueguen 2,M.Nguyen 1,L.Berdah 3, M. Lequesne 5,B.Mazières 6,E.Vignon 7 and M. Dougados 1 1 René Descartes University, Cochin Hospital, Institut de Rhumatologie, Paris, 2 INSERM U88, St Maurice Hospital, Paris, 3 NEGMA Laboratories, Toussus le Noble, 4 General Hospital, Dijon, 5 Leopold Bellan Hospital, Paris, 6 Rangueil Hospital, Toulouse and 7 Lyon-Sud Hospital, Pierre Bénite, France Abstract Objective. To determine a cut-off point above which a change in joint space width (JSW) could be considered as relevant in patients with hip osteoarthritis (OA) on the basis of predicted need for subsequent total hip arthroplasty (THA). Methods. A multicentre, prospective, longitudinal, 5-yr follow-up study was performed. A pelvic radiograph was obtained at entry and after 1 and 2 yr. For each film, the narrowest JSW was measured using a 0.1 mm graduated magnifying glass. The absolute and relative differences between baseline and 1 and 2 yr of follow-up were calculated. We determined the cut-off points above which an absolute or relative decrease in and 1 and 2 yr of follow-up could be considered relevant on the basis of the predicted need for THA during the remaining years of the study. The need for THA was categorized as yes or no. Thereafter, for each observed change in JSW (0.1 per 0.1 mm or 1% per 1%), the sensitivity and specificity for subsequent THA were calculated. The choice of cut-off was based on maximal sensitivity and specificity, using the graphic representation of correct classification probabilities. In this way it was possible to obtain the best measured JSW threshold with maximal true positive and minimal false positive results. Results. A total of 423 and 385 patients met the criteria for analysis using the decrease in JSW between baseline and 1 and 2 yr respectively. The best cut-off points were absolute decreases in JSW of 0.2 and 0.4 mm and relative decreases in JSW of 15 and 20% after 1 and 2 yr respectively, with corresponding ranges of sensitivity and specificity of and 67 78%. Conclusion. This work determined the cut-off above which a change in JSW could be considered clinically relevant in patients with hip OA, on the basis of predicted subsequent need for THA. For validation, similar studies should be conducted in other countries with different health-care systems. KEY WORDS: Relevant change, Predictive validity, Total hip arthroplasty, Hip osteoarthritis, Joint space width, Outcome measure. The emergence of agents for the treatment of osteoarthritis (OA) that might be considered as structuremodifying drugs has led to recommendations for methods to be used in studies evaluating these drugs w1 3x. Symptomatic variables are reliable, clinically relevant outcome measures, but are subjective and Submitted 15 December 2000; revised version accepted 20 July Correspondence to: M. Dougados, Institut de Rhumatologie, Cochin Hospital, 27 rue du Faubourg St Jacques, Paris cedex 14, France. may be influenced by treatments that do not interfere with cartilage metabolism, such as analgesics w4x. Consequently, symptomatic effects are considered as secondary outcomes in these trials. Structural variables are more accurate, have high intrinsic validity and are usually considered as the primary outcome to be assessed. Several methods of assessing structural variables have been proposed. Among these, the assessment of joint space width (JSW) (the interbone distance at the narrowest point, in millimetres) is currently accepted as the most sensitive technique. 142 ß 2002 British Society for Rheumatology

2 Relevant change in radiological progression of hip OA 143 However, this evaluation results in a continuous variable and does not discriminate between patients with and those without relevant change. The percentage of patients having radiological disease progression is an important end-point in trials and is easier to understand than mean changes. In addition, having an established definition of progression and non-progression allows comparison of data from different trials. Because JSW is evaluated routinely in daily practice, such a cut-off point may also facilitate the monitoring of OA patients. Thus, the determination of a cut-off point above which a change in JSW could be considered relevant in hip OA should be useful. Several approaches can be used to determine a cut-off above which a change in imaging variables could be considered relevant w5x. Distribution-based models describe features of the distribution of the measure in the population. In particular, the smallest detectable difference (SDD) is based on measurement error and thus on reproducibility w6x. In other words, a cut-off point determined by the use of SDD would help ensure that the changes observed were true changes rather than random fluctuation related to variability in the measurement procedure. Authority-based models are based on expert opinion, i.e. on the intuitive clinician s global assessment on the basis of gained experience and knowledge. Predictive models are driven experimentally and are used in evidence-based approaches. In a previous study, we determined the SDD on the basis of intraobserver progression score measurement error in the absolute progression of JSW in hip OA w7x. In the present study, we aimed to determine a cut-off above which a change in JSW could be considered relevant in patients with hip OA, based on prediction of further total hip arthroplasty. Methods Study design A multicentre, prospective, longitudinal, 5-yr follow-up study was designed. The study protocol was approved by the ethics committee of the Hôpital Cochin, Paris, France. Inclusion criteria These have been described previously w8x. Briefly, outpatients visiting a rheumatologist and fulfilling the American College of Rheumatology criteria for the diagnosis of hip OA w9x were enrolled in the study after written informed consent had been obtained. Other inclusion criteria were age between 50 and 75 yr, daily hip pain for at least 1 month during the last 3 months. Exclusion criteria were joint space width < 1mm at the narrowest point, radiographic medial or axial femoral head migration, secondary hip OA defined by the presence of a history of hip fracture, inflammatory rheumatic disease, osteonecrosis of the femoral head and Paget s disease. Structural evaluation An anteroposterior weight-bearing radiograph of the pelvis with the lower limbs in 158 internal rotation was obtained at entry and after 1 and 2 yr. All films were collected and analysed by one of us (ML) w10, 11x. Films were blinded with respect to patient identity and date. A randomization list was used for blinding with respect to chronology. The films of a single patient were placed side by side on a light-box and the narrowest JSW (identical for all films) was selected and measured (interbone distance) using a 0.1 mm graduated magnifying glass. The evaluation of the intra-observer reliability using 30 pairs of films, assessed twice after a 1-month interval, showed an intra-class coefficient of correlation of (95% confidence interval ). Decision for surgery This was made by the patient, the rheumatologist and the surgeon with no reference to radiographic change (although the rheumatologist and the surgeon had the opportunity to evaluate the last follow-up X-rays) anduor analysis of objective symptomatic variables. Analysis Absolute and relative changes in and 1 and 2 yr of follow-up evaluations were calculated. Analyses were performed in order to propose relevant thresholds, allowing us to transform the continuous variable (absolute and relative changes in JSW) into a dichotomous variable: progression or no progression. The patients were classified as requiring total hip arthroplasty (THA) or not requiring THA. Thereafter, different possible thresholds were evaluated: for each change observed in measured JSW (0.1 per 0.1 mm or 1% per 1%), we measured the sensitivity (percentage of patients with a decrease in measured JSW above the threshold, among the patients who underwent THA during the follow-up) and the specificity (percentage of patients with a decrease in measured JSW below the threshold, among the patients who did not have THA during the follow-up) for further THA. The choice of cut-off was based on maximal sensitivity and specificity, using the graphic representation of correct classification probabilities. In this way we were able to obtain the best measured JSW threshold with maximal true positive and the minimal false positive results w12x. Two analyses were performed, producing four different thresholds. The first analysis aimed to determine a cut-off point above which an absolute or relative decrease in and the 1-yr follow-up could be considered relevant on the basis of the prediction of THA during the following 4 yr. The second analysis aimed to determine a cut-off point above which an absolute or relative decrease in JSW between baseline and the 2-yr follow-up could be considered relevant on the basis of prediction of THA during the following 3 yr. In some instances, the interval between baseline and follow-up radiographs was not 12 or

3 144 J. F. Maillefert et al. 24 months. Only the pairs of films separated by intervals of 12 " 3 and 24 " 6 months were used for analysis. For each of the four thresholds, Kaplan Meier estimates of the cumulative probabilities of not having THA (according to the decrease in JSW above or below the threshold) were obtained. Results Five hundred and eight patients were recruited initially. In the first analysis, 39 patients (7.7%) underwent THA TABLE 1. Main baseline characteristics Parameter First analysis (422 patients) Second analysis (384 patients) Demographic data Age (yr; mean " S.D.) 63 " " 6.8 Sex (male, female; no.) 176, , 216 Body mass index 25.8 " " 3.4 (kgum 2 ; mean " S.D.) Symptoms Pain (mm; mean " S.D.) a 43.8 " " 19.3 Lequesne s index (mean " S.D.) b 7.6 " " 2.4 Radiography Femoral head migration Superolateral (no. patients) Superomedial (no. patients) Concentric (no. patients) The table shows the main baseline characteristics of the 422 patients included in the first analysis (determination of the cut-off point above which an absolute or relative decrease in and 1 yr could be considered relevant on the basis of predicted THA during the subsequent 4 yr) and the 384 patients included in the second analysis (determination of a cut-off point above which an absolute or relative decrease in and 2 yr of follow-up could be considered relevant on the basis of predicted THA during the subsequent 3 yr). a Measured on a 100-mm visual analogue scale. b A scale from 0 to 24 reflecting the effect of OA on daily activities. during the first year. Among the remaining 469 patients, 46 were excluded because they had an interval between baseline and follow-up that differed from 12 " 3 months. Among the 423 remaining patients, 422, whose main baseline characteristics are shown in Table 1, were observed over the following 4 yr. In these 422 patients, the mean JSW was 2.31 " 0.81 (S.D.) mm at baseline and 1.99 " 1.02 mm after 1 yr of follow-up (mean absolute and relative changes " 0.57 mm and 217 " 29% respectively). During the remaining 4 yr of the study, THA was performed in 149 of the 422 patients (35.3%). Thresholds of 20.2 mm and 215%, i.e. a decrease in JSW of at least 0.2 mm (15%), were the most relevant, with sensitivity of 75 and 68% (20.2 mm) and 74 and 78% (215%) respectively (Table 2). In the second analysis, 81 patients (15.9%) underwent THA during the first 2 yr. Among the 427 remaining patients, 42 were excluded as having an interval between baseline and follow-up X-rays different from 24 " 6 months. Among the 385 other patients, 384, whose main baseline characteristics are shown in Table 1, were observed during the following 3 yr. In these 384 patients, the mean JSW was 2.35 " 0.81 mm (S.D.) at baseline and 1.91 " 1.07 mm after 2 yr of follow-up (mean absolute and relative changes " 0.61 mm and " 32% respectively). During the remaining 3 yr of the study, THA was performed in 111 of the 384 patients (28.9%). Thresholds of mm and 220%, i.e. a decrease in JSW of at least 0.4 mm and 20%, were the most relevant, with sensitivity and specificity of 68 and 67% (20.4 mm) and 70 and 68% (220%) respectively (Table 2). Figure 1 shows one of the graphic representations of correct classification probabilities and Fig. 2 shows one of the Kaplan Meier estimates of the cumulative probabilities of not having THA, according to the decrease in JSW below or above a determined threshold. TABLE 2. Cut-off points above which an absolute or relative decrease in and 1 and 2 yr of follow-up could be considered relevant on the basis of prediction of THA during the subsequent 4 and 3 yr respectively Sensitivity Specificity Positive Negative No. of patients with No. of for subsequent for subsequent predictive predictive a decrease in JSW patients Threshold THA THA value value below the threshold Absolute decrease in mm 75% 68% 66.9% 79.2% 133 and 1 yr Relative decrease in % 74% 78% 68.5% 85.4% 162 and 1 yr Absolute decrease in mm 68% 67% 50% 80.5% 118 and 2 yr Relative decrease in % 70% 68% 47.9% 85.1% 163 and 2 yr The thresholds were obtained from the graphic representation of correct classification probabilities, showing for all possible changes in JSW (0.1 mm per 0.1 mm or 1% per 1%) the sensitivity (percentage of patients with a decrease in measured JSW above the threshold, among the patients who underwent THA during the follow-up period) and specificity (percentage of patients with a decrease in measured JSW below the threshold, among the patients who did not have THA during the follow-up period) for further THA. The best measured JSW thresholds, with the maximal true positive and minimal false positive results, were selected.

4 Relevant change in radiological progression of hip OA 145 FIG. 1. Determination of a cut-off point above which an absolute decrease in and the 2-yr followup could be considered relevant on the basis of prediction of THA during the subsequent 3 yr. The best threshold was 20.4 mm, with sensitivity 68% and specificity 67%. The curves were obtained taking into account all possible changes in JSW threshold. For each measured difference in JSW (0.1 mm per 0.1 mm), the sensitivity (percentage of patients with a decrease in measured JSW above the threshold, among the patients who underwent THA during the follow-up) and specificity ( percentage of patients with a decrease in measured JSW below the threshold, among the patients who did not have THA during the follow-up) for subsequent THA were used to construct the curve. This made it possible to obtain the best measured JSW thresholds. The curves determining the other thresholds (absolute decrease in and 1 yr of follow-up and the relative decreases in JSW between baseline and 1 and 2 yr of follow-up) were very similar and are not shown. Discussion This study determined the cut-off point above which a change in JSW could be considered clinically relevant in patients with hip OA on the basis of the prediction of subsequent THA. To our knowledge, thresholds in JSW progression in patients with hip OA, determined using this method, have not been available previously. This cut-off point could be used to differentiate between patients with and without a structurally relevant change in therapeutic trials and clinical practice. Because of the characteristics of the population, it might be difficult to extrapolate the results of this study to a general population of patients with hip OA. This study focused on a particular subgroup of patients, all of whom had, for example, painful, active disease. However, such characteristics are those commonly observed both in daily practice and in therapeutic trials evaluating the effects of particular drugs in hip FIG. 2. Kaplan Meier estimates of the cumulative probabilities of not having THA according to the decrease in JSW below or above the cut-off point (0.4 mm), determined from the absolute decrease in and the 2-yr follow-up and the prediction of THA during the subsequent 3 yr. The Kaplan Meier estimates of the cumulative probabilities of not having THA according to the decrease in JSW below or above the other cut-off points determined (absolute decrease in and the 1-yr follow-up and the relative decreases in and 1 and 2 yr of follow-up) led to very similar figures, which are not shown here. OA. The assessment of JSW seems to be related to the radiological procedure used and, in particular, to patient positioning. For example, weight-bearing may affect JSW in hip OA w13, 14x. In this study, the radiological procedure was standardized: all X-rays were taken with the patient standing with the lower limbs in 158 internal rotation. The threshold might have been different if another standardized procedure had been used. It must also be pointed out that individuals with baseline values below a threshold determined using the absolute decrease in JSW can never be regarded as having deteriorated w15x. Thus, the thresholds determined using the relative decrease in JSW should be preferred in trials examining structurally severe hip OA or, in daily practice, in monitoring patients with such severe disease. In this study, several thresholds were determined. Obtaining thresholds for the prediction of THA using several intervals between pairs of films, i.e. 1 and 2 yr, makes it possible to use them in trials of different duration or to perform intermediate analyses in 2-yr

5 146 J. F. Maillefert et al. follow-up trials. The accuracy of the proposed thresholds appeared to be good. The cut-off points determined with the relative decrease tended to have greater accuracy than those obtained with the absolute decrease in JSW. However, this method does not take account of the severity of structural deterioration at baseline. Moreover, in patients with severe baseline structural deterioration, a decrease of 15 or 20% in JSW corresponds to absolute decreases that are far less than measurement error. Thus, we recommend the use of one of the cut-off points determined using the absolute decrease in JSW rather than the relative decrease. The cut-off point determined using the absolute decrease in JSW was lower than the SDD (0.6 mm) w7x. Increasing the threshold to 0.6 mm would improve specificity but reduce sensitivity for the prediction of subsequent THA. Despite poorer accuracy, the threshold determined using the absolute decrease in and the 2-yr follow-up (0.4 mm) is preferable to that obtained by the use of the absolute decrease in JSW between baseline and the 1-yr follow-up (0.2 mm). A model based on the prediction of subsequent THA was used. This model has several advantages: it is probably clinically relevant, because THA is performed only in patients with severe disease; the variable THA or no THA is easy to ascertain; and changes in JSW have been shown to be highly predictive of the subsequent need for THA w8x. However, the choice of subsequent THA as the gold standard has some disadvantages. First, this choice is subjective: the goals of treatment in OA include not only the prevention of THA but also the relief of pain and the attainment and maintenance of optimal joint function, thus reducing disability and handicap and maintaining the risk of progression w16x. Thus, the need for THA has been proposed as a hard outcome measure in trials, but not as a replacement for other outcomes w8x. Secondly, the indications for THA might vary among centres, surgeons and patients, and might be affected by factors that are not closely related to the clinical presentation of the disease w17, 18x. Thirdly, despite the fact that the decision regarding surgery was made with no reference to radiographic change, it was potentially made with reference to the last assessment of radiographic damage, thus might have introduced some bias. Thus, the thresholds might have been different if they had been determined with other sets of patients in other countries. It is not possible to proceed differently in the absence of validated sets of criteria for considering THA. Such criteria have been proposed recently w19x, but as validation by others is still lacking they were not used in the present study. Because the decision with regard to THA in the present study took into account the opinions of the patient and at least two specialized practitioners (the rheumatologist and the surgeon) and, because the study used a multicentre design, some disparities in surgical decisions should have been taken into account. Economic considerations should not have affected the results as the great majority of the French population is insured by the National Health Service. However, for validation, similar studies should be conducted in other countries with different health-care systems. This work determined a cut-off point above which a change in JSW could be considered as clinically relevant in individuals with hip OA on the basis of prediction of subsequent THA. This cut-off point could be used to differentiate patients with and without a structurally relevant change, both in therapeutic trials and in clinical practice. However, for validation, similar studies should be conducted in other countries with different health-care systems. Acknowledgement This work was supported in part by NEGMA Laboratories. References 1. Lequesne M, Brandt K, Bellamy N et al. Guidelines for testing slow acting drugs in osteoarthritis. J Rheumatol 1994;21(Suppl. 41): Group for the Respect of Ethics and Excellence in Science (GREES). Recommendations for the registration of drugs used in the treatment of osteoarthritis. Ann Rheum Dis 1996;55: Altman RD, Brandt KD, Hochberg MC, Moskowitz RM, for the Task Force of the Osteoarthritis Research Society. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a Task Force of the Osteoarthritis Research Society. Osteoarthritis Cartilage 1996;4: Bolnot-Delmas D, Buch JP, Zeidler H, Dougados M. Ro in osteoarthritis of hip and knee: a doubleblind placebo-controlled multicentre dose-ranging study on analgesia. Pain 1996;64: Lassere MND, van der Heijde D, Johnson KR. Foundations of the Minimal Clinically Important Difference for imaging. J Rheumatol 2001;28: Lassere M, Boers M, van der Heijde D et al. Smallest detectable difference in radiological progression. J Rheumatol 1999;26: Dougados M, Gueguen A, Nguyen M et al. Radiological progression of hip osteoarthritis: definition, risk factors and correlations with clinical status. Ann Rheum Dis 1996;55: Dougados M, Gueguen A, Nguyen M et al. Requirement for total hip arthroplasty: an outcome measure of hip osteoarthritis? J Rheumatol 1999;26: Altman R, Alarcon G, Appelrouth D et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum 1991;34: Lequesne M. Quantitative measurement of joint space width during progression of osteoarthritis: chondrometry. In: Kuettner K, Goldberg V, eds. Osteoarthritis disorders. Rosemont: American Academy of Orthopedic Surgeons, 1995;30: Lequesne M, Cadet C, Auleley GR. New technique and reproducibility of the manual measurement of osteoarthritic hip joint space wabstractx. Osteoarthritis Cartilage 2000;8: Bruynesteyn K, van der Heijde D, Boers M et al. Minimum clinically important difference in radiological

6 Relevant change in radiological progression of hip OA 147 progression of joint damage over 1 year in rheumatoid arthritis: preliminary results of a validation study with clinical experts. J Rheumatol 2001;28: Auleley GR, Rousselin B, Ayral X, Edouard-Noel R, Dougados M, Ravaud P. Osteoarthritis of the hip: agreement between joint space width measurements on standing and supine conventional radiographs. Ann Rheum Dis 1998;57: Conrozier T, Tron AM, Mathieu P, Vignon E. Quantitative assessment of radiographic normal and osteoarthritic hip joint space. Osteoarthritis Cartilage 1995;3(Suppl. A): Dougados M, Le Claire P, van der Heijde D, Bloch DA, Bellamy N, Altman RD. Special article: response criteria for clinical trials on osteoarthritis of the knee and hip. Osteoarthritis Cartilage 2000;8: Dieppe P, Buckwalter JA. Management of limb joint osteoarthritis. In: Klippel JH, Dieppe PA, eds. Rheumatology, 2nd edn. London: Mosby, 1998: Charlson ME, Allegrante JP. Disparities in the use of total joint arthroplasty. N Engl J Med 2000;342: Hawker GA, Wright JG, Coyte PC et al. Differences between men and women in the rate of use of hip and knee arthroplasty. N Engl J Med 2000;342: Maillefert JF, Gueguen A, Nguyen M et al. A composite index for total hip arthroplasty in patients with hip osteoarthritis. J Rheumatol 2002;29: