Stratification of flare intensity identifies placebo responders in a treatment efficacy trial of patients with osteoarthritis

Scott-Lennox, Jane; McLaughlin-Miley, C; Lennox, Richard D.; Bohlig, Andrea; Cutler, Brian L.; Yan, Chongqing; Jaffe, Michael

doi:10.1002/1529-0131(200107)44:7<1599::aid-art283>3.0.co;2-n

Cited by 24 publications

(16 citation statements)

References 3 publications

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“…15 A common mistake, however, is to think that adjusting the treatment effect by including a covariate addresses whether the treatment effect differs according to that covariate. Such a strategy only neutralizes the effect of the confounder, but does not allow conclusions on the treatment effect within each subgroup (i.e.…”

Section: Confounder and Effect Modifiermentioning

confidence: 99%

Primer: the fallacy of subgroup analysis

Guillemin

2007

Nat Rev Rheumatol

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The identification of subgroups of patients from randomized clinical trials that are of specific interest for guiding clinical decisions can be an attractive idea; however, since such trials are designed for the comparison of groups of patients, performing subgroup analyses can result in misinterpretation of the data. Such analyses must, therefore, be performed and evaluated with caution: these should be pre-planned and included in the design of a suitably powered trial. Data obtained should be analyzed using formal statistical tests of interaction on proper subgroups rather than improper subgroups of patients, the results obtained should be delineated carefully, and details of how these analyses were performed, and how the data should be interpreted, should be reported in the trial paper. The caveats associated with this approach, such as the occurrence of false positive or false negative effects, chance differences in observed effects, lack of power to perform the analysis, floor or ceiling effects, issues relating to multiple statistical testing, and over-reporting and under-reporting are discussed in this review. Subgroup analyses can, however, provide valuable, albeit predominantly exploratory, information on which to base clinical decisions if they are performed in accordance with recommendations and guidelines, and do, therefore, have a legitimate place in rheumatology clinical trials.

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Section: Confounder and Effect Modifiermentioning

confidence: 99%

Primer: the fallacy of subgroup analysis

Guillemin

2007

Nat Rev Rheumatol

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“…Many studies evaluating pain flare-up have been conducted in patients with cancer [19][20][21] in whom it has been suggested that the presence of a pain flare-up may contribute to the development of more severe chronic pain. 20 The study conducted on the evaluation of flare-up intensity in OA patients 22 reported that, once the flare-up intensity is controlled, there was a dramatic pain reduction in patients with the most intense flare-ups. In this study, a total of 191 of 211 patients (etodolac-paracetamol, 94 patients; etodolac, 97 patients) reported a VAS Z7 at baseline.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Etodolac-Paracetamol Fixed Dose Combination in Patients With Knee Osteoarthritis Flare-up: A Randomized, Double-blind Comparative Evaluation

Pareek

Chandurkar

Ambade

et al. 2010

The Clinical Journal of Pain

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“…Studies with flare based designs may, however, be associated with large placebo response rates. 13 It is therefore arguable whether the ASAS-IC would behave similarly in NSAID efficacy trials without this criterion. In addition, it is yet unknown how the ASAS-IC behave in other clinical trials assessing for instance the efficacy of disease modifying drugs, anti-tumour necrosis factor α treatment, or physical therapy.…”

Section: Discussionmentioning

confidence: 99%

Comparison of statistically derived ASAS improvement criteria for ankylosing spondylitis with clinically relevant improvement according to an expert panel

Tubergen

Heijde²,

Anderson³

et al. 2003

Annals of the Rheumatic Diseases

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Objective: To investigate whether the recently developed (statistically derived) "ASsessment in Ankylosing Spondylitis Working Group" improvement criteria (ASAS-IC) for ankylosing spondylitis (AS) reflect clinically relevant improvement according to the opinion of an expert panel. Methods:The ASAS-IC consist of four domains: physical function, spinal pain, patient global assessment, and inflammation. Scores on these four domains of 55 patients with AS, who had participated in a non-steroidal anti-inflammatory drug efficacy trial, were presented to an international expert panel (consisting of patients with AS and members of the ASAS Working Group) in a three round Delphi exercise. The number of (non-)responders according to the ASAS-IC was compared with the final consensus of the experts. The most important domains in the opinion of the experts were identified, and also selected with discriminant analysis. A number of provisional criteria sets that best represented the consensus of the experts were defined. Using other datasets, these clinically derived criteria sets as well as the statistically derived ASAS-IC were then tested for discriminative properties and for agreement with the end of trial efficacy by patient and doctor. Results: Forty experts completed the three Delphi rounds. The experts considered twice as many patients to be responders than the ASAS-IC (42 v 21). Overall agreement between experts and ASAS-IC was 62%. Spinal pain was considered the most important domain by most experts and was also selected as such by discriminant analysis. Provisional criteria sets with an agreement of >80% compared with the consensus of the experts showed high placebo response rates (27-42%), in contrast with the ASAS-IC with a predefined placebo response rate of 25%. All criteria sets and the ASAS-IC discriminated well between active and placebo treatment (χ 2 =36-45; p<0.001). Compared with the end of trial efficacy assessment, the provisional criteria sets showed an agreement of 71-82%, sensitivity of 67-83%, and specificity of 81-88%. The ASAS-IC showed an agreement of 70%, sensitivity of 62%, and specificity of 89%. Conclusion: The ASAS-IC are strict in defining response, are highly specific, and consequently show lower sensitivity than the clinically derived criteria sets. However, those patients who are considered as responders by applying the ASAS-IC are acknowledged as such by the expert panel as well as by patients' and doctors' judgments, and are therefore likely to be true responders.

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Stratification of flare intensity identifies placebo responders in a treatment efficacy trial of patients with osteoarthritis

Cited by 24 publications

References 3 publications

Primer: the fallacy of subgroup analysis

Primer: the fallacy of subgroup analysis

Efficacy and Safety of Etodolac-Paracetamol Fixed Dose Combination in Patients With Knee Osteoarthritis Flare-up: A Randomized, Double-blind Comparative Evaluation

Comparison of statistically derived ASAS improvement criteria for ankylosing spondylitis with clinically relevant improvement according to an expert panel

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