Numbers needed to treat calculated from responder rates give a better indication of efficacy in osteoarthritis trials than mean pain scores

R Andrew Moore, Owen A Moore, Sheena Derry, Henry J McQuay, R Andrew Moore, Owen A Moore, Sheena Derry, Henry J McQuay

Abstract

Introduction: Osteoarthritis trials usually report average changes in visual analogue scale (VAS) pain, and examine the difference between treatment and placebo. We investigated whether dichotomous responder analysis provides a more informative interpretation of drug efficacy.

Methods: Merck supplied the number of patients who, by 6 weeks, had achieved pain relief compared with a baseline of 0% or more, 10% or more, 20% or more, and so on at equal intervals up to 90% or more. These different levels of pain relief were used to distinguish different definitions of responders, for example at least 50% pain relief from baseline. Numbers and percentages of patients achieving each level were identified. Information was sought from a dose-response trial over 6 weeks in osteoarthritis using placebo and using etoricoxib at 5, 10, 30 and 60 mg daily.

Results: With placebo, the proportions of patients achieving at least 20%, 50% and 70% pain relief over baseline at 6 weeks were 30%, 11% and 2%. With 60 mg etoricoxib the equivalent percentages were 74%, 49% and 29%. The numbers needed to treat for 30 mg and 60 mg etoricoxib to produce at least 50% pain relief at 6 weeks compared with placebo were 4.2 (95% confidence interval 3.8 to 8.6) and 2.6 (2.0 to 3.9), respectively. Levels of pain relief of 50% and above discriminated best between different doses of etoricoxib.

Conclusion: Responder analysis seemed to be more sensitive than examination of average changes in VAS pain scores. Validation would require calculations to be performed on a set of trials using individual patient data not available in publications.

Figures

Figure 1
Figure 1
Percentage of patients achieving various levels of pain relief at 6 weeks compared with baseline.
Figure 2
Figure 2
Number needed to treat for each dose of etoricoxib at each level of pain relief. NNT, number needed to treat.

References

    1. Bjordal JM, Klovning A, Ljunggren AE, Slørdal L. Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: a meta-analysis of randomised placebo-controlled trials. Eur J Pain. 2007;11:125–138. doi: 10.1016/j.ejpain.2006.02.013.
    1. Bjordal JM, Ljunggren AE, Klovning A, Slørdal L. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ. 2004;329:1317–1323. doi: 10.1136/bmj.38273.626655.63.
    1. Tubach F, Ravaud P, Giraudeau B. Managing osteoarthritis of the knee: conclusions about use of NSAIDs are misleading. BMJ. 2005;330:672. doi: 10.1136/bmj.330.7492.672-b.
    1. McQuay H, Moore A. Utility of clinical trial results for clinical practice. Eur J Pain. 2007;11:123–124. doi: 10.1016/j.ejpain.2006.09.001.
    1. Tubach F, Ravaud P, Beaton D, Boers M, Bombardier C, Felson DT, van der Heijde D, Wells G, Dougados M. Minimal clinically important improvement and patient acceptable symptom state for subjective outcome measures in rheumatic disorders. J Rheumatol. 2007;34:1188–1193.
    1. Seror R, Tubach F, Baron G, Falissard B, Logeart I, Dougados M, Ravaud P. Individualizing the WOMAC function subscale: incorporating patients' priorities for improvement to measure functional impairment in hip or knee osteoarthritis. Ann Rheum Dis. 2008;67:494–499. doi: 10.1136/ard.2007.074591.
    1. Fries S, Grosser T, Price TS, Lawson JA, Kapoor S, DeMarco S, Pletcher MT, Wiltshire T, FitzGerald GA. Marked interindividual variability in the response to selective inhibitors of cyclooxygenase-2. Gastroenterology. 2006;130:55–64. doi: 10.1053/j.gastro.2005.10.002.
    1. Sowers JR, White WB, Pitt B, Whelton A, Simon LS, Winer N, Kivitz A, van Ingen H, Brabant T, Fort JG, for the Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT) Investigators The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005;165:161–168. doi: 10.1001/archinte.165.2.161.
    1. Klepstad P, Dale O, Skorpen F, Borchgrevink PC, Kaasa S. Genetic variability and clinical efficacy of morphine. Acta Anaesthesiol Scand. 2005;49:902–908. doi: 10.1111/j.1399-6576.2005.00772.x.
    1. Lötsch J, Geisslinger G. Current evidence for a genetic modulation of the response to analgesics. Pain. 2006;121:1–5. doi: 10.1016/j.pain.2006.01.010.
    1. Moore RA, Edwards JE, McQuay HJ. Acute pain: individual patient meta-analysis shows the impact of different ways of analysing and presenting results. Pain. 2005;116:322–331. doi: 10.1016/j.pain.2005.05.001.
    1. McQuay HJ, Carroll D, Moore RA. Variation in the placebo effect in randomised controlled trials of analgesics: all is as blind as it seems. Pain. 1996;64:331–335. doi: 10.1016/0304-3959(95)00116-6.
    1. Kroenke K, West SL, Swindle R, Gilsenan A, Eckert GJ, Dolor R, Stang P, Zhou XH, Hays R, Weinberger M. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. JAMA. 2001;286:2947–2955. doi: 10.1001/jama.286.23.2947.
    1. Simon G. Choosing a first-line antidepressant: equal on average does not mean equal for everyone. JAMA. 2001;286:3003–3004. doi: 10.1001/jama.286.23.3003.
    1. Moore RA, McQuay H. Single-patient data meta-analysis of 3,453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997;69:287–294. doi: 10.1016/S0304-3959(96)03291-5.
    1. Farrar JT, Dworkin RH, Max MB. Use of the cumulative proportion of responders analysis graph to present pain data over a range of cut-off points: making clinical trial data more understandable. J Pain Symptom Manage. 2006;31:369–377. doi: 10.1016/j.jpainsymman.2005.08.018.
    1. Pritchett YL, McCarberg BH, Watkin JG, Robinson MJ. Duloxetine for the management of diabetic peripheral neuropathic pain: response profile. Pain Med. 2007;8:397–409. doi: 10.1111/j.1526-4637.2007.00305.x.
    1. Gottesdiener K, Schnitzer T, Fisher C, Bockow B, Markenson J, Ko A, DeTora L, Curtis S, Geissler L, Gertz BJ, Protocol 007 Study Group Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis. Rheumatology (Oxford) 2002;41:1052–1061. doi: 10.1093/rheumatology/41.9.1052.
    1. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310:452–454.
    1. Morris JA, Gardner MJ. Calculating confidence intervals for relative risk, odds ratios and standardised ratios and rates. In: Gardner MJ, Altman DG, editor. Statistics with Confidence – Confidence Intervals and Statistical Guidelines. London: BMJ Publishing Group; 1995. pp. 50–63.
    1. Oldman AD, Smith LA, McQuay HJ, Moore RA. A systematic review of treatments for acute migraine. Pain. 2002;97:247–257. doi: 10.1016/S0304-3959(02)00024-6.
    1. Barden J, Edwards JE, McQuay HJ, Wiffen PJ, Moore RA. Relative efficacy of oral analgesics after third molar extraction. Br Dent J. 2004;197:407–411. doi: 10.1038/sj.bdj.4811721.
    1. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118:289–305. doi: 10.1016/j.pain.2005.08.013.
    1. Kristensen LE, Christensen R, Bliddal H, Geborek P, Danneskiold-Samsøe B, Saxne T. The number needed to treat for adalimumab, etanercept, and infliximab based on ACR50 response in three randomized controlled trials on established rheumatoid arthritis: a systematic literature review. Scand J Rheumatol. 2007;36:411–417. doi: 10.1080/03009740701607067.
    1. McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical practice. Ann Intern Med. 1997;126:712–720.
    1. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006;2:CD005328.
    1. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;1:CD004257.
    1. Pham T, Van Der Heijde D, Lassere M, Altman RD, Anderson JJ, Bellamy N, Hochberg M, Simon L, Strand V, Woodworth T, Dougados M, OMERACT-OARSI Outcome variables for osteoarthritis clinical trials: the OMERACT-OARSI set of responder criteria. J Rheumatol. 2003;30:1648–1654.
    1. Donnor A, Eliasziw M. Statistical implications of the choice between a dichotomous or continuous trait in studies of interobserver agreement. Biometrics. 1994;50:550–555. doi: 10.2307/2533400.
    1. Bhandari M, Lochner H, Tornetta P. Effect of continuous versus dichotomous outcome variables on study power when sample sizes of orthopaedic randomized trials are small. Arch Orthop Trauma Surg. 2002;122:96–98. doi: 10.1007/s004020100347.
    1. Anderson JJ. Mean changes versus dichotomous definitions of improvement. Stat Methods Med Res. 2007;16:7–12. doi: 10.1177/0962280206070651.
    1. Moore RA, Derry S, McQuay HJ, Paling J. What do we know about communicating risk? A brief review and suggestion for contextualising serious, but rare, risk, and the example of cox-2 selective and non-selective NSAIDs. Arthritis Res Ther. 2008;10:R20. doi: 10.1186/ar2373.

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