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. 2004 Oct;63(10):1222–1226. doi: 10.1136/ard.2003.018861

Influence of guideline adherence on outcome in a randomised controlled trial on the efficacy of methotrexate with folate supplementation in rheumatoid arthritis

J Fransen 1, R Laan 1, M A F J van der Laar 1, T Huizinga 1, P L C M van Riel 1
PMCID: PMC1754779  PMID: 15361375

Abstract

Objective: To study the influence of rheumatologists' adherence to a methotrexate guideline on efficacy and toxicity in the treatment of rheumatoid arthritis.

Methods: In a 48 week randomised controlled trial of methotrexate, comparing folates with placebo, rheumatologists were advised on methotrexate dosage using a guideline reflecting daily practice. The influence of guideline non-adherence on outcome was analysed using generalised estimating equations and survival analysis.

Results: In 51% of the 411 study patients the guidelines were always followed. Non-adherence resulted in lower doses of methotrexate in 25% of cases, and higher doses in 24%. The reduction in the disease activity score was significantly greater (mean –0.4; p = 0.0085) in the adherent group than in the "low dose" group; the "high dose" group did not differ from the adherent group. Dropout caused by severe adverse events did not differ between the three groups.

Conclusions: There is an indication that adherence to guidelines on methotrexate dosage may benefit patients with rheumatoid arthritis by improving disease activity without increasing toxicity. For definite proof, a randomised controlled trial comparing guideline supported dosing with usual care is needed.

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Figure 1.

Figure 1

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 Differences in cumulative methotrexate dose over time. Methotrexate cumulative dose differences are calculated as differences of the non-adherence groups from the full adherence group. Differences are presented as medians. MTX, methotrexate; NA–, patients with a cumulative methotrexate dose at the end of the trial period that was lower than the guidelines proposed; NA+, patients with a cumulative methotrexate dose at the end of the trial period that was higher than the guidelines proposed.

Figure 2.

Figure 2

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 Course of disease activity score (DAS) over time.

Figure 3.

Figure 3

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 Survival analysis: dropout caused by severe adverse events. FA, patients with full guideline adherence; NA–, patients with a net lower methotrexate dose than the guidelines proposed; NA+, patients with a net higher methotrexate dose than the guidelines proposed.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cabana Michael D., Rushton Jerry L., Rush A. John. Implementing practice guidelines for depression: applying a new framework to an old problem. Gen Hosp Psychiatry. 2002 Jan-Feb;24(1):35–42. doi: 10.1016/s0163-8343(01)00169-4. [DOI] [PubMed] [Google Scholar]
  2. Cibere Jolanda, Sibley John T., Haga May. Rheumatologists' adherence to guidelines for misoprostol use in patients at high risk for nonsteroidal antiinflammatory drug gastropathy. J Rheumatol. 2002 Feb;29(2):339–346. [PubMed] [Google Scholar]
  3. Den Broeder A. A., Creemers M. C. W., van Gestel A. M., van Riel P. L. C. M. Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNF-alpha. Rheumatology (Oxford) 2002 Jun;41(6):638–642. doi: 10.1093/rheumatology/41.6.638. [DOI] [PubMed] [Google Scholar]
  4. Felson D. T., Anderson J. J., Meenan R. F. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum. 1992 Oct;35(10):1117–1125. doi: 10.1002/art.1780351003. [DOI] [PubMed] [Google Scholar]
  5. Fitzmaurice D. A., Hobbs F. D., Delaney B. C., Wilson S., McManus R. Review of computerized decision support systems for oral anticoagulation management. Br J Haematol. 1998 Sep;102(4):907–909. doi: 10.1046/j.1365-2141.1998.00858.x. [DOI] [PubMed] [Google Scholar]
  6. Fitzmaurice D. A., Hobbs F. D., Murray E. T., Bradley C. P., Holder R. Evaluation of computerized decision support for oral anticoagulation management based in primary care. Br J Gen Pract. 1996 Sep;46(410):533–535. [PMC free article] [PubMed] [Google Scholar]
  7. Fries J. F., Spitz P. W., Williams C. A., Bloch D. A., Singh G., Hubert H. B. A toxicity index for comparison of side effects among different drugs. Arthritis Rheum. 1990 Jan;33(1):121–130. doi: 10.1002/art.1780330117. [DOI] [PubMed] [Google Scholar]
  8. Hetlevik I., Holmen J., Krüger O. Implementing clinical guidelines in the treatment of hypertension in general practice. Evaluation of patient outcome related to implementation of a computer-based clinical decision support system. Scand J Prim Health Care. 1999 Mar;17(1):35–40. doi: 10.1080/028134399750002872. [DOI] [PubMed] [Google Scholar]
  9. Hetlevik I., Holmen J., Krüger O., Kristensen P., Iversen H., Furuseth K. Implementing clinical guidelines in the treatment of diabetes mellitus in general practice. Evaluation of effort, process, and patient outcome related to implementation of a computer-based decision support system. Int J Technol Assess Health Care. 2000 Winter;16(1):210–227. doi: 10.1017/s0266462300161185. [DOI] [PubMed] [Google Scholar]
  10. Hunt D. L., Haynes R. B., Hanna S. E., Smith K. Effects of computer-based clinical decision support systems on physician performance and patient outcomes: a systematic review. JAMA. 1998 Oct 21;280(15):1339–1346. doi: 10.1001/jama.280.15.1339. [DOI] [PubMed] [Google Scholar]
  11. Johnston M. E., Langton K. B., Haynes R. B., Mathieu A. Effects of computer-based clinical decision support systems on clinician performance and patient outcome. A critical appraisal of research. Ann Intern Med. 1994 Jan 15;120(2):135–142. doi: 10.7326/0003-4819-120-2-199401150-00007. [DOI] [PubMed] [Google Scholar]
  12. Montgomery A. A., Fahey T. A systematic review of the use of computers in the management of hypertension. J Epidemiol Community Health. 1998 Aug;52(8):520–525. doi: 10.1136/jech.52.8.520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Montgomery A. A., Fahey T., Peters T. J., MacIntosh C., Sharp D. J. Evaluation of computer based clinical decision support system and risk chart for management of hypertension in primary care: randomised controlled trial. BMJ. 2000 Mar 11;320(7236):686–690. doi: 10.1136/bmj.320.7236.686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ritchie D. M., Boyle J. A., McInnes J. M., Jasani M. K., Dalakos T. G., Grieveson P., Buchanan W. W. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med. 1968 Jul;37(147):393–406. [PubMed] [Google Scholar]
  15. Scott D. L. Clinical guidelines for management. Baillieres Clin Rheumatol. 1997 Feb;11(1):157–179. doi: 10.1016/s0950-3579(97)80039-8. [DOI] [PubMed] [Google Scholar]
  16. Simon R., Makuch R. W. A non-parametric graphical representation of the relationship between survival and the occurrence of an event: application to responder versus non-responder bias. Stat Med. 1984 Jan-Mar;3(1):35–44. doi: 10.1002/sim.4780030106. [DOI] [PubMed] [Google Scholar]
  17. Uitz E., Fransen J., Langenegger T., Stucki G. Clinical quality management in rheumatoid arthritis: putting theory into practice. Swiss Clinical Quality Management in Rheumatoid Arthritis. Rheumatology (Oxford) 2000 May;39(5):542–549. doi: 10.1093/rheumatology/39.5.542. [DOI] [PubMed] [Google Scholar]
  18. Vadher B., Patterson D. L., Leaning M. Evaluation of a decision support system for initiation and control of oral anticoagulation in a randomised trial. BMJ. 1997 Apr 26;314(7089):1252–1256. doi: 10.1136/bmj.314.7089.1252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Wolfe F., Cush J. J., O'Dell J. R., Kavanaugh A., Kremer J. M., Lane N. E., Moreland L. W., Paulus H. E., Pincus T., Russell A. S. Consensus recommendations for the assessment and treatment of rheumatoid arthritis. J Rheumatol. 2001 Jun;28(6):1423–1430. [PubMed] [Google Scholar]
  20. van Ede A. E., Laan R. F., Rood M. J., Huizinga T. W., van de Laar M. A., van Denderen C. J., Westgeest T. A., Romme T. C., de Rooij D. J., Jacobs M. J. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2001 Jul;44(7):1515–1524. doi: 10.1002/1529-0131(200107)44:7<1515::AID-ART273>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  21. van Gestel A. M., Prevoo M. L., van 't Hof M. A., van Rijswijk M. H., van de Putte L. B., van Riel P. L. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996 Jan;39(1):34–40. doi: 10.1002/art.1780390105. [DOI] [PubMed] [Google Scholar]
  22. van Gestel A. M., van Riel P. L. Evaluation of early rheumatoid arthritis disease activity and outcome. Baillieres Clin Rheumatol. 1997 Feb;11(1):49–63. doi: 10.1016/s0950-3579(97)80032-5. [DOI] [PubMed] [Google Scholar]
  23. van Riel P. L., Schumacher H. R., Jr How does one assess early rheumatoid arthritis in daily clinical practice? Best Pract Res Clin Rheumatol. 2001 Mar;15(1):67–76. doi: 10.1053/berh.2000.0126. [DOI] [PubMed] [Google Scholar]
  24. van der Heijde D. M., van 't Hof M., van Riel P. L., van de Putte L. B. Development of a disease activity score based on judgment in clinical practice by rheumatologists. J Rheumatol. 1993 Mar;20(3):579–581. [PubMed] [Google Scholar]

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