Assessment of treatment failure and treatment effectiveness: the case of leflunomide versus MTX

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J Rheumatol. 2003 Aug;30(8):1725-32.

Toward a definition and method of assessment of treatment failure and

treatment effectiveness: the case of leflunomide versus methotrexate.

Wolfe F, Michaud K, son B, Doyle J.

National Data Bank for Rheumatic Diseases, Wichita, Kansas, USA.

fwolfe@...

OBJECTIVE: Time to treatment discontinuation (TTD) is an accepted method

of assessing treatment effectiveness in the community, but is

susceptible to channeling bias and secular and cohort effects. In

addition, TTD does not consider the addition of new disease modifying

antirheumatic drugs (DMARD) to insufficiently effective therapies. We

expand the definition of treatment failure to include discontinuation or

addition of a second DMARD (1) to examine leflunomide (LEF) versus

methotrexate (MTX) effectiveness in clinical practice; (2) to obtain an

estimate of overall clinical effectiveness; and (3) to identify factors

associated with treatment successes and failure. In addition, (4) we

test the feasibility of performing a clinical trial using a longitudinal

data bank. METHODS: Using the National Data Bank for Rheumatic Diseases

longitudinal data bank, 1431 patients with rheumatoid arthritis (RA) who

began taking LEF or MTX as part of their routine medical care were

followed from 1998 through 2001. None of the 1431 patients had received

either treatment previously. Patients were assessed at 6 month intervals

for periods up to 36 months by mailed questionnaires concerning DMARD

therapy and demographic and RA severity factors. Kaplan-Meier survivor

functions and regression analyses were used to assess treatment

failure, defined as time to discontinuation or to the addition of a

second DMARD. RESULTS: For 756 patients taking LEF, the failure rate was

55.5 per 100 patient-years, and the median time to failure was 15 (95%

CI 13, 17) months. For 675 patients taking MTX the failure rate was 57.3

per 100 patient-years, and the median failure time was 14 (95% CI 12,

18) months. These differences were not statistically significant. The

overall rate of discontinuation was 68.7% of the failure rate.

Discontinuation was predicted by adverse effects [hazard ratio 1.76 (95%

CI 1.51, 2.04)] and by clinical status prior to starting DMARD, and

these results were not affected by specific DMARD treatment.

Discontinuation was more common with LEF, and addition of a second DMARD

was more common with MTX. More than 77% of treatment failures, defined

by use of additional therapy, resulted in starting anti-tumor necrosis

factor treatment rather than a conventional DMARD.

CONCLUSION: In an observational clinical trial using a contemporary

longitudinal data bank, with time to treatment failure as the outcome,

LEF and MTX had equal effectiveness as measured by time to treatment

failure. Treatment failure rates were substantially greater than noted

historically. Given the availability of many efficacious additional

treatment options, this increase in failure rate appears to reflect a

greater propensity to discontinue and/or add therapy.

PMID: 12913927

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