|Cost effectiveness of replacing diclofenac with a fixed combination of misoprostol and diclofenac in patients with rheumatoid arthritis
|Kristiansen I S, Kvien T K, Nord E
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The use of diclofenac and misoprostol for the treatment of patients with rheumatoid arthritis (RA).
The study population comprised patients with RA.
The study setting was a hospital. The economic study was carried out in Norway.
Dates to which data relate
The effectiveness and resource use data were gathered from studies published between 1953 and 1997. The cost data were taken from sources published between 1994 and 1997. The price year was 1996.
Source of effectiveness data
The effectiveness data were derived from a review of the literature, and a mail survey of 135 members of the Norwegian Society of Rheumatology.
A 6-month decision tree was used to model the cost-effectiveness of the two treatment strategies. Further details of the model and the parameter estimates are available on the University of Southern Denmark website. See 'Web Address' at the end of the abstract.
Outcomes assessed in the review
The outcomes assessed were the relief of rheumatic symptoms, dyspepsia, other side-effects, gastrointestinal (GI) bleeding or perforation, and quality of life.
Study designs and other criteria for inclusion in the review
The Misoprostol Ulcer Complications Outcome Safety Assessment (MUCOSA) study (see Other Publications of Related Interest) was selected for two reasons. Firstly, because the rate of withdrawal was over a long period of time. Secondly, because the study demonstrated high quality, scoring 4 out of 5 on the Jadad scale.
Sources searched to identify primary studies
Criteria used to ensure the validity of primary studies
Methods used to judge relevance and validity, and for extracting data
Number of primary studies included
Nine primary studies were included in the review.
Methods of combining primary studies
The base-case estimates were taken from one study, the MUCOSA study. The extreme estimates for the sensitivity analysis were taken from other studies.
Investigation of differences between primary studies
Results of the review
The probabilities in the base-case (lower and upper bound) were:
for dyspepsia, 0.15 (range: 0.083 - 0.23) with the misoprostol-diclofenac (M-D) combination and 0.13 (range: 0.044 - 0.19) with diclofenac alone;
for ulcer in patients with dyspepsia, 0.10 (range: 0.047 - 0.137) with the M-D combination and 0.28 (range: 0.13 - 0.38) with diclofenac alone;
for GI bleeding, 0.00545 (range: 0.00436 - 0.00750) with the M-D combination and 0.00720 (range: 0.00577 - 0.01149) with diclofenac alone;
for GI perforation, 0.000227 (range: 0.000182 - 0.000272) with the M-D combination and 0.00225 (range: 0.0018 - 0.0027) with diclofenac alone;
for fatality from GI bleeding, 0.10 (range: 0.03 - 0.33) with either the M-D combination or diclofenac alone;
for fatality from GI perforation, 0.10 (range: 0.07 - 0.33) with either the M-D combination or diclofenac alone;
for withdrawal from therapy, 0.275 (range: 0.10 - 0.324) with the M-D combination and 0.202 (range: 0.10 - 0.242) with diclofenac alone; and
for any side-effect, 0.53 (range: 0.42 - 0.74) with the M-D combination and 0.46 (range: 0.37 - 0.67) with diclofenac alone.
The risk of complications, relative to the population in the MUCOSA population, ranged from 0.53 in the presence of no risk factors to 4.90 in the presence of all risk factors. The risk factors were coronary heart disease, a history of peptic ulcer, patient aged greater than 75 years, and a history of GI bleeding.
The reduction in quality of life was 0.06 for RA alone, where a value of 1.0 represented perfect health.
Methods used to derive estimates of effectiveness
The estimates of effectiveness were obtained from a survey on the management of dyspepsia, which was posted to 135 members of the Norwegian Society of Rheumatology. The respondents were presented with three scenarios relating to the risk of ulcer complications. They were then asked their opinion on whether to discontinue non-steroidal anti-inflammatory drugs, to start ulcer medication, or to perform endoscopy.
The reduction in quality of life due to sequelae (for example, GI bleeding) seem to have been estimated from the authors' own assumptions.
Estimates of effectiveness and key assumptions
The probability of discontinuing the M-D treatment, starting ulcer medication, and performing endoscopy was 4.2% in patients at low-risk of developing complications, 0% in the medium-risk group, and 27.1% in the high-risk group. The probability of discontinuing diclofenac alone, starting ulcer medication, and performing endoscopy was 7.4% in the low-risk group, 0% in the medium-risk group, and 41.9% in the high-risk group.
The reductions in quality of life in the base-case (upper and lower bound) were:
for GI bleeding, 0.34 (range: 0.28 - 0.40);
for GI perforation, 0.44 (range: 0.35 - 0.53);
for dyspepsia, 0.01 (range: 0.005 - 0.03);
for ulcer, 0.03 (range: 0.005 - 0.05);
for withdrawn non-steroidal anti-inflammatory treatment, 0.02 (range: 0.005 - 0.04); and
for diarrhoea or abdominal pain, 0.01 (range: 0.005 - 0.03).
Measure of benefits used in the economic analysis
The measures of health benefit were the numbers of life-years gained and quality-adjusted life-years (QALYs) gained. The utility weights were derived from the results of the Short Form 36 health survey using the person trade-off method and the authors' assumptions.
The direct costs were not discounted since the timeframe was less than one year. The quantities were not reported separately from the costs. The direct costs were for inpatient care, physician visits, drugs and endoscopy, for which unit costs were given. The quantity/cost boundary adopted was that of the hospital. The quantities and costs were estimated from the results of the survey distributed to physicians. The unit costs were obtained from diagnosis-related group charges, fee schedules for medical services, and pharmaceutical market prices. The price year was 1996.
Statistical analysis of costs
The authors reported the expected costs per life-year gained, indicating that costs were treated stochastically.
The indirect costs were not included.
Norwegian kroner (NKr). The exchange rate was 7.00 Nkr = US$1.00.
The sensitivity analyses were conducted on all of the model parameters, using the ranges from the literature or the base-case plus or minus 20%.
Estimated benefits used in the economic analysis
When diclofenac was replaced by the fixed M-D combination, gains of 0.0016 QALYs and 0.0021 life-years were realised in men. The corresponding gains in women were 0.0019 QALYs and 0.0025 life-years.
The cost per patient was $327 with the fixed M-D combination and $298 for diclofenac alone.
Synthesis of costs and benefits
For men with a risk of GI complications, the incremental cost-effectiveness of replacing diclofenac with the fixed M-D combination was $13,700 per life-year saved and $18,100 per QALY gained. The corresponding values for women were $11,800 per life-year saved and $15,100 per QALY gained.
For men with no risk factors, the incremental cost-effectiveness of replacing diclofenac with the fixed M-D combination was $45,900 per life-year saved and $95,900 per QALY gained. The corresponding values for women were $39,400 per life-year saved and $72,700 per QALY gained.
For patients with more than two risk factors, replacing diclofenac with the fixed M-D combination was associated with a cost-saving. The risk factors were coronary heart disease, a history of peptic ulcer, age greater than 75 years, and a history of GI bleeding.
These results were sensitive to changes in the probability of dyspepsia and other side-effects, the probability of GI complications, mortality from complications, and life expectancy.
The replacement of diclofenac with a fixed misoprostol-diclofenac (M-D) combination was cost-effective when restricted to those rheumatoid arthritis (RA) patients at increased risk of serious gastrointestinal (GI) events.
CRD COMMENTARY - Selection of comparators
The comparator used was justified on the grounds that it was a current treatment alternative. You should decide if these health technologies are relevant to your setting.
Validity of estimate of measure of effectiveness
The authors undertook a review of the literature to derive the effectiveness estimates, although they did not state whether a systematic review of the literature had been undertaken. In addition, there were insufficient details of the review process. They justified their selection of one study, which seems to have been appropriate.
The additional effectiveness estimates of the clinical management of dyspepsia were, appropriately, derived from experts' opinions. The validity of these estimates therefore depended on the means of gaining these opinions, many of the details of which were provided. The validity of the results was enhanced by conducting sensitivity analyses to account for variations in the estimates. The source of the ranges was given.
Validity of estimate of measure of benefit
The estimation of benefits was modelled. The instrument used to derive a measure of health benefit, the person trade-off based on the Short Form 36 health survey, was appropriate. However, it was impossible to elucidate the means by which the authors accounted for the complications.
Validity of estimate of costs
There were several positive features of the cost analysis. First, all the relevant direct cost categories seem to have been included. Second, sensitivity analyses were performed, thus enhancing the generalisability of the results. Third, the price year was reported, which made reflation exercises in other settings possible. However, the resource quantities and market prices for non drug items were not given, which reduced the generalisability. The authors stated that, in Norway, the prices stated would be equivalent to the market prices given the state system and the lack of discounting.
The authors made appropriate comparisons of their findings with those from other studies. In addition, they addressed the issue of generalisability to other settings through the sensitivity analysis. The authors do not appear to have presented their results selectively. The study considered patients with RA and this was reflected in the authors' conclusions, although they acknowledge that the MUCOSA group had mild disease. The authors also acknowledged that the use of the Short Form 36 health survey implied that utility weights were based on judgements, rather than on public preference.
Implications of the study
The cost-effectiveness of misoprostol depends heavily on the risk of GI complications, the cost of misoprostol and diclofenac compared with diclofenac alone, and the cost, effectiveness, and toxicity of alternative drugs. Replacing diclofenac with a fixed M-D combination was cost-effective, or even cost-saving, when restricted to RA patients at increased risk of serious GI events.
Caution should be exercised when interpreting the QALY results, since the method of obtaining the weights was unclear. However, given the sensitivity analysis, with appropriate information on other technologies, there might be sufficient information to judge cost-effectiveness.
Source of funding
Supported by G D Searle and Company, Skokie (IL), USA.
Kristiansen I S, Kvien T K, Nord E. Cost effectiveness of replacing diclofenac with a fixed combination of misoprostol and diclofenac in patients with rheumatoid arthritis. Arthritis and Rheumatism 1999; 42(11): 2293-2302
Other publications of related interest
Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving non-steroidal anti-inflammatory drugs. Annals of Internal Medicine 1995;123:241-9.
Subject indexing assigned by NLM
Anti-Inflammatory Agents, Non-Steroidal /adverse effects /economics /therapeutic use; Anti-Ulcer Agents /adverse effects /economics /therapeutic use; Antirheumatic Agents /adverse effects /economics /therapeutic use; Arthritis, Rheumatoid /drug therapy /economics; Cost-Benefit Analysis; Diclofenac /adverse effects /economics /therapeutic use; Drug Therapy, Combination; Female; Gastric Mucosa /drug effects; Health Status; Humans; Misoprostol /adverse effects /economics /therapeutic use
Date bibliographic record published
Date abstract record published