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Validating literature-based models with direct clinical trial results: the cost-effectiveness of secondary prophylaxis for PCP in AIDS patients |
Freedberg K, Hardy D, Holzman R, Tosteson A, Craven D |
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Record Status 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. Health technology Using trimethoprim-sulfamethoxazole (TMP-SMX) versus aerosolised pentamidine(AP) in the prevention of recurrent Pneumocystis carinii pneumonia (PCP) in AIDS patients with a previous PCP experience.
Economic study type Cost-effectiveness analysis.
Study population Adult AIDS patients with a previous PCP experience.
Setting Hospital. The economic study was carried out in Boston, USA
Dates to which data relate Effectiveness data used in the literature-based model were obtained from published studies carried out between 1988-1991. The effectiveness data used in the trial-based model were collected between July 1988 and July 1991. Resource utilisation was not reported. Costing information was derived from data collected in 1991 and 1992. Price years were not stated.
Source of effectiveness data The estimates for final outcomes were obtained from both a single randomised study (ACTG 021) and a review of previously completed studies.
Link between effectiveness and cost data Costing was not undertaken on the same patient sample as that used in the trial-based effectiveness study. The cost data were collected retrospectively.
Study sample Power calculations were used to determine the sample size. A total of 310 patients were randomly allocated to either the TMP-SMX group (n=154 with a median age of 36 years) or the AP group (n=156 with a median age of 36 years).
Study design The study was a randomised, controlled, open-label trial, carried out at 23 sites of the AIDS Clinical Trial Group (ACTG). The study had a median duration of follow-up of 17.4 months. A total of 31 patients were considered as lost to follow-up.
Analysis of effectiveness The intention to treat principle was used in the analysis of effectiveness. The primary health outcomes assessed were rates of recurrence of PCP and toxicity. The groups were comparable in terms of all base-line characteristics except haemoglobin level, which was not considered clinically important.
Effectiveness results The PCP recurrence rates at 18-month follow-up were 11.4% in the TMP-SMX group and 27.6% in the AP group, (p<0.001). The adjusted related risk was 3.25 (95% CI: 1.72 to 6.160, (p<0.001). Annual PCP recurrence rates were:no prophylaxis, 66%, TMP-SMX, 3.5%, and AP, 18.5%.
Toxicity rates from prophylaxis were:
TMP-SMX, 47% (overall) and27% (major);
AP, 44% (overall) and4% (major).
Clinical conclusions In patients with AIDS who are receiving zidovudine, trimethoprim-sulfamethoxazole is more effective than aerosolised pentamidine in conventional doses for the prevention of recurrent Pneumocystis infection.
Modelling A Markov simulation model was used to project the costs and effects of alternative health technologies over the 3-year time horizon of the model.
Outcomes assessed in the review The outcomes assessed in the review were the annual PCP recurrence rate and toxicity for AIDS patients using no prophylaxis, TMP-SMX, and AP.
Study designs and other criteria for inclusion in the review Prospective randomised trials and a retrospective non-randomised trial were included in the review. No inclusion/exclusion criteria were stated.
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 3 prospective randomised trials and 1 retrospective non-randomised trial were included in the review.
Methods of combining primary studies Investigation of differences between primary studies Results of the review Annual PCP recurrence rates were:
no prophylaxis, 66%;
TMP-SMX, 6.6%;
AP = 6.6%.
Toxicity rates from prophylaxis were:
TMP-SMX = 50% (overall), 17% (major);
AP = 20% (overall), 2% (major).
Methods used to derive estimates of effectiveness Assumptions about effectiveness estimates were also made by the authors.
Estimates of effectiveness and key assumptions In the literature-based model, it was assumed that both prophylactic agents had the same level of efficacy. Annual PCP recurrence rates were 6.6% for TMP-SMX and 6.6% for aerosolised pentamidine (AP).
Measure of benefits used in the economic analysis The benefit measure was life-years gained.
Direct costs Costs were discounted. Resource utilisation was not reported separately from the costs. Cost items were reported separately. Specifically, direct costs included TMP-SMX, major and minor toxicity treatment costs, aerosolised pentamidine and associated medication which were all based on average wholesale prices derived from a 1992literature source. Costs for nebulizers, physician visits, monitoring and complete blood counts were obtained through Boston City Hospital cost-to-charge ratio conversions (1992)The costs of recurrent PCP (and AIDS-related conditions) lifetime treatment were included, based upon the AIDS Cost and Services Utilisation Survey figures (1991, 1992). The price date was not stated.
Sensitivity analysis One-way sensitivity analysis varied: AP costs; overall TMP-SMX toxicities; AP PCP prevention efficacy levels; AIDS lifetime treatment costs; non-compliance rates; and projected life expectancies.
Estimated benefits used in the economic analysis Life expectancy rates in the literature based model were:
no prophylaxis, 1.430 years;
TMP-SMX, 2.051 years, and
AP, 2.066 years.
The corresponding values for the trial-based model were:
no prophylaxis, 1.430 years;
TMPSMX, 2.076 years,
AP, 1.935 years.
Confidence intervals and p values were not stated. Life expectancy was increased by 0.621 years (literature) and 0.646 years (trial), using TMP-SMX treatment, compared with no prophylaxis. Life expectancy was increased by0.636 years (literature) and 0.505 years (trial), using AP treatment compared with no prophylaxis. The difference in life expectancies was not statistically significant. All life expectancies were discounted at a rate of 5%. The time horizon of the model was three years.
Cost results The annual PCP prophylaxis TMP-SMX initialised costs were $468 (literature) and $656 (trial). An AP initialised treatment process cost $1,577 (literature) and $1,573 (trial). All costs were discounted at 5%. The total costs of the strategies (over the three year time horizon of the model) were:no prophylaxis, $42,080 (both literature and trial); TMP-SMX, $42,300 (literature) and $42,550 (trial); and AP, $43,960 (literature) and $44,000 (trial).
Synthesis of costs and benefits The incremental cost-effectiveness ratios for TMP-SMX per life-year saved were $350 (literature), and $720 (trial) compared to no prophylaxis. AP produced incremental cost-effectiveness ratios per life-year saved of $2,950 (literature), and $3,800 (trial), compared with no prophylaxis. The incremental cost-effectiveness ratio for AP was $110,880 (literature) compared with TMP-SMX. TMP-SMX was dominant over AP based on data obtained from the trial. The sensitivity analysis established the robustness of the results to the change in baseline values.
Authors' conclusions Literature-based cost-effectiveness models are useful in developing health policy before clinical trials are completed. Clinical trial results, when available, can be used to validate and revise these models. For secondary PCP prophylaxis in AIDS patients, TMP-SMX is substantially more cost-effective than aerosolised pentamidine.
CRD COMMENTARY - Selection of comparators The reason for the choice of the comparator is clear. Validity of estimate of measure of benefit The estimates of the benefits in the trial-based model and the literature-based model are likely to be internally valid given the use of a randomised design. Validity of estimate of costs Resource utilisation was not reported separately from the costs. Adequate details of methods of cost estimation were given. No price dates for the analysis were provided, which could hamper cost comparisons across studies. The study lacked a prospective and well-designed cost analysis as the authors acknowledged. Other issues As acknowledged by the authors, the more recent treatment strategies were not included in the analysis. Implications of the study A well-designed randomised control trial is required to examine new prophylaxis strategies that were not included in the authors' model. Source of funding Supported in part by grants from the Agency for Health Care Policy and Research (1-RO1-HS06694) and from the Division of AIDS of the National Institute of Allergy and Infectious Diseases (N01-A1-95030).
Bibliographic details Freedberg K, Hardy D, Holzman R, Tosteson A, Craven D. Validating literature-based models with direct clinical trial results: the cost-effectiveness of secondary prophylaxis for PCP in AIDS patients. Medical Decision Making 1996; 16: 29-35 Other publications of related interest Hardy D W, Feinberg J, Finkelstein D M et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the Acquired Immunodeficiency Syndrome. New England Journal of Medicine 1992;327:1842-1949.
Indexing Status Subject indexing assigned by NLM MeSH AIDS-Related Opportunistic Infections /prevention & Anti-Infective Agents /therapeutic use; Antifungal Agents /therapeutic use; Cost-Benefit Analysis; Decision Support Techniques; Health Care Costs; Humans; Markov Chains; Models, Statistical; Pentamidine /therapeutic use; Pneumonia, Pneumocystis /prevention & Reproducibility of Results; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination /therapeutic use; control; control AccessionNumber 21996008059 Date bibliographic record published 31/07/1999 Date abstract record published 31/07/1999 |
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