Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis.

Angus DC, Linde-Zwirble WT, et al; PROWESS Investigators.

Crit Care Med. 2003 Jan;31(1):1-11. [abstract]

Reviewed by Nilesh Mehta MD, Children's Hospital, Boston

Review posted November 30, 2004

I. What is being studied?:

The study objective:

To assess the incremental cost-effectiveness of drotrecogin alfa (activated) treatment for adults with sepsis, compared to conventional therapy, over a 28-day period.

The study design:

This economic analysis based it assumptions on results from a prospective, large, (n=1690) multinational (11 countries), multicenter (164 hospitals), placebo-controlled, randomized phase III trial of drotrecogin alfa (activated) in patients admitted to adult ICUs with sepsis. A subset of patients (33%) treated in the United States formed the Cost cohort, which provided the estimates of hospital costs. These same patients from the US were used to project life expectancy. Lifetime healthcare expenditure was modeled using age-specific annual costs from a 1987 published survey, projected to year 2000 by National Center for Health statistics. Estimates of age-specific nursing home costs were also added.

In an attempt to minimize bias, the investigators specified the intended analyses and filed a data analysis plan before unblinding the data.

The outcomes assessed:

1. Incremental short-term healthcare costs (days 1-28) per 28-day survivor.
2. Incremental lifetime healthcare costs per quality-adjusted life-year (QALY).

QALYs are generated by multiplying each predicted remaining year of life by a numeric estimate of the quality of those years. The authors recognize that there are no long-term quality-adjusted survival data for survivors of severe sepsis; and assigned to each 28-day survivor the average quality-adjusted survival of someone in the general population with the same life expectancy, rather than someone of the same age. The general population quality-of-life estimates were derived from the Beaver Dam Health Outcome Study. (1)

II. Are the results valid?

1.Did the analysis provide a full economic comparison of the health care strategies?

Yes. The study reports the costs and outcomes from both the treatment strategies. The analysis was conducted from the U.S. societal perspective, results may not be transferable to other countries as US life expectancy, and US healthcare costs may be very different from some other countries. Cost of healthcare expenditure was estimated from a subgroup of 552 (of total 705) U.S. patients. Measured short-term (28-day) and projected estimates of lifetime healthcare costs are reported for the placebo and treatment (drotrecogin alfa activated) arm of this cost cohort. Authors attempted to include indirect healthcare costs and excluded non-healthcare costs. Details of the estimation of indirect costs are unclear and there is no mention of productivity changes.

The analysis is a cost-effectiveness study and estimates are provided after adjustment for quality of life, QALY (cost-utility analysis).

Each 28-day survivor was assigned the average quality-adjusted survival of someone in the general population (Beaver Dam Health Outcome Study data) with a similar life expectancy (rather than age-matched). In the absence of long-term quality adjusted survival data for sepsis survivors, this method allows approximate estimation of expected values and assigns lower quality of life scores for sepsis patients compared to age-matched general population. (Another economic analysis study has used composite index utility score adopted from the post-discharge quality of life of ARDS patients (2, 3).

2. Were the costs and outcomes properly measured and valued?

A. Was clinical effectiveness established?

Yes. This analysis was carried out prospectively and concurrently with a large placebo-controlled, randomized trial (PROWESS) and thus has high internal validity. The PROWESS trial showed a 19.4% relative risk reduction and a 6.1% absolute risk reduction for death in adults with severe sepsis and drotrecogin alfa is approved by the FDA for use in patients with APACHE scores of 25 or more.

Authors do acknowledge that the magnitude of clinical effect may be exaggerated in a well-controlled clinical trial when compared to routine clinical practice. Also, the magnitude of the PROWESS trial and its rigid entry criteria may hamper the external validity of this analysis and make it less generalizable.

Authors have reported the short-term outcome from the trial data and projected the long-term outcomes using modeling from published data.

B. Were costs measured accurately?

Yes. The analysis provides detailed cost measurements for the U.S. cohort. Billing records provided data for the non-pharmacy hospital costs and these were adjusted for the institution-specific cost-to-charge ratios and Consumer Price Index. Study. Drug costs were calculated by multiplying the cost of individual drug vial ($210/5 mg vial and $840/20 mg vial) with the minimum number of vials required based on per-patient dosage in the trial. Post-discharge daily costs were assigned based on patient location. Subsequent acute hospital care costs (estimated $1170), physician charges, supportive home care ($200) and nursing home care costs ($270) were accounted for.

However, the estimated costs of treatment related side effects such as clinically significant bleeding, has not been included in this analysis. In their economic analysis of this treatment, Manns et al added $122 per patient to account for the increased risk of bleeding reported in the PROWESS trial (based on an estimated cost of $8306/GI bleed in the ICU). (2)

Both short-term (28-day) and long-term (estimated life-time) cost-effectiveness ratios with adjustment for quality of life are reported. An annual discount rate of 3% was applied to long-term costs. The costs were in year 2000 U.S. dollars.

3. Was appropriate allowance made for uncertainties in the analysis?

The authors carried out sensitivity analysis by varying the estimates of hospital costs, postdischarge to day 28 costs, drug acquisition costs, lifetime costs, lifetime survival and the composite index utilities by ±25%. The detailed sensitivity analyses for lifetime costs estimation in this study included two-way analyses, varying discount rates for costs and effects, altering penalty for survivors based on presence of septic shock etc.

Sensitivity analysis for the lifetime costs is presented in the form a tornado diagram. The cost per QALY reached $100,000 when: a) the average survival for 28-day survivors was decreased to 6.6yrs, b) average annual utility was cut to 0.33, c) study drug costs increased 2.6-fold, d) long-term costs increased 2.7-fold, e) hospital costs increased 5.8-fold or f) the post-discharge costs increased 5.8-fold.

4. Are estimates of costs and outcomes related to the baseline risk in the treatment population?

The cost cohort (552 U.S. patients) had a greater proportion of medical (rather than surgical) patients, and these patients had more underlying diseases and were more frequently admitted from a skilled nursing facility. Surgical patients had a higher total and mean daily costs compared to the medical patients.

The trial appropriately compares the effect of study drug with placebo and the remaining management of patients with sepsis is uniform. [Unless the study drug has more side effects and it costs more to treat those complications that occur as a result of the study drug's use!] Subgroup analysis was decided a priori and included division of patients into risk categories based on the APACHE II scores.

III. What are the results?

1.What were the incremental costs and outcomes of each strategy?

Drotrecogin alfa (activated) treatment increased short-term (28-day) costs by $9800 (±$2900) and survival by 0.061 (±0.022) lives saved per treatment. The cost per 28-day survivor was a total of $160,000 per life saved with an 84.7% probability that the cost-effectiveness ratio was less than $250,000.

Drotrecogin alfa (activated) incremental cost per life-year gained was $33,000 (with 89.1% probability that the ratio was less than $100,000). The cost per QALY was $48,800 (82% probability that the ratio was less than $100,000).

2. Do incremental costs and outcomes differ between subgroups?

Subgroup cost-effectiveness analyses are presented in four quadrants as 95% confidence ellipses generated by Fieller's method. Subgroup comparisons were performed based on age, location before hospitalization, co-morbidity status; the sample sizes of the subgroups were really too small for meaningful comparisons. Authors report that cost-effectiveness was worse for older patients and the treatment was cost-ineffective for patients in the lower two APACHE II quartiles.

Details of the subgroup analysis are not provided in terms of dollar amounts. In their economic analysis of activated protein C treatment, Manns et al incorporated the estimated relative risk of death (based on the FDA ad hoc analysis of the PROWESS trial data) and showed an increase in the cost per life-year gained of up to $575,054 for patients with APACHE II scores of 24 (2).

3. How much does allowance for uncertainty change the results?

Sensitivity analysis showed that the cost per QALY remained well under $100,000 despite wide variations in physician costs, hospital costs within first 28 days, long-term costs, and drug costs. The results do not change with uncertainty in long-term survival costs and average utility (or quality of life) unless these increase by 75% beyond the values used in this analysis. There was a variation in the estimated treatment effectiveness in the APACHE subgroups.

The authors also explored the consequences of the fact that survivors who had been sicker might have fewer years of life. A worse penalty (0.39) was applied to all those who survived septic shock and a slightly better penalty (0.53) to all those who survived without incurring shock, during the sensitivity analysis.

IV. Will the results help me in caring for my patients?

1. Are the treatment benefits worth the harms and costs?

The PROWESS trial showed a significant decrease in mortality associated with the use of Drotrecogin alfa (activated) in a subgroup of patients in an adult ICU, with APACHE scores of 25 or more. In this subgroup of patients, the use of Drotrecogin alfa (activated) resulted in a 19.4% relative risk reduction and a 6.1% absolute risk reduction for death. The cost of treatment per 28-day survivor was $160,000 and the cost per QALY was $48,800. Whilst the cost-effectiveness of the amount spent to save a QALY is a value judgment, the above figures seem to be at par with some commonly accepted therapies in modern medicine.

However, the risk of bleeding in the PROWESS trial was significant and morbidity associated with major bleeds (CNS, GIÉ) and the costs incurred to treat these complications have to be accounted for.

2. Could my patients expect similar health outcomes? Are the study patients similar to my own? Is the study clinical management similar to my local practice?

The PROWESS trial included adults admitted to the ICU. This population is widely different from the baseline pediatric population. The subgroup of patients in the adult ICU with APACHE 25 or more, who are most likely to benefit from the treatment, appear to be distinct from the pediatric ICU population and will have a much higher baseline mortality rate. Thus, it is difficult to extrapolate the results of this study to my patients and one may not expect similar outcomes.

3. Could I expect similar costs?

Transferability of costs (and cost-effectiveness) estimates between populations is likely to be problematic. The dosage of drug used, local purchasing, cost of side-effects or treatment complications such as GI bleed or CNS bleed, etc., are some factors which makes it difficult to compare the cost-effectiveness of Dotrecogin alfa (activated) between the PROWESS population and my pediatric population.

References

1. Fryback DG, Dasbach EJ, Klein R, et al: The Beaver Dam Health Outcomes Study: Initial catalog of health-state quality factors. Med Decis Making 1993; 13: 89-102 [abstract]
2. Manns BJ, Lee H, Doig CJ, et al: An economic evaluation activated protein C treatment for severe sepsis. N Engl J Med 2002; 347: 993-1000 [abstract]
3. Angus DC, Musthafa AA, Clermont G, et al. Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;163:1389-1394. [abstract]

 

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