Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis

Abstract

Background: Activated drotrecogin alfa (human activated protein C, rhAPC), is produced by recombinant DNA technology, and purports to improve clinical outcomes by counteracting the inflammatory and thrombotic consequences of severe sepsis. Controversy exists around the clinical benefits of this drug and an updated economic study that considers this variability is needed.

Methods: A systematic literature review was performed using Medline, Embase and the International Network of Agencies for Health Technology Assessment (INAHTA) databases to determine efficacy, safety and previous economic studies. Our economic model was populated with systematic estimates of these parameters and with population life tables for longer term survival information. Monte Carlo simulations were used to estimate the incremental cost-effectiveness ratios (ICERs) and variance for the decision analytic models.

Results: Two randomized clinical trials (RCTS) of drotrecogin alfa in adults with severe sepsis and 8 previous economic studies were identified. Although associated with statistical heterogeneity, a pooled analysis of the RCTs did not show a statistically significant 28-day mortality benefit for drotrecogin alfa compared to placebo either for all patients (RR: 0.93, 95% CI: 0.69, 1.26) or those at highest risk as measured by APACHE II >or= 25 (RR: 0.90, 95% CI: 0.54, 1.49). Our economic analysis based on the totality of the available clinical evidence suggests that the cost-effectiveness of drotrecogin alfa is uncertain (< 59% probability that incremental cost-effectiveness ratio (ICER) life year gained (LYG) <or= $50,000/LYG) when applied to all patients with severe sepsis. The economic attractiveness of this therapy improves when administered to those at highest risk as assessed by APACHE II >or= 25 (93% probability ICER <or= $50,000/LYG) but these results are not robust to different measures of disease severity.

Conclusion: The evidence supporting the clinical and economic attractiveness of drotrecogin alfa is not conclusive and further research appears to be indicated.

Figure 1

Simplified decision analytic model employed. *The individual survival probabilities between 28 days and 30 months were included in the model but are not shown in this figure. A similar tree was used in the bleeding and non-bleeding arms, and for the drotrecogin alfa and placebo arms (not shown). After the 30 months a Markov model was employed (determined by the node M).

Figure 2

28-day mortality meta-analysis. Some of the numbers in the graph are approximations as they were derived from figures in the published studies.

Figure 3

In-Hospital mortality meta-analysis. Some of the numbers in the graph are approximations as they were derived from figures in the published studies.

Figure 4

Cost-effectiveness plane for all patients – 10,000 Monte Carlo simulations (20-year time horizon, 3% discounting). The points to the left of the vertical line correspond to a lower efficacy and higher cost with drotrecogin alfa compared to placebo.

Figure 5

Cost-effectiveness plane for patients with APACHE II ≥ 25 – 10,000 Monte Carlo simulations (20-year time horizon, 3% discounting). The points to the left of the vertical line correspond to a lower efficacy and higher cost with drotrecogin alfa compared to placebo.

Figure 6

Acceptability curve (incremental cost/LYG). Lifetime decision model (all patients, 3% discounting, 20-year time horizon). LYG = life-years gained.

Figure 7

Acceptability curve (incremental cost/LYG). Lifetime decision model (high risk patients with APACHE II = 25, 3% discounting, 20-year time horizon). LYG = life-years gained.