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The cost-effectiveness of adjunctive corticosteroids for patients with septic shock
Kelly J Thompson, Colman B Taylor, Balasubramanian Venkatesh, Jeremy Cohen, Naomi E Hammond, Stephen Jan, Qiang Li, John Myburgh, Dorrilyn Rajbhandari, Manoj Saxena, Ashwani Kumar, Simon R Finfer, for the ADRENAL Management Committee and Investigators and the ANZICS Clinical Trials Group
Crit Care Resusc 2020; 22 (3): 191-199
- Kelly J Thompson 1, 2
- Colman B Taylor 1, 2
- Balasubramanian Venkatesh 1, 2, 3, 4
- Jeremy Cohen 1
- Naomi E Hammond 1, 2, 5, 6
- Stephen Jan 1, 2
- Qiang Li 1
- John Myburgh 1, 2, 7
- Dorrilyn Rajbhandari 1
- Manoj Saxena 1, 2
- Ashwani Kumar 1
- Simon R Finfer 1, 2, 5, 6
- for the ADRENAL Management Committee and Investigators and the ANZICS Clinical Trials Group 8
OBJECTIVE: To determine whether hydrocortisone is a cost-effective treatment for patients with septic shock.
DESIGN: Data linkage-based cost-effectiveness analysis.
SETTING: New South Wales and Queensland intensive care units.
PARTICIPANTS AND INTERVENTION: Patients with septic shock randomly assigned to treatment with hydrocortisone or placebo in the Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial.
MAIN OUTCOME MEASURES: Health-related quality of life at 6 months using the EuroQoL 5-dimension 5-level questionnaire. Data on hospital resource use and costs were obtained by linking the ADRENAL dataset to government administrative health databases. Clinical outcomes included mortality, health-related quality of life, and quality-adjusted life-years gained; economic outcomes included hospital resource use, costs and cost-effectiveness from the health care payer perspective. We also assessed cost-effectiveness by sex. To increase the precision of cost-effectiveness estimates, we conducted unrestricted bootstrapping.
RESULTS: Of 3800 patients in the ADRENAL trial, 1772 (46.6%) were eligible and 1513 (85.4% of those eligible) were included. There was no difference between hydrocortisone or placebo groups in regards to mortality (218/742 [29.4%] v 227/759 [29.9%]; HR, 0.93; 95% CI, 0.78–1.12; P = 0.47), mean number of QALYs gained (0.10 ± 0.09 v 0.10 ± 0.09; P = 0.52), or total hospital costs (A$73 515 ± 61 376 v A$69 748 ± 61 793; mean difference, A$3767; 95% CI, –A$2891 to A$10 425; P = 0.27). The incremental cost of hydrocortisone was A$1 254 078 per quality-adjusted life-year gained. In females, hydrocortisone was cost-effective in 46.2% of bootstrapped replications and in males it was cost-effective in 2.7% of bootstrapped replications.
CONCLUSIONS: Adjunctive hydrocortisone did not significantly affect longer term mortality, health-related quality of life, health care resource use or costs, and is unlikely to be cost-effective.
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No licensed pharmacological treatments for sepsis are available, and the accepted principles of management are early recognition, appropriate antibiotic treatment, and cardiovascular and other organ system support. 10, 11
The Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial 14
We conducted a cost-effectiveness analysis of a subset of patients included in the ADRENAL trial to determine the long term costs and health-related consequences of treatment at 6 months, and economic outcomes from the health care payer perspective in New South Wales and Queensland.
Study designADRENAL (NCT01448109) was an international, investigator-initiated, blind, randomised controlled trial comparing intravenous infusions of hydrocortisone and placebo in mechanically ventilated intensive care patients with septic shock. Between March 2013 and April 2017, 3800 patients were enrolled from 69 intensive care units (ICUs) in Australia, New Zealand, Saudi Arabia, Denmark and the United Kingdom. Eligible patients were randomly assigned to receive either a continuous intravenous infusion of hydrocortisone (Solu-Cortef Powder for injection, Pfizer, Australia) at a dose of 200 mg per day or matching placebo, for up to 7 days while in the ICU. 14
For this cost-effectiveness analysis, we prospectively designed a study protocol and statistical analysis plan (Online Appendix). The analysis was limited to patients enrolled in ADRENAL in the Australian states of NSW and Queensland, where we were able to obtain data on ongoing health care resource use by linking the study and administrative health databases. Patients were followed up 6 months after enrolment. Written informed consent or consent to continue after enrolment was obtained for all patients in accordance with local legal and ethical requirements. Ethics approval for data linkage to administrative health records was obtained from the Metro South Human Research Ethics Committee (Queensland), Royal Prince Alfred Hospital Ethics Committee (NSW) and New South Wales Population and Health Services Ethics Committee (NSW).
Procedures and outcomes
Clinical outcomes of mortality, health-related quality of life, and quality-adjusted life-years gained were assessed 6 months after enrolment. Vital status (alive or dead) was obtained from state-specific death registries. In survivors, health-related quality of life was assessed using the EuroQoL 5-dimension 5-level (EQ-5D-5L) questionnaire 18
Health care resource use. Health care resource use data were collected from the ADRENAL trial database and administrative health records in NSW and Queensland through the admitted patient and emergency department databases for a period of 6 months after enrolment. Health care resource use outcomes included the duration of the index ICU and hospital admission, as well as subsequent admissions to ICU and hospital, and visits to emergency departments.
Costs. Costs included hospital, ICU and emergency department visits 6 months after enrolment. Hospital and ICU costs were calculated using Australian Refined Diagnosis Related Group reimbursement costings. ICU costs were also calculated separately using a per bed-day cost, based on the Australian Independent Hospital Pricing Authority’s National Pricing Model, multiplied by the length of ICU stay. To calculate emergency department costs, we applied national average costs for each presentation to the emergency department based on whether the presentation did or did not result in hospital admission as determined by the Independent Hospital Pricing Authority’s National Hospital Cost Data Collection (Online Appendix). 22, 23, 24
Cost-effectiveness. The analysis was conducted from the health care payer perspective of the Australian health care system. Australia has a universal health care system, in which the public hospital system provides free access for services incurred. To calculate cost-effectiveness, we used total hospital-related costs and quality-adjusted life-years gained at 6 months. Incremental cost-effectiveness ratios providing the cost per quality-adjusted life-year gained were calculated as a ratio between the difference in mean costs between the patients who received hydrocortisone and those who received placebo and the difference in mean quality-adjusted life-years gained between those groups.
To provide an estimate of the precision of the calculated incremental cost-effectiveness ratios, we conducted non-parametric bootstrapping using unrestricted random sampling, 25, 26
Statistical analysisWe analysed data on an intention-to-treat basis and report assumptions related to missing data in the statistical analysis plan (Online Appendix). We compared binary outcomes for treatment allocation using the χ2 test. Continuous data were compared using the t test. The probability of survival was assessed using Kaplan–Meier survival analysis, using the log-rank test to compare groups and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Health care resource use and costs are reported as mean ± standard deviation (SD), using the t test to compare means and the χ2 test for proportions, reported as mean differences and odds ratios (ORs) with 95% CIs, respectively.
In a post-hoc analysis, we assessed the representativeness of the study cohort by comparing the baseline characteristics and outcomes from ADRENAL between three separate groups of patients: the patients enrolled in NSW and Queensland for whom data linkage was used (cost-effectiveness analysis cohort); patients enrolled in Australian states outside of NSW and Queensland; all patients enrolled in ADRENAL outside of NSW and Queensland, including international sites.
ResultsOf 3800 patients enrolled in ADRENAL, 1772 (46.6%) were enrolled in NSW and Queensland and eligible for inclusion in the cost-effectiveness analysis. Of them, 886 (50.0%) were assigned hydrocortisone and 886 (50.0%) were assigned placebo. Linkage data and consent were obtained for 1513 patients, 754 in the hydrocortisone group and 759 in the placebo group. Mortality data at 6 months were available for 742 patients (98.4%) in the hydrocortisone group and 746 patients (98.3%) in the placebo group. For those alive at time of follow-up, health-related quality-of-life data were obtained for 479/524 (91.4%) patients in the hydrocortisone group and 455/519 patients (87.7%) in the placebo group (Figure 1). The baseline characteristics of patients were similar between treatment groups (Table 1).
Clinical outcomesAt 6 months after enrolment, 218 of 742 patients (29.4%) in the hydrocortisone group and 227 of 759 patients (29.9%) in the placebo group had died, and the probability of survival to 6 months was similar in the two groups (HR 0.93; 95% CI, 0.78–1.12; P = 0.47) (Online Appendix, figure 1). There were no significant differences in health-related quality-of-life domains at 6 months between the hydrocortisone and placebo groups. There was no statistically significant difference between groups in the mean quality-of-life utility value in survivors (0.41 ± 0.39 v 0.40 ± 0.39; P = 0.52) or the mean number of quality-adjusted life-years gained (0.10 ± 0.09 v 0.10 ± 0.09; P = 0.52) at 6 months (Table 2).
Healthcare resource use and costsThere was no significant difference in the mean duration of the initial ICU or hospital stay between hydrocortisone and placebo groups. At 6 months, there was no significant difference between hydrocortisone and placebo groups in the number and duration of readmissions to ICU or hospital, or in the number of patients presenting to the emergency department. There were no significant differences in hospital, ICU and emergency department costs between hydrocortisone and placebo groups (Table 3). Overall, ICU costs for the index admission were about 50% lower when using the Australian Refined Diagnosis Related Group ICU costing compared with the per bed-day ICU costing (Table 3).
In patients included in the cost-effectiveness analysis cohort, there was no significant difference in the mean duration of the initial ICU admission between the hydrocortisone and placebo groups (10.7 ± 10.4 days v 10.8 ± 10.2 days; mean difference, –0.11 days; 95% CI, –1.16 to 0.93; P = 0.83). In patients not included in the cost-effectiveness analysis cohort, limited to Australia and in all countries, hydrocortisone was associated with a shorter duration of initial ICU stay: 9.0 ± 10.4 days v 10.4 ± 10.5 days (mean difference, –1.34 days; 95% CI, –2.45 to –0.23; P = 0.02) and 10.6 ± 11.0 days v 11.9 ± 13.1 days (mean difference, –1.29 days; 95% CI, –2.3 to –0.28; P = 0.01), respectively (Table 3 and (Online Appendix, table 2).
DiscussionIn our cost-effectiveness analysis of a subgroup of patients in the ADRENAL trial, we found no significant difference in clinical outcomes at 6 months and no difference in the costs of ICU or hospital admission between mechanically ventilated patients with septic shock assigned to receive hydrocortisone and those assigned to placebo. Despite hydrocortisone being an inexpensive therapy, 33
We observed a difference in cost-effectiveness between females and males, suggesting hydrocortisone may be more cost-effective in females, where hydrocortisone was associated with higher mean utility values and lower total hospital costs, compared with placebo. Whether there is a sex difference in the immunologic and anti-inflammatory response to exogenous cortisol in patients with septic shock has not previously been evaluated. It remains to be elucidated whether this is a chance finding or whether hydrocortisone is more cost-effective in females.
Our study has several strengths. It was a pre-specified component of a large, pragmatic, multicentre international randomised controlled trial, with high indices of internal and external validity. We used a sample from the two highest recruiting jurisdictions in the ADRENAL trial, representing 40% of the trial population. We followed a pre-specified statistical analysis plan and conducted our study according to established cost-effectiveness analysis methods using individual patient data from the trial and linking these data to established health administrative databases. This enabled us to obtain detailed downstream information about long term patient-centred outcomes and costs, including costing the sequelae of treatment. We tested two methods to cost the ICU length of stay, to verify the validity of our results. In the ICU environment, the cost of a single intervention, such as administering hydrocortisone to patients with septic shock, is far outweighed by the costs of overall treatment, where staffing accounts for up to 70% of costs. 34, 35
Our study also has some limitations. The analysis was limited to the perspective of the health care payer. We acknowledge the limitation of omitting other potential direct and indirect costs, including: outpatient visits to physicians and allied health care providers, pharmaceutical costs, and opportunity costs such as productivity losses for both patients and caregivers. We judged that hospital resource use obtained from health administrative data would likely represent the totality of health care resource use after ICU discharge following an episode of septic shock. We acknowledge that these data may not be sensitive to variations in ICU resource use associated with complications. Our subgroup analysis was restricted to patients enrolled in NSW and Queensland. We could not quantify the number of these patients who died or were readmitted to hospital outside of these states.
A reduction in ICU length of stay was observed in patients enrolled in the ADRENAL trial outside of NSW and Queensland, but not in those included in the cost-effectiveness analysis cohort. This could be related to high bed-occupancy rates (> 80%) and exit block (13%) in Australian ICUs, where the majority of patients were enrolled. 36
While 22 comparable randomised controlled trials assessing the effect of corticosteroids on mortality of patients with septic shock have been conducted, 37
In our study, there were discrepancies in average ICU costs for patients with septic shock dependent on which costing method was used. Cost estimates that were generated with Australian Refined Diagnosis Related Group ICU cost weights were about half of those generated using the Independent Hospital Pricing Authority average hourly ICU cost. 23