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Original Article

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

Correspondence: kthompson@georgeinstitute.org

  • Author Details
    • 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
    1. The George Institute for Global Health, Sydney, NSW, Australia.
    2. University of New South Wales, Sydney, NSW, Australia.
    3. Princess Alexandra Hospital, University of Queensland, Brisbane, QLD, Australia.
    4. The Wesley Hospital, Brisbane, QLD, Australia.
    5. Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
    6. Malcolm Fisher Department of Intensive Care Medicine, Royal North Shore Hospital, Sydney, NSW, Australia.
    7. St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia.
    8. ADRENAL Management Committee and Investigators and the ANZICS Clinical Trials Group.
  • Competing Interests
    None declared
  • Abstract
    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.
  • References
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Sepsis is life-threatening organ dysfunction due to a dysregulated immune response to infection. 1 With an estimated annual global incidence of 48.9 million cases and about 11 million deaths, 2 it is a World Health Organization global health priority. 3 Between 2000 and 2017, survival from sepsis in high income countries improved with in-hospital mortality decreasing from 35% 4 to 27%. 5 For those who survive, half will make a full recovery, 6 with others reporting ongoing physical, cognitive and mental health impairments which are associated with increased health care resource use and costs. 7, 8, 9

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 Corticosteroids have been used as an adjunctive therapy in patients with sepsis for the past 40 years, 12 but trials examining their effect on outcomes have reached conflicting conclusions, resulting in widespread variability in clinical practice. 13

The Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL) trial 14 was a randomised controlled trial of hydrocortisone compared with placebo in patients with septic shock. The ADRENAL investigators reported no difference in the primary outcome of mortality at 90 days between patients who did and did not receive a 7-day continuous infusion of hydrocortisone. 15 Patients who received hydrocortisone had more rapid resolution of shock, and a shorter duration of mechanical ventilation and treatment in intensive care. 15 These beneficial effects on secondary outcomes suggest the use of hydrocortisone may be associated with reduced health care resource use and costs, but the cost-effectiveness of corticosteroid treatment for patients with septic shock has not been previously evaluated. 16, 17

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.
 

Methods

Study design

ADRENAL (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
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 in structured telephone interviews conducted within 2 weeks of the 6-month follow-up date by trained research coordinators at participating ICUs. The EQ-5D-5L is a validated assessment tool that collates responses to five domains of quality-of-life assessments including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression scored across five levels (no problems, slight problems, moderate problems, severe problems, extreme problems or unable). A utility of zero is equivalent to death and one indicates full life. As patients were mechanically ventilated at the time of recruitment, a utility value of zero was assumed at baseline. Patients who died at any point during the trial were assigned a utility value of zero. The EQ-5D-5L was valued using the UK and Australian reference algorithms. 19, 20, 21

Economic outcomes
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 We report all cost information in Australian dollars as of 6 October 2017 (the last date of patient follow-up).

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 presented as cost-effectiveness planes to report the overall incremental cost per quality-adjusted life-year gained. We assessed cost-effectiveness based on two pre-specified subgroups that were determined prior to randomisation including illness severity (Acute Physiology and Chronic Health Evaluation [APACHE] II score ≥ 25 ν < 25, where higher scores are associated with a higher risk of death) 27 and sex and/or gender (female ν  male, hereafter respectfully referred to as sex), in accordance with emerging best practice recommendations. 28, 29, 30, 31, 32

Statistical analysis

We 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.
 

Results

Of 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 outcomes

At 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 Appendixfigure 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 costs

There 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).
 

Cost-effectiveness

At 6 months after trial enrolment, hydrocortisone was more effective and less expensive than placebo in 10.5% of bootstrapped replications, and more effective and more costly in 63.1% of bootstrapped replications (Figure 2 and Online Appendix, table 1). The incremental hospital-related costs of treatment with hydrocortisone, compared with placebo, were A$1 254 078 per quality-adjusted life-year gained. There were no significant differences in the incremental cost-effectiveness ratio for patients with an APACHE II score of 25 or greater, or less than 25. In females, hydrocortisone was more effective and less costly than placebo in 46.2% of bootstrapped replications, and more effective and more costly in 23.5% of bootstrapped replications. In males, hydrocortisone was more effective and less costly than placebo in 2.7% of bootstrapped replications, and more effective and more costly in 65.0% of bootstrapped replications (Online Appendix, table 1).

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).

Discussion

In 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 costs were higher in the hydrocortisone group without gains in quality-adjusted life-years, indicating an overall low probability of cost-effectiveness when assessing total hospital-related costs at 6 months.

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 As such, cost-effectiveness analyses in the ICU environment should not solely focus on treatment acquisition costs, but rather the overall costs of ICU and potential savings made by using interventions that reduce overall ICU costs — for example, through a reduction in duration of ICU treatment.

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 Earlier resolution of shock and liberation from mechanical ventilation, observed in the hydrocortisone group in the overall ADRENAL cohort, are often used as criteria for discharge to a step-down unit or to ward-based care, particularly in health care systems in low- and middle-income countries where availability of intensive care beds is limited and the user pays for individual components of the intensive care services. This suggests that context-specific decisions around ICU admission and discharge could be influenced by existing service capacity, as well as health care systems and patient affordability, and these may have bearing on realisable savings from hydrocortisone treatment. In health systems where patient affordability relating to critical care service access is an important consideration, even small reductions in ICU length of stay may result in significant savings. It is possible that the reduced duration in ICU and hospital stay observed in patients in the hydrocortisone group enrolled outside of NSW and Queensland may mean that the probability of hydrocortisone being cost-effective in other jurisdictions is higher. However, we did not have sufficient data to assess this.

While 22 comparable randomised controlled trials assessing the effect of corticosteroids on mortality of patients with septic shock have been conducted, 37 to our knowledge this is the first study to include a cost-effectiveness analysis and long term assessment of clinical and economic outcomes. The beneficial effects of corticosteroids in reducing ICU-related morbidity reported in ADRENAL are supported by similar effects reported in the Hydrocortisone plus Fludrocortisone for Adults with Septic Shock trial. 38 Our results provide new information showing that use of corticosteroids in patients with septic shock is not associated with additional long term complications at 6 months.

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 This does not affect the relative cost-effectiveness of the two options, but it has service planning and budgetary implications. Ensuring that such cost weights reflect actual resource use will enable publicly funded ICU services to receive adequate funding for treating the sickest patients, including those with septic shock. Given the increasing demand for and cost of ICU services, 39 research aimed at determining a pragmatic costing method that is sensitive to the health service use implications associated with variations in morbidity is required.
 

Conclusions

This economic evaluation of ADRENAL trial participants recruited in NSW and Queensland found no evidence to suggest that hydrocortisone, when compared with placebo, improves health-related quality of life or reduces longer term costs. In view of the reduced length of ICU stay observed for patients receiving hydrocortisone who were recruited to ADRENAL outside of NSW and Queensland, these results should be considered in the broader context of the health systems in which they are being applied.
 
Acknowledgements: We thank the research staff at participating ICUs in NSW and Queensland, Australia, for their assistance with study recruitment and data collection. This study was funded by the Australian and New Zealand Intensive Care Foundation. The ADRENAL trial was funded by the National Health and Medical Research Council of Australia.

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