key: cord-0824691-dgglfir1
authors: Sinha, Pranay; Linas, Benjamin P
title: Combination therapy with tocilizumab and dexamethasone cost-effectively reduces Coronavirus disease 2019 mortality
date: 2021-05-06
journal: Clin Infect Dis
DOI: 10.1093/cid/ciab409
sha: 20c80c1f30af79dfe8480e3836d74c69ea8df648
doc_id: 824691
cord_uid: dgglfir1

Recent randomized trials suggest that interleukin-6 inhibitors like tocilizumab have mortality benefit for patients with severe coronavirus disease-2019. We employed a decision tree to investigate their cost-effectiveness and found that tocilizumab is cost-effective with an estimated incremental cost-effectiveness ratio of $16520 per quality-adjusted life year gained (95% credible interval 10760-51530).

M a n u s c r i p t

Although compelling observational data suggested that IL-6 inhibitors such tocilizumab and sarilumab reduce mortality and morbidity associated with severe Coronavirus disease 2019 (COVID-19) due to SARS-Coronavirus-2 (SARS-CoV-2), this effect was not seen in early randomized clinical trials. [1] [2] [3] Recently, two large randomized controlled trials demonstrated a meaningful mortality benefit. The number needed to treat to prevent mortality was 12 and 16, respectively, in the REMAP-CAP and RECOVERY studies. [4, 5] IL-6 inhibitors are now recommended for patients with severe or critical COVID-19 by the UK COVID-19 guidelines as well as the Infectious Diseases Society of America. To inform use of IL-6 inhibitors, we developed a decision tree model to investigate the cost-effectiveness of adding tocilizumab to dexamethasone for severe COVID-19 disease.

We incorporated data from the RECOVERY group entitled "Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, openlabel, platform trial" in Britain into a decision tree model to project the life expectancy, discounted lifetime medical costs, and incremental cost effectiveness ratio (ICER) of three strategies for managing severe COVID-19 (Supplementary figure 1). [4] 1. Dexamethasone 2. Both Dexamethasone and tocilizumab (combination therapy) 3. Supportive care alone Given the higher COVID-19 mortality in the UK compared to the USA, we also considered a scenario where the relative risks for death after receiving dexamethasone or combination therapy are the same as M a n u s c r i p t reported in the RECOVERY trial, but mortality with supportive care alone is similar to that of US cohorts.

Model structure: The decision tree model simulates progression from severe COVID-19 disease to survival or death.

Costs: We obtained cost of dexamethasone ($12 for 6mg orally for 10 days) and tocilizumab ($5304 for 800mg intravenous single dose) from goodrx.com. [ Table 1 )

We assumed the mean age of the cohort to be 63 based on trial data. We calculated probabilities of mortality in each strategy from reported clinical trial data. (Supplementary Table 1 ).

Based on observed data from New York City, we simulated a lower absolute mortality rate (14.6%) without treatment and assumed the same relative risks of death for dexamethasone and combination therapy that were observed in RECOVERY. [12] Sensitivity analyses:

To assess the robustness of our results, we conducted both deterministic and probabilistic sensitivity analyses. To conduct deterministic sensitivity analysis, we defined a priori feasible ranges around core parameter values and then repeated the analysis multiple times, each time ranging one parameter value through its feasible interval. We present the results of one-way sensitivity analyses in tornado diagrams. Next, we conducted two-way sensitivity analyses, in which we simultaneously varied the cost of tocilizumab ($2652-$10608) and the mortality associated with combination therapy at the same time. We used a wider range of mortality for both the base case (0.219-0.329) and low mortality scenarios (0.092-0.138). We present the results of two-way sensitivity analyses in standard two-dimensional arrays.

M a n u s c r i p t

Lastly, we performed probabilistic sensitivity analysis (PSA). We defined uncertainty in parameter values using probability density functions (PDFs) around each parameter value. We then employed Monte Carlo simulation to repeat the analysis 10,000 times, each time drawing the value of all model parameters from their PDF. We assumed beta distribution for survival probabilities and gamma distributions for costs. The result is 10,000 model outcomes, each one incorporating simultaneous uncertainty from all model parameters.

We present the results of PSA using cost-effectiveness acceptability curves. In addition, we represent uncertainty around base case results using 95% credible intervals (CI) from PSA.

Base case analysis 

The ICER for combination therapy as compared to just dexamethasone was $26,840/QALY (95% CI: $14,800-$101,030). (Table 1) M a n u s c r i p t

For both scenarios, one-way sensitivity analyses found that the two parameters with the greatest impact on the ICER were age (baseline assumption 63.3, range 37.9-91.8) and mortality associated with dexamethasone (baseline assumption: 0.328, range +/10%). The ICER of combination therapy compared to dexamethasone alone increased with increasing age and decreasing mortality rate on dexamethasone. At, the upper bound of age, the ICER was $42,730/QALY and at the lower bound of dexamethasone mortality rate it was $29,290/QALY. (Supplementary Figure 3 )

In two-way sensitivity analysis, for both the base case and lower mortality scenarios, the dexamethasone and tocilizumab combination remained cost-effective over most combinations of the cost of tocilizumab and benefits associated with combination therapy. The analysis did identify combinations, however, that resulted in combination therapy not being cost-effective. In the base case, when we assumed that the mortality associated with combination therapy was >=0.323 and the cost of tocilizumab was >=$5516, the ICER of combination therapy was >$100,000/QALY. In the low mortality scenario, when mortality with combination therapy was >= 0.131 and the cost of tocilizumab was >= $9490, the ICER was >$100,000/QALY (Supplementary Figure 4 )

Cost-effectiveness conclusions were highly robust to uncertainty. As seen in the cost-effectiveness acceptability curve, dexamethasone and tocilizumab combination was favored at a WTP of $100,000 in >98% of iterations in the base case scenario, and >76% in the lower mortality scenario. (Supplementary Figure 5) M a n u s c r i p t Discussion:

Our model suggests that the addition of tocilizumab to dexamethasone is likely a cost-effective intervention to reduce mortality from severe COVID-19 based on data from the RECOVERY trial. Combination therapy remained cost-effective in a lower mortality scenario, similar to observed rates in the USA, although probabilistic sensitivity analyses suggest that the favorability of combination therapy would be less certain if mortality rate among patients with severe COVID-19 was reduced through secular means.

We assumed a large range of tocilizumab costs in sensitivity analyses given regional variations in costs and dosing. While the RECOVERY and REMAP-CAP trials advocated for an 800mg dose with provisions for a second dose, other centers have reported encouraging results with a single 400mg dose. [1] If future studies validate the lower dose, the cost-effectiveness would increase considerably. These analyses have been done from the perspective of the United States. In lower and middle income countries, price reductions in tocilizumab would likely be necessary given lower willingness-to-pay thresholds.

This analysis has limitations. The ICERs we report are likely underestimates, as we did not have access to primary trial data and were therefore unable to account fo reductions in mechanical ventilation, length of hospitalization, or severity of chronic lung disease in those receiving combination therapy. However, the goal of this analysis was to assess cost-effectiveness which we were able to demonstrate with the mortality benefit alone. Including additional benefits of combination therapy would strengthen our conclusions. Furthermore, this model cannot reconcile the contradictory findings of earlier studies of tocilizumab for COVID-19 which did not demonstrate mortality benefit. This may be because earlier studies included individuals with less severe disease, received tocilizumab A c c e p t e d M a n u s c r i p t after inflammatory damage had occurred, and differences in corticosteroid use. [1, 3] To avoid overestimation of mortality benefit, we used data from the RECOVERY study to parameterize our model as it reported a lower estimate for mortality benefit compared to REMAP-CAP. We also employed probabilistic sensitivity analysis as well as scenario analysis to thoroughly explore the uncertainty in mortality benefit. We conclude that unless the RECOVERY trial committed sizable type 1 errors, tocilizumab is almost certainly costeffective, even in settings with lower expected mortality.

In conclusion, tocilizumab in addition to dexamethasone is a costeffective intervention for individuals severely ill with COVID-19.

M a n u s c r i p t Notes:

The funders had no role in study design, analysis, or reporting.

This work was supported by the National Institutes of Health grant R01DA046527 and P30DA040500 to BPL and 5T32AI052074-13 to PS.

We do not report any conflicts of interest.

Early administration of Interleukin-6 inhibitors for patients with severe Covid-19 disease is associated with decreased intubation, reduced mortality, and increased discharge

Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia

Interleukin-6 Receptor Inhibition in Covid-19 -Cooling the Inflammatory Soup

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial

Interleukin-6 receptor antagonists in critically ill patients with Covid-19

Projected NHEA-Aligned MEPS expenditures

Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on cost-effectiveness in health and medicine

Respiratory function in patients post-infection by COVID-19: a systematic review and meta-analysis

Skills of the trade: the Tufts cost-effectiveness analysis registry

Clinical characteristics of Covid-19 in New York city

A c c e p t e d M a n u s c r i p t M a n u s c r i p t