key: cord-0271167-4lsz8srp
authors: Poremba, M.; Dehner, M.; Perreiter, A.; Semma, A.; Mills, K.; Sakoulas, G.
title: Intravenous Immunoglobulin (IVIG) in Treating Non-ventilated COVID-19 Patients with Moderate to Severe Hypoxia is Pharmacoeconomically Favorable When Appropriately Targeted
date: 2021-09-27
journal: nan
DOI: 10.1101/2021.09.26.21264152
sha: 5d4542167bcc16f84da23bbed5ce3513718756e7
doc_id: 271167
cord_uid: 4lsz8srp

Background: Prior studies have shown that intravenous immunoglobulin (IVIG) can improve outcomes in patients with COVID-19, but the high costs of IVIG leave questions as to its pharmacoeconomic value. Methods: The hospital costs of 2 IVIG vs. non-IVIG COVID-19 patient groups were compared. The first cohort was a case-control analysis of 10 non-ventilated moderately to severely hypoxic COVID-19 patients who received IVIG (Privigen) matched 1:2 with 20 control patients of similar age, body mass index (BMI), degree of hypoxemia, and co-morbidities. The second cohort consisted of patients enrolled in a previously published randomized open-label prospective study of 14 COVID-19 patients receiving standard of care (SOC) versus 13 patients who received SOC plus IVIG (Octagam 10%). Results: Among the first case control population, mean total direct costs including IVIG for the treatment group was $21,982 per IVIG-treated case versus $42,431 per case for matched non-IVIG receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs including IVIG for the treatment group was $28,268 per case versus $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. 24% of the non-IVIG patients had hospital costs exceeded $80,000, as compared to none of the IVIG patient host (p=0.016, Fisher exact test). Conclusion: When allocated to the appropriate patient type (moderate to severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More importantly, it may reduce the demand on scare critical care resources during the COVID-19 pandemic.

Intravenous immunoglobulin (IVIG) has been available in most hospitals for 4 decades with broad therapeutic applications in the treatment of a variety of inflammatory, infectious, autoimmune, viral diseases, and Kawasaki disease via multifactorial mechanisms of immune modulation. Retrospective studies have shown potential benefit of IVIG treatment for COVID-19 ARDS in adults and the associated multisystem inflammatory syndrome in children (MIS-C). [1] [2] [3] [4] [5] [6] [7] The benefit of IVIG may be more based on earlier timing of administration rather than on dose. 2 Detailed case series have also been recently published with sufficient clinical granularity in their presentation to point to individual patient cases where very obvious benefit was seen. 8 Three prospective randomized studies evaluating IVIG in COVID-19 were recently published. A randomized placebo-controlled double-blind study of 59 patients (30 IVIG, 29 placebo) was performed in Iran between May-June 2020. 9 Multivariate logistic regression showed lack of IVIG receipt, along with increasing age, lower diastolic blood pressure and increased serum lactate dehydrogenase were associated with higher mortality. A second study at two hospitals in San Diego, CA (USA) was an open label randomized prospective study of 33 COVID-19 patients (16 IVIG, 17 controls) comparing standard of care (n=17) vs. standard of care plus IVIG 0.5g/kg daily x 3 days and showed a lower rate of progression to respiratory failure requiring mechanical ventilation in COVID-19 patients (13%, 2/16 with IVIG vs. 41%, 7/17 without IVIG, p=0.12). 10 While this difference did not achieve statistical significance among the collective subject cohorts, a post-hoc analysis of patients with A-a gradient >200 mm Hg showed statistically significant reduction in progression to mechanical ventilation, shorter duration length in the ICU and total hospital stay and improvement in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint Despite these positive results, the relatively high costs of IVIG makes its pharmacoeconomic value uncertain. Therefore, we performed an analysis of healthcare costs of hypoxic COVID-19 treated patients with IVIG compared to COVID-19 patients not given IVIG.

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Design: All patients in this study were hospitalized at a single site located in San Diego, California. This analysis received approval from the health system's Institutional Review Board (IRB), and was granted a waiver of subject authorization given the retrospective nature of the study. Treatment patients in both cohorts received IVIG 0.5 g/kg adjusted body weight daily for 3 consecutive days.

Patient Cohort #1-Retrospective Case Control: IVIG (Privigen 10%, CSL Behring) was utilized off-label to treat moderate to severely ill non-ICU patients with COVID-19 requiring > 3 liters O2 by nasal cannula, not mechanically ventilated, but considered at high risk for respiratory failure. Pre-set exclusion criteria for IVIG off-label use in the treatment of COVID-19 were age >70, active malignancy, organ transplant recipient, renal failure, heart failure, or dementia. Controls were obtained from a list of all COVID-19 patients admitted matched based to cases 2 to 1 on the bases of age (+/-10 years), body mass index (+/-10), gender, co-morbidities present at admission (eg.

hypertension, diabetes mellitus, lung disease, or history of tobacco use) and maximum oxygen requirements within the first 48 hours of admission. In situations where more than two potential matched controls were identified for a subject, the two controls with ages closest to the treatment patient were selected. One IVIG patient was excluded because only 1 matched age control could be found. Pregnant patients who otherwise fulfilled criteria for IVIG administration were also excluded from this analysis.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint Outcomes: Cost data was independently obtained from our finance team who provided us with the total direct cost and the total pharmaceutical cost associated with each admission. We also compared total length of stay (LOS) and ICU LOS between treatment arms, as these were presumed to be the major drivers of cost difference. We used the paired Wilcoxon rank sum test for our case-control group and the Fisher exact test for our prospective randomized cohort.

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The copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint

Case-Control Analysis: A total of 10 COVID-19 hypoxic patients received Privigen IVIG outside of clinical trial settings. Oxygen requirement within the first 48 hours ranged from 3L via nasal cannula to requiring bi-level positive pressure airway (BiPAP) with 100% oxygen, median age was 56 and median Charlson comorbidity index was 1.

These 10 patients were matched to 2 control patients based on oxygen requirements who did not receive IVIG, yielding 20 patients with median age 58.5 years, Charlson comorbidity index of 1 ( Table 1) .

The mean (standard deviation, SD) total direct hospital cost per case, including IVIG and other drug cost, for the 10 IVIG-treated COVID-19 patients was $21,982 (4, 734) . For the control patients, direct hospital cost per case was $42,431 (48,158), a difference of $20,449 per case (p=0.6187). Thus, the mean IVIG hospital cost per case was reduced 48% compared to the matched control case cost. This difference was heavily driven by 4 control patients (20%) with hospital costs >$100,000, marked by need for ICU transfer, mechanical ventilation, and longer hospital stays. All four of these patients required ventilation during their admission. This mitigation of progression to mechanical ventilation was consistent with our previously published open-label randomized prospective IVIG, the financial assessment of which is reviewed below.

While total direct cost was lower in the treatment arm, the mean drug cost for the treatment arm was $3,121.97 greater than the mean drug cost in the control arm (p=0.001622), consistent with the high cost of IVIG therapy ( Table 2) .

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The copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint 8 LOS information was obtained as this was thought to be a primary driver of direct costs. The average LOS in the IVIG arm was 8.4 days while the average LOS in the control arm was 13.6 days. An average difference of 5.2 days was noted between groups (p = 0.5884). The average ICU LOS in the IVIG arm was 0 days while the average ICU LOS in the control arm was 5.3 days. An average difference of 5.3 days was noted between groups (p = 0.04057). As with the differences in cost, the differences in LOS was primarily driven by the four outlier cases in our control arm, who each had a LOS >25 days, as well as an ICU LOS >20 days.

Randomized Open-Label Patient Cohort: Patient characteristics, length of stay, and receipt of mechanical ventilation for the IVIG and control patients were previously published and showed reduction in mechanical ventilation and hospital LOS with IVIG. 10 Comparing the hospital cost of the IVIG patients to the control patients from this trial revealed similar results to the matched case-control analysis discussed above. Mean (SD) total direct cost, including IVIG, for the treatment group was $28,268 (19, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

Supported by published literature, 13 our hospital had been utilizing IVIG in the treatment of viral acute respiratory distress syndrome (ARDS) with anecdotal success prior to COVID-19. Therefore, our group moved quickly to perform a randomized openlabel pilot study of IVIG (octagam-10%) in COVID-19, and noted significant clinical benefit that might translate into hospital cost savings. 10 Over the course of the pandemic, evidence has accumulated that IVIG may play an important role in COVID-19 therapeutics, as summarized in a recent review. 14 However, despite these results, the relatively high acquisition costs of IVIG raised questions as to its pharmacoeconomic value, particularly with such a high volume of COVID-19 patients with hypoxia in light of limited clinical data.

Indeed, a year and a half into the pandemic, COVID-19 therapeutics data can be summarized into either high-quality trials showing marginal benefit for some agents or low-quality trials showing greater benefit for other agents, with IVIG studies falling into the latter category. 15 This phenomenon may speak to pathophysiological heterogeneity of the COVID-19 patient population. High quality trials lack the granularity to capture and single out relevant patient subsets of maximal therapeutic benefit, with those subsets diluted out by other patient types for which no benefit is seen. Meanwhile, the more granular low quality trials are criticized as underpowered and lacking general translatability to practice. Furthermore, the lower quality trials are inclusive of some of subsequently refuted data that unfortunately have been embraced by politically-driven pandemic quackery, potentially working against the unbiased interpretation of data from other small trials that may actually be meaningful.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We then went back to the patients from the randomized prospective trial and compared costs for the 13 of 16 IVIG patients and 14 of 17 of the control patients for whom data was available. Among this group, we found net cost reduction of $34,439 per case, or a 55% cost reduction per case. The higher costs seen in the randomized patient cohort may be due to a combination of the fact that the patients had slightly higher comorbidity indices than the case-control group (median Charlson comorbidity index of 2 in both groups) and the fact that they were treated earlier in the pandemic (May-June 2020) as opposed to the case-control group patients who were treated in November-December 2020.

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The copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint 1 2 It was notable that the cost savings across both groups was derived largely from the reduction in the approximately 20-25% of control patients that went on to critical illness including mechanical ventilation, extracorporeal membrane oxygenation (ECMO) and prolonged ICU stays. Indeed, 8 of 34 of control patients but none of the 23 IVIG patients generated hospital costs in excess of $100,000, a difference that was statistically significant even for such a small sample size. Therefore, reducing these very costly outlier events in the minority of patients translated into net savings across the board.

In addition to reducing costs, reducing progression to critical illness is extremely important during heavy waves of COVID-19, when the sheer volume of patients severely strains the relative scarcity of ICU beds, mechanical ventilators, and ECMO. Therefore, reducing the need for these resources would have a vital role that cannot be measured economically.

The major limitations of this study include the small sample size and the potential lack of generalizability of these results to all hospital centers. Our group has generated considerable experience in IVIG utilization in COVID-19 and as a result, has identified a 'sweet spot' where benefit was seen clinically and economically. However, it remains to be determined if IVIG will benefit patients with greater illness severity such as those in the ICU, on mechanical ventilation, or ECMO. Furthermore, while a significant morbidity and mortality burden of COVID-19 rests in extremely elderly patients and those with end-organ comorbidities such as renal failure and heart failure, it is uncertain if their COVID-19 adverse outcomes can be improved with IVIG or other therapies. We believe such patients may limit the pharmacoeconomic value of IVIG due to their generally . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint poorer prognosis regardless of intervention. On the other hand, COVID-19 patients who are not that severely ill with minimal to no hypoxia generally will do well regardless of therapy and IVIG intervention may be potentially be an unnecessary treatment expense.

Evidence for this was hinted in our pilot trial 10 and supported in a recent meta-analysis of IVIG therapy in Several other therapeutic options with high acquisition costs have seen an increase in use during the COVID-19 pandemic despite relatively lukewarm data.

Remdesivir, the first drug found to have a beneficial effect on hospitalized patients with COVID-19, is priced at $3,120 for a complete five day treatment course in the United

States. This was in line with initial pricing models from the Institute for Clinical and Economic Review (ICER) in May 2020, assuming a mortality benefit with remdesivir use. After the SOLIDARITY trial was published, which showed no mortality benefit associated with remdesivir use, ICER updated their pricing models and released a statement that the price of remdesivir was too high to align with demonstrated benefits in June 2020. 17,18 More recent data demonstrates that remdesivir may be beneficial, but only if administered to patients with < 6 days of symptoms. 19 However, only a minority of patients present to the hospital early enough in their illness for remdesivir to be beneficial. 19 Tocilizumab, an interleukin-6 (IL-6) inhibitor, saw an increase in use during the pandemic. An 800 mg treatment course for COVID-19 costs $3,584. The efficacy of this treatment option came into question after the COVACTA trial failed to show a difference in clinical status or mortality in COVID-19 patients who received tocilizumab versus placebo. 20,21 A more recent study pointed to a survival benefit of tocilizumab in COVID-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint 19, driven by a very large sample size (>4000), yielding statistically significant but perhaps clinically insignificant effects on survival (31% mortality versus 35% mortality). 22 This latter study points to the extremely large sample sizes required to capture statistically significant benefits of expensive interventions in COVID-19, which our data demonstrate may benefit only a fraction of patients (20-25% of patients in the case of IVIG). A more granular clinical assessment of these other interventions is needed to be able to capture the patient subtypes where tocilizumab, remdesivir, and other therapies will be viable pharmacoeconomically in the treatment of COVID-19, or other virallymediated cases of ARDS.

In summary, while IVIG has a high drug acquisition cost, utilization of IVIG in hypoxic COVID-19 patients resulted in reduced costs per COVID-19 case by approximately 50% and a reduction in use of critical care resources. The difference was consistent between two cohorts differing in ways of patient identification (randomized trial vs. off-label use in pre-specified COVID-19 patient types), IVIG products used (Octagam 10% vs Privigen), and time period in the pandemic (Waves 1 and 2 in May/June 2020 vs. November/December 2020). Higher costs of care of control patients was driven largely by ~25% of patients that required costly hospital critical care resources, a group mitigated by IVIG. When allocated to the appropriate patient type (patients with moderate to severe but not critical illness, < age 70 without pre-existing comorbidities of end-organ failure or active cancer), IVIG can reduce hospital costs in COVID-19 care. Given that IVIG has shown potential benefit in a variety of viral illnesses, care must be taken in future viral pandemics to identify specific patient populations where IVIG has the most anticipated benefit.

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The copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint 1 5

Author GS was a consultant for and received research funding from Octapharma, Inc.

This study was unfunded.

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The copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint

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It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprintThe copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.26.21264152 doi: medRxiv preprint