Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System

Key Points Question What is the real-world experience with edaravone in patients with amyotrophic lateral sclerosis (ALS) within a national integrated health care system? Findings In this cohort study of data from 369 US veterans with documented or probable ALS, a significantly greater proportion of acute all-cause hospitalizations was associated with edaravone treatment and, among users receiving at least 6 months of treatment, an increased likelihood of ALS-related hospitalization was associated with edaravone treatment compared with riluzole-only treatment. Meaning While these findings should be interpreted with caution, in this evaluation, edaravone (mostly used with riluzole) was associated with more hospitalizations compared with riluzole-only therapy; more evidence is needed to evaluate edaravone treatment outcomes in real-world settings.


Introduction
Since 2005, the US Department of Veterans Affairs (VA) health care system has provided care for more than 4000 veteran patients with amyotrophic lateral sclerosis (ALS), one of the largest ALS patient populations in a US health care system. Within the Veterans Health Administration (VHA), ALS is a presumptive service connection (eg, subsequent ALS diagnosis is related to veteran's prior military service), with automatic qualification for VA benefits, including prescription coverage. 1 Pharmacotherapy has been limited, with only 2 treatments approved for ALS by the US Food and Drug Administration (FDA). 2, 3 Edaravone was approved by the FDA in May 2017. 4 Prior to edaravone approval, riluzole was the only FDA-approved treatment. 5 Riluzole was shown to significantly increase survival at 12 and 21 months in a randomized placebo-controlled trial; however, median survival was improved by only approximately 100 days (532 days for riluzole; 449 days for placebo). 6 Moreover, this benefit was not observed in patients aged 75 years and older or those with advanced ALS. 7 Survival was not assessed in the edaravone clinical trial. 8 Edaravone was approved based on a clinical trial in Japanese patients demonstrating some benefit in delaying ALS progression, with inclusion criteria based on a post hoc subgroup analysis. 8 These criteria limited treatment to patients with early-stage ALS (<2 years from diagnosis) who were independent and well functioning (ALS Functional Rating Scale-Revised [ALS-FRS-R] score Ն2 per item [12 items, each rated on a 5-point scale, 0 indicating inability to perform and 4 indicating normal ability], forced vital capacity Ն80%). Notably, less than 7% of ALS patients meet these stringent inclusion criteria. [9][10][11] Some observational studies on edaravone use, safety, and effectiveness include non-US, nonveteran populations. [10][11][12][13] Given limited real-world data on edaravone and the number of veteran patients with ALS, the VA Pharmacy Benefits Management (PBM) designated edaravone for prior authorization drug review nationally, to ensure consistent adjudication, track use, and support appropriate use. The VA Center for Medication Safety (VAMedSAFE) developed a surveillance effort within a national, integrated system and sought to answer the question of how to leverage these real-world data to monitor patient characteristics and use, as well as assess the safety and effectiveness of edaravone.

Methods
This VAMedSAFE surveillance initiative and its assessment were reported according to the Revised Standards for Quality Improvement Reporting Excellence (SQUIRE 2.0) guidelines. This database drug-use evaluation received approval from the VA institutional review board. A waiver of informed consent was granted because the database research involved no more than minimal risk to the patients reviewed and therefore could not be practicably carried out without the requested waiver of alteration per VA policy.

PBM National Prior Authorization Drug Review Program
The VA PBM finalized Criteria for Use (CFU) for edaravone in July 2017, based on evidence from clinical trials and input from subject matter experts; by contrast, riluzole does not have CFU in the VA. 14 The edaravone CFU inclusion criteria allow its use in patients with preserved ability to walk or self-feed, providing access to treatment for a much broader ALS population compared with clinical trial criteria 8 or non-VA health plans. 15 Selected exclusion criteria include significant respiratory insufficiency or difficulty as measured by ALS-FRS-R subscores and comorbidities that complicate assessment of ALS (eg, Parkinson disease, dementia, and schizophrenia). 14 The ALS-FRS-R is an assessment scale for functional impairment, with cumulative scores from 12 items ranging from 0 indicating worst to 48 indicating best, and was used in edaravone clinical trials. 16,17 For prior authorization drug review, an ALS-FRS-R score (that reflects function at the time of the request) and other documentation are submitted via an interfacility consultation to a central data set, where information is reviewed and, when indicated, approved centrally by a pharmacy team.

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While the CFU includes discontinuation criteria and recommendations for monitoring respiratory function and assessing ALS-FRS-R score every 6 months, 14 decisions to continue therapy and follow-up are deferred to local facilities and professionals. The ALS-FRS-R score on the consultation was summarized.

Descriptive Measures
Descriptors included drug use and safety or mortality. Measures included treatment cycles, discontinuation rates, and riluzole use. 20 CFU criteria require that edaravone be administered in accordance with the package insert. 14 For maintenance treatment, edaravone is administered as an intravenous (IV) infusion daily for 10 of 14 days, followed by a 14-day drug-free period (28-day cycle). 4 Given that some cycles were administered by community care professionals and likely not captured in VA data, cycles were estimated using the days from the first to last edaravone prescription fill, divided by 28. Discontinuation was assumed if no further treatment cycles were recorded within 60 days of the last dose and before the end of the evaluation period. Patients receiving edaravone included those with riluzole use (edaravone with riluzole), defined as receiving 1 or more riluzole prescription fills after initiation of and before discontinuation of edaravone treatment, and those without riluzole use (edaravone alone). Riluzole use prior to edaravone initiation was also categorized.
Measures of mortality and voluntarily reported edaravone ADRs were described. Proportion of deaths and time from edaravone initiation until death were summarized for the cohort of edaravone ever-users. 11 Edaravone-related ADRs reported to VA-ADERS during the surveillance period were described by severity, ADR type, and frequency.

Comprehensive Safety and Effectiveness Evaluation
VAMedSAFE conducted a retrospective, propensity score-matched cohort evaluation comparing the safety and effectiveness of edaravone use (alone or with riluzole) with riluzole only. Data sources and variables were the same as described in Surveillance Methods, adding inpatient hospitalizations and ALS-FRS-R scores from the Corporate Data Warehouse that were manually entered into the electronic health record prespecified fields (ie, data in free text were not captured). The cohorts consisted of veteran patients with a diagnosis of ALS and 1 or more prescription fills of edaravone or riluzole between August 1, 2017, and December 31, 2018 (eFigure in the Supplement). Exclusion criteria reflect CFU exclusion and discontinuation criteria 14 and included those with diagnosis codes for excluded comorbidities, dyspnea, or orthopnea, or procedure codes for bilevel positive airway pressure, mechanical ventilation, or tracheostomy within 2 years before prescription initiation.
Edaravone and riluzole-only users were matched 1:3, using a caliper width of 0.2 of the logit of the propensity score. 21 The propensity score was developed using predefined baseline confounders of receipt of edaravone and ALS progression (age Ն65 years, sex, race/ethnicity, marital status, priority group, VA copay, and duration of ALS). [11][12][13] Duration of ALS was categorized as less than or equal to 2 years, more than 2 years, or unknown, 8 based on the first date of a documented ALS diagnosis code to date of edaravone initiation. If the first ALS diagnosis code occurred after edaravone initiation, the duration of ALS was categorized as unknown. Balance after matching was assessed by a standardized mean difference of less than 0.1. 21 The index date was the first prescription fill of edaravone or riluzole within the period August 1, 2017, to December 31, 2018. Acute outcomes, defined as events occurring within the 6-month follow-up period after the index date, 10 were assessed for the overall matched cohorts. These

Statistical Analysis
An analysis was conducted for chronic users of each cohort, defined as those receiving at least 6 months of treatment. 11,13 As in the overall analysis, death was included. Additional outcomes were evaluated to assess ALS progression. These included hospitalization associated with ALS, dyspnea, or orthopnea (per diagnosis codes) and surrogate markers of functional decline (procedure codes for tracheostomy, mechanical ventilation, and percutaneous endoscopic gastrostomy [PEG] tube placement), reflecting CFU discontinuation criteria. 14 Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs for chronic outcomes. Veteran patients were followed from the index date to the date of the first outcome, prescription discontinuation, death, or the end of evaluation, whichever came first. Additionally, frequency of events, mean time to event, and events per 100 person-years of follow-up were summarized. Analysis was conducted using SAS version 9.2 (SAS Institute Inc).

Patient Baseline Characteristics
As  product bag leakage, dyspnea or chest discomfort, anemia, chills or tremor, and rash. Among severe edaravone ADRs reported (eg, ADRs associated with hospitalization, urgent intervention, and/or risk of organ damage), there was 1 death, associated with progression of liver disease in a patient with liver disease prior to edaravone initiation. The other 3 severe ADR reports described dyspnea or leg edema, pneumonia and pulmonary embolism, and pneumonia or respiratory depression.

Comprehensive Safety and Effectiveness Evaluation
For the propensity score-matched analysis, 223 patients receiving edaravone (72.6% edaravone with riluzole, 27.4% edaravone alone) (eTable 1 in the Supplement) were matched to 669 patients receiving riluzole-only treatment (eFigure in the Supplement). Propensity score-matching diagnostics showed balance between edaravone and riluzole-only groups (eTable 3 in the Supplement). The overall matched groups were mostly diagnosed with ALS in the past 2 years (68.6% edaravone; 68.5% riluzole) ( Table 3 Acute outcomes were summarized for the overall matched cohorts (

Discussion
To our knowledge, this evaluation is the largest pharmacovigilance initiative of edaravone users in a US health care system, providing a real-world analysis of patient characteristics, use, safety, and effectiveness of edaravone use within the VHA. As of September 2019, 369 veteran patients, with relatively high ALS-FRS-R scores at initiation, had received edaravone. The VA provides an important point of access to this treatment option, given that most edaravone users had no prescription copay (97%) and 33% enrolled in VA care in fiscal year 2017 or later. In this descriptive monitoring of use, edaravone discontinuation was common (approximately 60%). Additionally, in those who discontinued, a clinically significant proportion (49.5%) received only 1 to 3 infusions.   When comparing use of edaravone (alone or with riluzole) with riluzole-only use, we found that significantly greater acute all-cause hospitalization events were associated with edaravone compared with riluzole-only use. Among chronic users, edaravone was similarly associated with increased hazard ratios of ALS-associated hospitalization. Notably, although times to PEG placement, tracheostomy, and mechanical ventilation were longer for edaravone chronic users compared with riluzole-only, edaravone was significantly associated with increased hazard ratios for PEG placement and not significantly associated with tracheostomy and mechanical ventilation benefits. Death was less common among edaravone chronic users (18.0 per 100 patient-years; 29.3 per 100 patient-years riluzole-only treatment); however, this finding was not statistically significant (HR, 0.77; 95% CI, 0.43-1.18). Overall, the comprehensive evaluation findings may suggest mixed results with diseaseprogression and safety events as well as increased hazard ratios of ALS-associated hospitalization with edaravone use relative to riluzole-only use.

Strengths and Limitations
The strengths of this comprehensive surveillance initiative are its large size and its comparative evaluation. Our measures for use, safety, and effectiveness are consistent with those reported from other health systems. [10][11][12]20 Additionally, database methods allowed for timely national surveillance compared with retrospective medical record review. 10 In the propensity-matched cohort evaluation, the edaravone cohort included many patients who used edaravone with riluzole (72.6%), which reflects the real-world dual use of these treatments. Notably, the edaravone clinical trial allowed patients to continue receiving riluzole, and its use was common (91%). 18 These VAMedSAFE will continue to conduct biannual surveillance of these and other safety signals.
To our knowledge, this is the first evaluation within a US health care system to use a matchedcohort, time-to-event analysis to assess safety and effectiveness of edaravone compared with an active comparator. Okada et al 13 used survival analysis to compare tracheostomy-free survival between Japanese edaravone users (n = 27) and a historical control cohort (n = 30), for up to 80 months; a survival benefit was associated with edaravone treatment (HR for death, 0.37; 95% CI, 0.20-0.74). However, 37% (10 of 27) discontinued edaravone but were not censored, meaning survival was not associated with drug exposure. Within an Italian ALS clinic, edaravone users (n = 31) were compared with a historical-control cohort (n = 50); findings suggested no clinically or statistically significant differences in ALS-FRS-R score, respiratory function, or muscle strength, at 3or 6-month follow-up. 12 Abraham et al 11 compared edaravone users with at least 6 months of treatment (n = 20) with contemporaneous non-edaravone users (71) at 1 Israeli clinic. There was no difference in effectiveness, but mortality was numerically greater in the edaravone group. None of these studies used matching, and the latter 2 studies 11,12 did not account for differential follow-up or censoring due to death or tracheostomy.
This evaluation has limitations. First, the edaravone cohort was overall less healthy 14 than edaravone clinical trial participants, 8 which may explain the disease progression observed.
Importantly, because riluzole is not regulated by VA CFU and is an oral drug whereas edaravone requires infusions, riluzole-only users are likely different from edaravone users in complex ways.
Potentially, some riluzole users were sicker; edaravone is reserved for ALS patients with good Consequently, despite our efforts to match patients receiving edaravone and those receiving riluzoleonly treatment, residual confounding or baseline differences are likely. To maintain a larger pool of matching candidates, we did not use a new-user design for the riluzole-only cohort, which introduces bias toward favorable responders to riluzole. Matching on additional factors may improve comparison, including ALS-FRS-R score components, ALS-onset type (bulbar vs nonbulbar), and pulmonary and muscular function. 10 Second, some outcomes were infrequently captured in VA databases (eg, ALS-FRS-R score and functional-status surrogate markers). Edaravone exposure was based on only the first and last prescription fill dates within the VHA, as we could not capture cycles received in non-VHA settings. In addition, we did not exclude PEG-tube use at baseline (allowed per CFU) and could not assess if PEG-tube outcomes were incident (reflecting decreases in function or discontinuation criterion).

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Overall, the challenge of assessing edaravone safety and effectiveness is that ALS progression is unpredictable and heterogeneous. 3,10,11,13 Simply, are adverse events related to disease progression, treatment, or both? Disease complications, death, or treatment discontinuation may occur prior to evaluation of drug effectiveness. In our evaluation, patients receiving riluzole-only treatment continued to receive treatment longer (mean 403.9 days, riluzole-only treatment; mean 305.1 days, edaravone), given differential censoring. This censoring bias may be addressed in future studies (if effectiveness is the primary interest) by applying survival models accounting for competing risks 22 (eg, accounting for differential death or discontinuation between comparators).

Conclusions
The results of this study should be construed as exploratory given inherent methodologic limitations.
Notably, this surveillance evaluation identified that patients using edaravone (mostly with riluzole) had unexpected outcomes, which raises questions about its benefit in VHA patients and underscores the importance of further studies. To confirm these findings, robust research designs with in-depth medical record review are needed to better characterize drug exposure, reasons for discontinuation, outcomes, and covariates. The VA will continue to track and monitor the safe and appropriate use of edaravone and provide timely information to optimize veteran ALS care.