2219: Time-Dependent Evaluation of Glucocorticoid Exposure Duration and Major Adverse Cardiovascular Events in a Cohort of Veterans with Rheumatoid Arthritis

Beth Wallace¹, Yuqing Gao², H. Myra Kim³, Punyasha Roul⁴, Ted Mikuls⁵, Daniel Clauw⁶, Bryant England⁷, Joshua Baker⁸, Brian Sauer⁹, Grant Cannon¹⁰, Shirley Cohen-Mekelberg¹, Wyndy Wiitala², Jeremy Sussman¹, Rodney Hayward¹ and Akbar Waljee¹, ¹University of Michigan Department of Internal Medicine; Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI, ²Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI, ³Center for Statistical Consultation and Research, University of Michigan; Center for Clinical Management Research, VA Ann Arbor Healthcare Center, Ann Arbor, MI, ⁴UNMC, Omaha, NE, ⁵Division of Rheumatology, University of Nebraska Medical Center, Omaha, NE, ⁶University of Michigan Department of Anesthesia, Ann Arbor, MI, ⁷University of Nebraska Medical Center, Omaha, NE, ⁸University of Pennsylvania, Philadelphia, PA, ⁹Salt Lake City VA/University of Utah, Salt Lake City, UT, ¹⁰Retired, Salt Lake City, UT

Background/Purpose: Three-quarters of RA patients use glucocorticoids (GC) at some point to manage RA symptoms. Prior work suggests recent GC use is associated with major adverse cardiovascular events (MACE) in RA, but does not adequately account for prior GC exposure or time-varying MACE risk.

Methods: In this retrospective cohort study, we used national VA administrative data to identify RA patients with an initial VA rheumatology visit (index date) in 2010-2018. Exclusions included age < 40 or >90, non-RA rheumatologic disorders, prior MACE, or CHF during a lookback period of up to 5 years. We used pharmacy dispensing data to calculate days' supply of GC per 6-month period, empirically categorized as 0, 1-7, 8-90, >90 days (exposure). We used VA claims and National Death Index data to identify first MACE, updating every 6 months (outcome). We defined MACE as MI, stroke/TIA, cardiac arrest, coronary revascularization, or death from CV cause. Patients were censored at non-CV death, or 2 years after last VA service use (Fig. 1). We estimated the overall effect of prior period GC on the 6-month lagged MACE outcome using a marginal structural model with stabilized weights. This approach was chosen to account for current and prior time-varying confounders that may affect current GC use. Key time-varying covariates used for model weights included a) cumulative GC duration between index date and exposure period, calculated using pharmacy claims; b) continuous 5-year MACE risk percentage, estimated using the Veteran's Affairs Risk Score for CV Disease (VARS-CV) (Table 1). VARS-CV uses medical and pharmacy claims, vital signs, and labs to recalibrate the ACC/AHA risk model for the Veteran population. It calculates a continuous 5-year risk percentile that can be categorized as low (< 3%), medium (3-9%) or high ( >9%) to align with ACC/AHA 10-year cutoffs of < 7.5%, 7.5%-20%, and >20%.

Results: Among 19,280 patients (mean age 63 years, 84% male), median 5-year MACE risk at baseline was 5.3%; 3,869 patients (20%) had high MACE risk (Table 1). Mean cumulative GC duration in the 12 months after index date was 63.3 days overall, and 67.0 days for those with high MACE risk. Incident MACE occurred in 4.2% of patients overall, and in 7.1% with high MACE risk. Median time to MACE was 1,079 days. Using a traditional pooled logistic regression model adjusted only for baseline covariates, compared to 0 days of GC use, relative odds of MACE was 1.45 (95% CI 0.97-2.17) for 1-7 days of use, 1.42 (1.14-1.77) for 8-90 days, and 1.99 (1.66-2.39) for >90 days. In the weighted model accounting for time-varying covariates, relative odds of MACE was 1.54 (0.95-2.49) for 1-7 days of use, 1.78 (1.21-2.61) for 8-90 days, and 2.17 (1.70-2.78) for >90 days (Table 2).

Conclusion: In this national RA cohort, we observed a dose-response relationship between days of GC use in the past 6 months and odds of first MACE in the next 6 months, independent of other time-varying CV risk factors and prior GC use. Future work will examine how other MACE risk factors may alter the relative effect of GC use on MACE, the effect of GC dose, the delayed impact of remote GC use, and effects of GC use on subsequent MACE.
Figure 1: Study design

Table 1: Baseline characteristics by 5-year risk of major adverse cardiovascular events (MACE)

Table 2: Association between glucocorticoid use per 6 month period and odds of MACE during the following 6 months.
Disclosures: B. Wallace, None; Y. Gao, None; H. Kim, None; P. Roul, None; T. Mikuls, Gilead Sciences, Bristol-Myers Squibb, Horizon, Sanofi, Pfizer Inc; D. Clauw, Aptinyx, AbbVie/Abbott, Pfizer, Allergan, Fasken Martineau DuMoulin LLP, Heron Therapeutics, Inc, Eli Lilly, Kellogg, Hansen, Todd, Figel & Frederick, PLLC, H. Lundbeck A/S, Marks & Clerk Law LLP, Neumentum Inc., Nix Patterson LLP, Regeneron, Samumed, Swing Therapeutics, Inc., Tonix Pharmaceuticals, Inc., Virios Therapeutics, Inc., Zuber Lawler & Del Duca LLP, Arbor Medical Innovations LLC; B. England, Boehringer-Ingelheim; J. Baker, Bristol-Myers Squibb(BMS), RediTrex, Pfizer; B. Sauer, None; G. Cannon, None; S. Cohen-Mekelberg, None; W. Wiitala, None; J. Sussman, None; R. Hayward, None; A. Waljee, None.