Background/Purpose: Gout is associated with high comorbidity, including cardiovascular (CV), metabolic, and renal disease,¹ with even higher burden in uncontrolled gout patients (pts).² CV (myocardial infarction [MI], stroke) and thromboembolic (VTE) event incidence of 17.34 and 3.65/1000 PY,^3,4 respectively, was reported in gout pts, with higher incidence after flare (CV within 120 days,³ VTE within 30 days⁴). This link may be from systemic inflammatory consequences of seemingly local gout flares.^5,6 Maintaining serum urate (SU) < 6 mg/dL reduces flares over time.⁷ However, initiating urate-lowering therapy (ULT) can induce flare, raising the question of CV/VTE event with ULT initiation. Here, we examine CV/VTE events after pegloticase initiation in this pooled post hoc analysis of clinical trial pts.

Methods: Phase 3,⁸ MIRROR OL,⁹ and MIRROR RCT¹⁰ pts with ≥1 pegloticase infusion were included (244 biweekly dosing [110 with methotrexate {MTX}], 84 monthly dosing), with focus on biweekly (on-label) pts. All had uncontrolled gout and received flare prophylaxis (FP) ≥1 wk before first dose. Standard pre-infusion prophylaxis was used, including 125 mg IV methylprednisolone or 200 mg hydrocortisone. Gout flare and CV/VTE events were identified using treatment-emergent (TE) AEs during 24 wks of therapy. Flare exposure window was 120 days.³

Results: 5/328 pts (1.5%; 4 monotherapy colchicine FP, 1 pegloticase+MTX ibuprofen FP) beginning pegloticase had ≥1 CV/VTE event (cardiac arrest [CA, n=2]; CHF, DVT, MI, TIA [n=1 each]), with all occurring during the flare exposure window (time from first TE flare, range: 18-130 days; time from most-recent TE flare: 3-69 days). 3 CV/VTE events occurred in 244 pts receiving biweekly pegloticase (1.2%, 35.4/1000 PY), with 2 in monotherapy pts (1.5%; CA, CHF) and 1 in a pegloticase+MTX pt (0.9%; CA). 176/244 (72.1%) had ≥1 TE flare. Pts with and without flare were similar but those with flare had more frequent pre-treatment flares (10.9±13.6 vs 5.3±5.7 flares/year [median: 7 vs 3]).

Conclusion: 1.2% of pts had CV/VTE events during biweekly pegloticase therapy, with similar incidence (35.4/1000 PY) to the general gout population (20.99-44.7/1000 PY^3,4,11) and lower than with XOI initiation (51.8-99.3/1000 PY¹²). All events occurred within the 120 days of flare when pts were at higher risk.^3,4 Of note, pts with TE flares had higher pre-treatment flare rates than those without. Maintaining SU < 6 mg/dL decreases gout flares over time⁷ so a treat-to-target approach with ULT may be of critical importance for maintaining gout pt health over the long-term.

References

1. Zhu Y et al. Am J Med 2012;125:679-87 e1
2. Francis-Sedlak M et al Rheumatol Ther 2021;8:183-97
3. Cipolletta E et al. JAMA 2022;328:440-50
4. Cipolletta E et al. Arthritis Rheumatol 2023 [ePub]
5. Pillinger M et al. Arthritis Rheumatol 2022;74 (sup 9)
6. Wu H et al. Medicine 2022;101:e30242
7. Shoji A et al. Arthritis Rheum 2004;51:321-5
8. Sundy JS et al. JAMA 2011;306:711-20
9. Botson JK et al. J Rheumatol 2021;48:767-74
10. Botson JK et al. Arthritis Rheumatol 2023;75:293-304
11. Clarison LE et al. Ann Rheum Dis 2015;74:642-7
12. Foody J et al. Am Health Drug Benefits 2017;10:393-401

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-emergent-major-adverse-cardiovascular-and-thromboembolic-events-were-infrequent-during-pegloticase-therapy-pooled-clinical-trial-findings/