Jeffrey A Sparks1,2, Kathleen M M Vanni3, Matthew A Sparks4,5, Chang Xu3, Leah M Santacroce3, Robert J Glynn2,6,7, Paul M Ridker2,7, Daniel H Solomon3,2. 1. Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts jsparks@bwh.harvard.edu. 2. Harvard Medical School, Boston, Massachusetts. 3. Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, Massachusetts. 4. Division of Nephrology Duke University School of Medicine, Durham, North Carolina jsparks@bwh.harvard.edu. 5. Renal Section, Durham Veterans Affairs Health Care System, Durham, North Carolina. 6. Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, Massachusetts. 7. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Abstract
BACKGROUND: Low-dose methotrexate (LD-MTX) is contraindicated in advanced CKD, but kidney safety in normal kidney function or mild-to-moderate CKD is less clear. METHODS: We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15-20 mg/week) or placebo. All participants took folic acid 1 mg 6 days/week. Exclusion criteria included systemic rheumatic disease and creatinine clearance <40 ml/min. The least-squares mean ΔeGFR from baseline was calculated at each study visit; the difference in eGFR between LD-MTX and placebo was compared. We used Cox proportional hazard models to compare rates of kidney AEs for LD-MTX versus placebo. RESULTS: A total of 2391 participants were randomized to LD-MTX and 2395 to placebo. At baseline, the mean age was 66 years, 19% were female, and mean eGFR was 80.0 ml/min per 1.73 m2 (54% had Stage 2 CKD and 18% had Stage 3 CKD). Median follow-up was 23 months. The LD-MTX group had less decline in eGFR than placebo (difference in least-squares mean ΔeGFR from baseline to on-treatment visits: 0.93 ml/min per 1.73 m2, 95% confidence interval [95% CI], 0.45 to 1.40, P<0.001). There were 138 (incidence rate [IR], 2.97 per 100 person-years) kidney AEs in the LD-MTX group and 184 (IR, 3.99 per 100 person-years) among placebo (hazard ratio [HR] 0.73, 95% confidence interval [95% CI], 0.59 to 0.91) during safety laboratory monitoring. CONCLUSIONS: These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD at baseline.
BACKGROUND: Low-dose methotrexate (LD-MTX) is contraindicated in advanced CKD, but kidney safety in normal kidney function or mild-to-moderate CKD is less clear. METHODS: We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15-20 mg/week) or placebo. All participants took folic acid 1 mg 6 days/week. Exclusion criteria included systemic rheumatic disease and creatinine clearance <40 ml/min. The least-squares mean ΔeGFR from baseline was calculated at each study visit; the difference in eGFR between LD-MTX and placebo was compared. We used Cox proportional hazard models to compare rates of kidney AEs for LD-MTX versus placebo. RESULTS: A total of 2391 participants were randomized to LD-MTX and 2395 to placebo. At baseline, the mean age was 66 years, 19% were female, and mean eGFR was 80.0 ml/min per 1.73 m2 (54% had Stage 2 CKD and 18% had Stage 3 CKD). Median follow-up was 23 months. The LD-MTX group had less decline in eGFR than placebo (difference in least-squares mean ΔeGFR from baseline to on-treatment visits: 0.93 ml/min per 1.73 m2, 95% confidence interval [95% CI], 0.45 to 1.40, P<0.001). There were 138 (incidence rate [IR], 2.97 per 100 person-years) kidney AEs in the LD-MTX group and 184 (IR, 3.99 per 100 person-years) among placebo (hazard ratio [HR] 0.73, 95% confidence interval [95% CI], 0.59 to 0.91) during safety laboratory monitoring. CONCLUSIONS: These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD at baseline.
Authors: Paul M Ridker; Brendan M Everett; Aruna Pradhan; Jean G MacFadyen; Daniel H Solomon; Elaine Zaharris; Virak Mam; Ahmed Hasan; Yves Rosenberg; Erin Iturriaga; Milan Gupta; Michelle Tsigoulis; Subodh Verma; Michael Clearfield; Peter Libby; Samuel Z Goldhaber; Roger Seagle; Cyril Ofori; Mohammad Saklayen; Samuel Butman; Narendra Singh; Michel Le May; Olivier Bertrand; James Johnston; Nina P Paynter; Robert J Glynn Journal: N Engl J Med Date: 2018-11-10 Impact factor: 91.245
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Authors: Kathleen M M Vanni; Nancy Berliner; Nina P Paynter; Robert J Glynn; Jean MacFadyen; Joshua Colls; Fengxin Lu; Chang Xu; Paul M Ridker; Daniel H Solomon Journal: ACR Open Rheumatol Date: 2020-11-17