Effect of Cyclooxygenase-2 Inhibition on Renal Function in Elderly Persons Receiving a Low-Salt Diet

A Randomized, Controlled Trial

  1. Suzanne K. Swan, MD;
  2. David W. Rudy, MD;
  3. Kenneth C. Lasseter, MD;
  4. Charles F. Ryan, PhD;
  5. Kristin L. Buechel, PA-C;
  6. Laurence J. Lambrecht, PharmD;
  7. Manuel B. Pinto, BE;
  8. Stacy C. Dilzer, RN;
  9. Olga Obrda, BS;
  10. Kimberly J. Sundblad, BSN;
  11. Carol P. Gumbs, BA;
  12. David L. Ebel, BS, RPh;
  13. Hui Quan, PhD;
  14. Patrick J. Larson, MS;
  15. Jules I. Schwartz, PharmD, MPH;
  16. Thomas A. Musliner, MD;
  17. Barry J. Gertz, MD, PhD;
  18. D. Craig Brater, MD; and
  19. Siu-Long Yao, MD
  1. From Hennepin County Medical Center and Total Renal Research, Inc., Minneapolis, Minnesota; Indiana University, Indianapolis, Indiana; Clinical Pharmacology Associates, Miami, Florida; PPD, Austin, Texas; and Merck Research Laboratories, Rahway, New Jersey.

    Abstract

    Background: Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects.

    Objective: To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients.

    Design: A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study.

    Setting: Clinical research units.

    Patients: 75 patients 60 to 80 years of age.

    Intervention: In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet.

    Measurements: Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values.

    Results: Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 mL/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced.

    Conclusions: The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.

    Article and Author Information

    • Disclosure: Ms. Gumbs, Mr. Ebel, Dr. Quan, Mr. Larson, Dr. Schwartz, Dr. Musliner, Dr. Gertz, and Dr. Yao are employees of Merck and Co., Inc. Dr. Brater has served as a consultant to Merck and Co., Inc., on cyclooxygenase-2 inhibitors and renal function. Dr. Brater's role involved assistance with the design of the protocols reported in this article, assessment and interpretation of the study results reported herein, and assessment of the Merck database on rofecoxib and renal function.

    • Acknowledgments: The authors thank Elaine Gould for expert administrative assistance.

    • Grant Support: By Merck and Co., Inc.

    • Requests for Single Reprints: Siu-Long Yao, MD, Merck Research Laboratories, RY33-640, 126 East Lincoln Avenue, Rahway, NJ 07065-0900; e-mail, siulong_yao{at}merck.com.

    • Requests To Purchase Bulk Reprints (minimum, 100 copies): the Reprints Coordinator; phone, 215-351-2657; e-mail, reprints{at}mail.acponline.org.

    • Current Author Addresses: Dr. Swan: Division of Nephrology, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415.

    • Dr. Rudy: University of Kentucky, K512 Kentucky Clinic, Lexington, KY 40536-0284.

    • Dr. Lasseter, Mr. Pinto, and Ms. Dilzer: Clinical Pharmacology Associates, 2060 NW 22nd Avenue, Miami, FL 33142.

    • Dr. Ryan: 11849 Rim Rock Trail, Austin, TX 78737.

    • Ms. Buechel and Dr. Lambrecht: Total Renal Research, Inc., 914 South 8th Street, Minneapolis, MN 55404-1249.

    • Ms. Obrda: PPD Development, 706A Ben White Boulevard, Austin, TX 78704-7016.

    • Ms. Sundblad: Department of Psychiatry, Indiana University School of Medicine, 1701 North Capitol Avenue, BCC-C100, Indianapolis, IN 46202.

    • Ms. Gumbs: Merck Research Laboratories, 126 East Lincoln Avenue (RY33-660), Rahway, NJ 07065-0980.

    • Mr. Ebel and Dr. Yao: Merck Research Laboratories, 126 East Lincoln Avenue (RY33-640), Rahway, NJ 07065-0980.

    • Dr. Quan and Mr. Larson: Merck Research Laboratories, 126 East Lincoln Avenue (RY33-404), Rahway, NJ 07065-0980.

    • Dr. Schwartz: Merck Research Laboratories, 126 East Lincoln Avenue (RY33-632), Rahway, NJ 07065-0980.

    • Dr. Musliner: Merck Research Laboratories, 126 East Lincoln Avenue (RY32-557), Rahway, NJ 07065-0980.

    • Dr. Gertz: Merck Research Laboratories, 126 East Lincoln Avenue (RY33-600), Rahway, NJ 07065-0980.

    • Dr. Brater: Department of Medicine, Indiana University School of Medicine, 545 Barnhill Drive, Emerson Hall, Room 317, Indianapolis, IN 46202-5124.

    • Author Contributions: Conception and design: S.K. Swan, D.W. Rudy, L.J. Lambrecht, K.J. Sundblad, H. Quan, P.J. Larson, T.A. Musliner, B.J. Gertz, D.C. Brater, S.-L. Yao.

    • Analysis and interpretation of the data: S.K. Swan, K.C. Lasseter, C.F. Ryan, K.L. Buechel, L.J. Lambrecht, M.B. Pinto, S.C. Dilzer, O. Obrda, C.P. Gumbs, D.L. Ebel, H. Quan, P.J. Larson, J.I. Schwartz, B.J. Gertz, D.C. Brater, S.-L. Yao.

    • Drafting of the article: S.K. Swan, D.C. Brater, S.-L. Yao.

    • Critical revision of the article for important intellectual content: S.K. Swan, D.W. Rudy, K.C. Lasseter, C.F. Ryan, K.L. Buechel, L.J. Lambrecht, M.B. Pinto, S.C. Dilzer, O. Obrda, K.J. Sundblad, C.P. Gumbs, D.L. Ebel, H. Quan, P.J. Larson, J.I. Schwartz, T.A. Musliner, B.J. Gertz, D.C. Brater, S.-L. Yao.

    • Final approval of the article: S.K. Swan, D.W. Rudy, K.C. Lasseter, C.F. Ryan, K.L. Buechel, L.J. Lambrecht, M.B. Pinto, S.C. Dilzer, O. Obrda, K.J. Sundblad, C.P. Gumbs, D.L. Ebel, H. Quan, P.J. Larson, J.I. Schwartz, T.A. Musliner, B.J. Gertz, D.C. Brater, S.-L. Yao.

    • Provision of study materials or patients: S.K. Swan, D.W. Rudy, K.C. Lasseter, C.F. Ryan, L.J. Lambrecht, O. Obrda, K.J. Sundblad, D.C. Brater.

    • Statistical expertise: H. Quan, P.J. Larson, S.-L. Yao.

    • Obtaining of funding: D.C. Brater.

    • Administrative, technical, or logistic support: K.C. Lasseter, C.F. Ryan, K.L. Buechel, O. Obrda, C.P. Gumbs, D.L. Ebel, D.C. Brater, S.-L. Yao.

    • Collection and assembly of data: S.K. Swan, C.F. Ryan, K.L. Buechel, K.J. Sundblad, H. Quan, P.J. Larson, J.I. Schwartz, D.C. Brater, S.-L. Yao.

    Summary for Patients

    • Summaries for Patients:Effects of COX-2 Inhibitors, a New Class of Anti-Inflammatory Drugs, on Kidney Function in Older Patients Ann Intern Med July 4, 2000 133:1
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    1. Ann Intern Med July 4, 2000 vol. 133 no. 1 1-9
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