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Original Research |

New Fibrate Use and Acute Renal Outcomes in Elderly Adults: A Population-Based Study

Ying Y. Zhao, MD; Matthew A. Weir, MD; Michael Manno, MSc; Peter Cordy, MD; Tara Gomes, MHSc; Daniel G. Hackam, MD, PhD; David N. Juurlink, MD, PhD; Muhammad Mamdani, PharmD, MPH; Louise Moist, MD, MSc; Chirag R. Parikh, MD, PhD; J. Michael Paterson, MSc; Ron Wald, MD, MPH; Zhan Yao, MSc; and Amit X. Garg, MD, PhD
[+] Article and Author Information

From the Yale University School of Medicine, New Haven, Connecticut; University of Western Ontario, London, Ontario, Canada; Institute for Clinical Evaluative Sciences, University of Toronto, and Keenan Research Centre in the Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada; and McMaster University, Hamilton, Ontario, Canada.

Disclaimer: Drs. Zhao and Garg, Mr. Manno, and Ms. Yao had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgment: The authors thank Dr. Hertzel C. Gerstein for his advice on this manuscript as well as Brogan Inc., Ottawa, for use of its Drug Product and Therapeutic Class Database.

Grant Support: This project was conducted at the Institute for Clinical Evaluative Sciences and was supported by a grant from the Ontario Ministry of Health and Long-Term Care Drug Innovation Fund. The Institute for Clinical Evaluative Sciences is funded by an annual grant from the Ministry of Health and Long-Term Care. Dr. Weir was supported by the Clinician Investigator Program at the University of Western Ontario. He also receives funding from the Ministry of Health and Long-Term Care. Dr. Hackam was supported by a Canadian Institutes of Health Research New Investigator Award. Dr. Wald was supported by the Randomized Controlled Trial Mentoring Program of Canadian Institutes of Health Research. Dr. Garg was supported by a Canadian Institutes of Health Research Clinician-Scientist Award.

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1981.

Reproducible Research Statement: Because of legal and privacy requirements, all primary data are contained within the Institute for Clinical Evaluative Sciences. The data creation plan and analytic protocol can be shared with approved individuals through written agreements with the corresponding author.

Corresponding Author: Amit X. Garg, MD, PhD, Room ELL-101, Westminster, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada; e-mail, mailto:amit.garg@lhsc.on.ca.

Current Author Addresses: Dr. Zhao: 4624 Tournament Court, Windsor, Ontario N9G 2P8, Canada.

Dr. Weir: 800 Commissioners Road East, Room ELL-121, London, Ontario N6A 5W9, Canada.

Mr. Manno, Ms. Gomes, Dr. Juurlink, Mr. Paterson, and Ms. Yao: 2075 Bayview Avenue, G-106, Toronto, Ontario M4N 3M5, Canada.

Dr. Cordy: 248 Hunt Club Drive, London, Ontario N6H 3Z1, Canada.

Dr. Hackam: 1400 Western Road, London, Ontario N6G 2V2, Canada.

Dr. Mamdani: 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.

Dr. Moist: 800 Commissioners Road East, Room A2-338, London, Ontario N6A 5W9, Canada.

Dr. Parikh: 950 Campbell Avenue, Mail Code 151B, West Haven, CT 06516.

Dr. Wald: 61 Queen Street East, Toronto, Ontario M5C 2T2, Canada.

Dr. Garg: 800 Commissioners Road East, Room ELL-101, London, Ontario N6A 5W9, Canada.

Author Contributions: Conception and design: Y.Y. Zhao, P. Cordy, T. Gomes, D.G. Hackam, D.N. Juurlink, M. Mamdani, L. Moist, C.R. Parikh, J.M. Paterson, R. Wald, A.X. Garg.

Analysis and interpretation of the data: Y.Y. Zhao, M.A. Weir, M. Manno, P. Cordy, T. Gomes, D.G. Hackam, D.N. Juurlink, M. Mamdani, L. Moist, C.R. Parikh, J.M. Paterson, R. Wald, Z. Yao, A.X. Garg.

Drafting of the article: Y.Y. Zhao, M.A. Weir, A.X. Garg.

Critical revision of the article for important intellectual content: Y.Y. Zhao, M.A. Weir, P. Cordy, T. Gomes, D.G. Hackam, D.N. Juurlink, M. Mamdani, L. Moist, C.R. Parikh, J.M. Paterson, R. Wald, Z. Yao, A.X. Garg.

Final approval of the article: Y.Y. Zhao, M.A. Weir, P. Cordy, T. Gomes, D.G. Hackam, D.N. Juurlink, M. Mamdani, L. Moist, C.R. Parikh, J.M. Paterson, R. Wald, Z. Yao, A.X. Garg.

Provision of study materials or patients: A.X. Garg.

Statistical expertise: M. Manno, T. Gomes, D.G. Hackam, D.N. Juurlink, M. Mamdani, Z. Yao, A.X. Garg.

Obtaining of funding: M.A. Weir, D.N. Juurlink, M. Mamdani, J.M. Paterson, A.X. Garg.

Administrative, technical, or logistic support: Y.Y. Zhao, T. Gomes, A.X. Garg.

Collection and assembly of data: Y.Y. Zhao, M.A. Weir, M. Manno, T. Gomes, Z. Yao, A.X. Garg.


Ann Intern Med. 2012;156(8):560-569. doi:10.7326/0003-4819-156-8-201204170-00401
Text Size: A A A

Background: Fibric acid derivatives (fibrates) have been shown to increase serum creatinine level in randomized trials.

Objective: To assess renal outcomes in elderly adults within 90 days of a new fibrate prescription.

Design: Population-based cohort study.

Setting: Ontario, Canada.

Patients: Patients aged 66 years or older with a new outpatient prescription for a fibrate or ezetimibe (comparator drug) between January 2004 and December 2008.

Measurements: Hospitalization for an increase in serum creatinine level (primary outcome) and consultation with a nephrologist, receipt of dialysis for severe acute kidney injury, all-cause mortality, and increases in serum creatinine level (secondary outcomes). All outcomes were assessed within 90 days of a new prescription for ezetimibe or a fibrate.

Results: Compared with ezetimibe users (n = 61 831), fibrate users (n = 19 072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease.

Limitations: Because hospitalizations for an increase in serum creatinine level were underestimated, absolute differences may be misleading. Most patients (91%) were prescribed fenofibrate. Serum creatinine levels were measured as part of routine care and were not available for everyone or at predefined times.

Conclusion: New fibrate use in elderly adults was associated with an increase in serum creatinine level and a small 90-day absolute increase in hospitalizations and nephrologist consultations. There was no detectable effect on dialysis for severe acute kidney injury or on mortality. The mechanism and clinical significance of the increase in serum creatinine level with fibrates is unclear.

Primary Funding Source: Ontario Ministry of Health and Long-Term Care Drug Innovation Fund.

Figures

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Appendix Figure 1.

Study flow diagram.

Two or more of the exclusion criteria may have applied to certain patients.

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Figure 1.

Acute (90-day) changes in serum creatinine level after fibrate and ezetimibe use.

IQR = interquartile range.

* Comparison of changes in serum creatinine level between fibrate and ezetimibe users by using the Wilcoxon rank-sum test.

† Figure excludes an outlier with baseline estimated glomerular filtration rate below 60 mL/min per 1.73 m2 and increase in serum creatinine level of 607 µmol/L (6.9 mg/dL) after fibrate use.

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Figure 2.

Modification of the association between fibrate use and hospitalization for an increase in serum creatinine level, by diabetes, statin use, and CKD.

The number of events (and the proportion of patients who had an event) was assessed by diagnostic codes. This underestimated the true event rate because codes are specific but not sensitive. We adjusted for age (per year); sex; accrual date (per year); socioeconomic status (per quintile of household income); the number of unique drug products in the 12 mo before accrual (per drug); use of nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, calcium-channel blockers, statins, or diuretics; and evidence of coronary artery disease, diabetes mellitus, hypertension, peripheral vascular disease, congestive heart failure, or CKD (using records from the 5 y before the index date). CKD = chronic kidney disease.

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Appendix Figure 2.

Comparison of change in serum creatinine level among fibrate users and ezetimibe users, by baseline eGFR.

eGFR = estimated glomerular filtration rate.

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Appendix Figure 3.

90-day changes in serum creatinine level after fibrate use, by baseline eGFR.

eGFR = estimated glomerular filtration rate.

* Comparison of changes in serum creatinine level between those with eGFR 60 mL/min per 1.73 m2 or higher and those with eGFR below 60 mL/min per 1.73 m2 by using the Wilcoxon rank-sum test.

† Figure excludes an outlier with baseline eGFR below 60 mL/min per 1.73 m2 and increase in serum creatinine level of 607 µmol/L (6.9 mg/dL) after fibrate use.

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