Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies

doi:10.1016/j.ejim.2015.03.008

European Journal of Internal Medicine

Volume 26, Issue 4, May 2015, Pages 285-291

https://doi.org/10.1016/j.ejim.2015.03.008 Get rights and content

Highlights

•
Significant risk of AKI was observed among most of the studied NSAIDs.
•
Risks of individual NSAIDs were not significantly different from each other.
•
Risk of COX-2 inhibitors did not reach a statistical significance.

Abstract

Background

The association between acute kidney injury (AKI) and use of non-steroidal anti-inflammatory drugs (NSAIDs) is well established. However, little is known about the comparative risk of individual NSAIDs, including specific COX-2 inhibitors.

Methods

We conducted a systematic review and meta-analysis of cohort studies that reported relative risk, hazard ratio or standardized incidence ratio with 95% confidence comparing AKI risk in NSAID users versus non-users. Pooled risk ratios and 95% confidence intervals for individual NSAIDs were calculated using random-effect, generic inverse variance methods.

Results

Five studies were identified and included in our data analysis. Pooled risk ratios were calculated for seven traditional NSAIDs and two specific COX-2 inhibitors, including indomethacin, piroxicam, ibuprofen, naproxen, sulindac, diclofenac, meloxicam, rofecoxib and celecoxib that were evaluated in at least two studies. Our meta-analysis was able to demonstrate a statistically significant elevated AKI risk among most of the included traditional NSAIDs. The pooled risk ratios were fairly consistent among individual traditional NSAIDs, ranging from 1.58 to 2.11. Differences between pooled risk ratios did not reach statistical significance (p ≥ 0.19 for each comparison). Elevated AKI risk was also observed in diclofenac, meloxicam, rofecoxib and celecoxib users, although did not achieve a statistical significance.

Conclusion

A statistically significant elevated AKI risk among traditional NSAID users has been demonstrated in this meta-analysis. The pooled risk ratios among individual traditional NSAIDs were not significantly different. The pooled risk ratios of specific COX-2 inhibitors and the two traditional NSAIDs with the most COX-2 selectivity (diclofenac and meloxicam) were also comparable with other traditional NSAIDs even though they did not achieve a statistical significance.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of medications in the United States [1] despite their several notorious adverse effects, particularly gastrointestinal (GI) bleeding and renal dysfunction [2], [3]. NSAIDs work by inhibiting the cyclooxygenase (COX) enzyme which has two isoforms, COX-1 and COX-2. Traditional NSAIDs inhibit both isoforms while the newer specific COX-2 inhibitors have a substantially higher specificity for the COX-2 isoform, thus preserving the anti-inflammatory property of COX-2 inhibition while theoretically reducing the adverse effect related to inhibition to the COX-1 isoform [2]. A superior GI safety profile of specific COX-2 inhibitors has been demonstrated in several randomized controlled trials and epidemiological studies [4], [5], [6], [7] though this benefit is offset by the increased risk of serious cardiovascular events [8], [9].

Acute kidney injury (AKI) associated with the use of NSAIDs has been well-documented by several population-based studies as well, with the relative risks compared with non-user ranging from 1.6 to 2.2 [10], [11], [12]. However, little is known about the risk of individual NSAIDs, including specific COX-2 inhibitors. Further data are needed to quantify the risk of AKI associated with individual NSAIDs to help physicians in selecting the most appropriate treatment for individual patients. Thus, we conducted this systematic review and meta-analysis of observational studies that compared the risk of AKI in NSAID users versus non-users to provide pooled risk ratios for AKI associated with use of each NSAID.

Section snippets

Search strategy

Two investigators (P.U. and W.C.) independently searched published studies indexed in Medline, EMBASE and Cochrane databases from inception to September 2014. The search terms were compiled from the terms for AKI, the names of individual drugs, the therapeutic class and the mode of action in conjunction with the terms for observational studies that were suggested by Furlan et al. [13]. The detailed search strategy is provided as Supplementary material 1. A manual search of references of

Results

Our search strategy yielded 2201 potentially relevant studies (495 studies from Medline, 1706 studies from EMBASE and none from Cochrane library), including 301 duplicates. 1810 studies were excluded based on the review of titles and abstracts, leaving ninety studies for full-length article review. Fifty-two studies were excluded since they were not observational studies while twenty were excluded as they were descriptive studies without a control group. Eight studies reported the overall risk

Discussion

To the best of our knowledge, this is the first meta-analysis of observational studies that compares the risk of AKI among individual NSAIDs. We were able to estimate the risk for most of the commonly used NSAIDs in the USA.

Our study was able to demonstrate a statistically significant elevated AKI risk among most of the included traditional NSAIDs. The highest risk ratio was observed among indomethacin users while the lowest risk was found in subjects who used sulindac. However, as mentioned

Conclusion

In conclusion, a statistically significant elevated AKI risk among traditional NSAID users has been demonstrated in this meta-analysis. The pooled risk ratios were fairly consistent among individual traditional NSAIDs, ranging from 1.58 to 2.11. These pooled risk ratios were not significantly different from each other. The pooled risk ratios of specific COX-2 inhibitor and the two traditional NSAIDs with the most COX-2 selectivity (diclofenac and meloxicam) were comparable to other traditional

Conflicts of interest

The authors have declared no conflicts of interest. The results presented in this paper have not been published previously in whole or part.

Funding

None.

Acknowledgments

Patompong Ungprasert: study design, data search and collection, statistical analysis, and writing the manuscript.

Wisit Cheungpasitporn: data search and collection and writing the manuscript.

Cynthia S. Crowson: statistical analysis and revising the manuscript.

Eric L. Matteson: study design and revising the manuscript.

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Original ArticleIndividual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies

Highlights

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Search strategy

Results

Discussion

Conclusion

Conflicts of interest

Funding

Acknowledgments

J Clin Epidemiol

Control Clin Trials

J Clin Epidemiol

Am J Kidney Dis

Am J Med

Frequency of use of acetaminophen, nonsteroidal anti-inflammatory drugs, and aspirin in US women

Pharmacoepidemiol Drug Saf

Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications

J Pharm Sci

What is the “safest” non-steroidal anti-inflammatory drugs?

Am Med J

Observational study of upper gastrointestinal haemorrhage in elderly patients given selective cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs

BMJ

Celecoxib versus diclofenac in the management of osteoarthritis of the knee

Scand J Rheumatol

Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo

J Rheumatol

Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study

JAMA

Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial

N Engl J Med

Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2

JAMA

Non-steroidal anti-inflammatory drugs and acute renal disease: a case control study

Pharmacoepidemiol Drug Saf

Non-steroidal anti-inflammatory drugs and hospitalization for acute renal failure

QJM

Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury

Pharmacoepidemiol Drug Saf

Original Article
Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies