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Major Side Effects of Nonsteroidal Anti-Inflammatory Drugs: Gastrointestinal and Cardiovascular Risks of Etodolac and Interaction of NSAIDs with Cardioprotective Effects of Acetylsalicylic Acid.

  • Author / Creator
    Al-qahtani, Zuhair
  • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are administered for their anti-inflammatory, analgesic, and antipyretic properties. Thus, NSAIDs are one of the most commonly prescribed group of medications to relieve pain and inflammation associated with inflammatory conditions such as rheumatoid arthritis. Nevertheless, reports of cardiovascular (CV) adverse events began to emerge since early 2000 and subsequent placebo-controlled studies showed that COX-2 inhibitors like rofecoxib were associated with life threatening CV incidents. However, some meta-analyses suggested that such a risk is not restricted to highly COX 2 inhibitors, but also applies to other NSAIDs. This is while many reports suggest that Acetylsalicylic acid (ASA) reduces such a risk. Etodolac, a generic NSAID, thus cost-effective, with a confirmed efficacy and high tolerability, is a potential alternative to other least cost-effect NSAIDs. Hence, the drug possesses high affinity for COX-2 over COX-1 isoenzyme, it is believed that etodolac demonstrate a safe gastrointestinal (GI) profile than other NSAIDs. However, it has been established that NSAIDs are heterogonous in causing CV incidents, etodolac has not been thoroughly investigated regard its CV toxicity, particularly in presence of covariates such as underlying inflammation conditions or use of ASA. It has been suggested that the concomitant use of some NSAIDs diminishes the extent of platelet aggregation effects of ASA, however, many epidemiological studies suggest that the addition of the latter reduces the CV risk attributed to the use of NSAIDs. We hypothesized that etodolac exposure is not associated with serious GI events compared with other NSAIDs, including COX-2 selective inhibitors, and etodolac use is not associated with increased of CV risk compared with non-users, users of conventional as well as COX-2 selective NSAIDs. Also, we hypothesized that the cardioprotective effects of ASA are reduced upon concomitant administration with other NSAIDs. To test these theories, we carried out comprehensive systematic searches and performed a meta-analysis. We searched various databases up to October 2017 for randomized and non-randomized trials that reporting myocardial/vascular, all-cause mortality and/or GI adverse events after etodolac use. We looked, also, for molecular interaction studies between the drugs and long-term clinical outcomes based on randomized clinical trials and epidemiological observations that reported the effect estimates of CV risks (OR, RR or HR; 95% CI) of the interacting drugs alone or in combinations. Comparisons were made between outcomes after ASA alone, other NSAIDs alone and ASA with naproxen, ibuprofen, celecoxib, meloxicam, diclofenac or rofecoxib. Titles and abstracts of included studies were retrieved and screened independently by two reviewers to identify potentially relevant studies. Additionally, the reference lists were scanned for relevant studies. The combined odds ratio estimates (OR; 95% CI) of GI and CV risks of etodolac were calculated using the random effect meta-analysis model when a significant heterogeneity across included trials is detected, otherwise fixed effect model was performed. Our analyses of published evidence suggest that etodolac demonstrate a significantly lower rate of serious GI adverse events such as ulcers and bleeding compared with other NSAIDs. Furthermore, the drug use was not associated with an increased CV risk compared with non-user or other NSAIDs, such as naproxen and celecoxib. Our results in ASA and other NSAIDs interactions showed conflicting platelet aggregation data for ibuprofen, naproxen and celecoxib. Nevertheless, for naproxen, the interaction at the aggregation level did not amount to a loss of cardioprotective effects of ASA. Similarly, for ibuprofen, the results overwhelmingly suggest no negative clinical CV outcomes following the combination therapy. Meloxicam and rofecoxib neither interacted with ASA at the level of platelet aggregation nor altered clinical outcomes. The clinical outcomes data for celecoxib and diclofenac are in conflict. We concluded that etodolac is well tolerated in terms of GI adverse events and has a safe CV profile. Also, ASA appears to maintain its cardioprotective effect in the presence of naproxen, ibuprofen, meloxicam and rofecoxib. The limited available data suggest that the effect of interaction at the platelet aggregation level may dissipate shortly, or the reduced platelet aggregation yielded by the interaction may be sufficient for cardioprotection. In addition, cardioprotective effect of ASA, despite reduced platelet aggregation caused by other NSAIDs, may be through its involvement in other mechanisms such as the renin angiotensin system and/or metabolism of arachidonic acid to biologically active compounds mediated by CYP450.

  • Subjects / Keywords
  • Graduation date
    Fall 2018
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3NK36M85
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.