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Background:
Systematic Review

Appropriate Prescription of Non-Steroidal Anti-Inflammatory Drugs in Geriatric Patients—A Systematic Review

by
Carolina Costa
1,2,
Diana Soares
1,
Ana Borges
3,
Ana Gonçalves
4,
José Paulo Andrade
2,5 and
Hugo Ribeiro
2,6,7,8,*
1
Health Family Unit Barão do Corvo, Local Health Unit Gaia and Espinho, 4434-502 Vila Nova de Gaia, Portugal
2
Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
3
Health Family Unit Covelo, Local Health Unit S. João, 4200-319 Porto, Portugal
4
Health Family Unit Santo André de Canidelo, Local Health Unit Gaia and Espinho, 4434-502 Vila Nova de Gaia, Portugal
5
RISE@Health, 4200-319 Porto, Portugal
6
Community Support Team in Palliative Care Gaia, Local Health Unit Gaia and Espinho, 4434-502 Vila Nova de Gaia, Portugal
7
Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
8
Center for Innovative Biomedicine and Biotechnology—CIMAGO, 3000-548 Coimbra, Portugal
*
Author to whom correspondence should be addressed.
BioChem 2024, 4(4), 300-312; https://doi.org/10.3390/biochem4040015
Submission received: 28 August 2024 / Revised: 24 September 2024 / Accepted: 4 October 2024 / Published: 11 October 2024
(This article belongs to the Special Issue Feature Papers in BioChem)
Browse Figure
Versions Notes

Abstract

:
The elderly population is growing worldwide. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed, but their adverse events can pose significant risks. Different NSAID molecules can exhibit varying risk profiles. This study aims to evaluate the cardiovascular, gastrointestinal, and renal safety profiles of ibuprofen, naproxen, acemetacin, diclofenac, celecoxib, and etoricoxib in elderly patients. A comprehensive literature search was conducted in PubMed and Cochrane Library. For the selection of articles, we used Medical Subject Headings (MeSH) terms “aged” sequentially and together with “ibuprofen”, “diclofenac”, “naproxen”, “acemetacin”, “celecoxib”, and “etoricoxib”. To assess the quality and interest of the articles, four independent reviewers screened titles and abstracts to identify potentially eligible studies. Strength of Recommendation Taxonomy (SORT) was used to rate the quality of individual studies and to establish recommendation strengths (RS). From 2086 articles identified, 39 studies met the inclusion criteria. Twenty studies analyzed cardiovascular safety, fourteen gastrointestinal safety, and four renal safety. When CV risk is the main concern celecoxib or naproxen are a good first choice (RS B). In high GI risk addition of PPI to naproxen or celecoxib use should be recommended (RS A). When renal function is on focus, celecoxib remains as first line of therapy (RS A). Diclofenac in the geriatric population should be avoided (RS B). Celecoxib is a good choice for elderly patients for whom it is difficult to direct pain treatment based on a single known risk factor (RS B).

1. Introduction

Over the last decades, population aging has become evident, with a continuous increase in the elderly population worldwide [1]. Europeans are living longer than ever before. EU-27’s median age is projected to increase by 4.5 years over the next three decades, reaching 48.2 years by 2050 [2]. Portugal shows the same tendency, with the population aged 65 years or older representing 24% of the national population in 2023 [3].
Aging is a normal process, during which humans experience a decline in organic, functional, and social status. This leads to enhanced vulnerability and increased risk of various aging-related diseases that become more disabling, chronic, degenerative, and are frequently associated with pain [4,5]. Geriatric patients present characteristics make them twice more likely to have adverse drug events [6]. This should be taken into account when prescribing different drugs [7].
Chronic pain is one of the most common conditions encountered in clinical practice, particularly in elderly patients, and is associated with substantial impairment, depression, anxiety, and isolation [8]. As stated in the consensus-based definition by the International Association for Hospice & Palliative Care, palliative care can be defined as “active holistic care of individuals with serious health-related suffering due to severe illness, with aims to improve the quality of life of patients, their families and their caregivers”. Many age-related diseases lack curative treatments. Effective pain management in the elderly is critical to improving these patients’ quality of life, functional capacity, and performance status [9]. As such, pain treatment is a palliative measure.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for their analgesic, anti-inflammatory, and antipyretic properties. NSAIDs exert their effects primarily through inhibiting COX-1 and COX-2 enzymes, which play a crucial role in synthesizing prostaglandins and thromboxane. With pain and inflammation being common in older adults, these drugs are frequently used and difficult to manage, attending to the various morbidities that are common in this population [10]. In fact, NSAIDs are one of the most commonly responsible medicines to cause adverse drug events, accounting for approximately 11% of the preventable drug-related hospital admissions [6].
Side effects of NSAIDs are known and described in the literature, namely significant risks concerning cardiovascular (CV), gastrointestinal (GI), and renal impairment [11]. Nevertheless, different types of molecules are available, with pharmacokinetic characteristics that can make them more or less suitable for each situation [5].
Naproxen is a reversible inhibitor of COX isozymes and has a higher potency for COX-1 than COX-2. Ibuprofen inhibits COX-1 and COX-2 with comparable potency while diclofenac and celecoxib have intermediate COX-2 selectivity. Etoricoxib is considered a highly selective COX-2 inhibitor due to its greater potential for sparing COX-1 activity [12]. These affinity differences impact their potential for adverse effects: COX-1 is constitutively present in the gastroduodenal mucosa and mediates its cytoprotection. Therefore, COX-1 inhibition entails greater risks of adverse GI effects. COX-2 plays an important role in the regulation of renal function, is inducible, and is primarily involved in the inflammatory response, being that its inhibition is associated with CV toxicity [13].
Naproxen, ibuprofen and diclofenac are three of the most used NSAIDs worldwide [14]. According to INFARMED—National Authority for Medicines and Health Products—celecoxib and etoricoxib are the selective cyclooxygenase-2 (COX-2) inhibitors available in oral formulation in Portugal. Acemetacin showed promising results in terms of safety profile due to its phase 2 hepatic biotransformation and less renal elimination [5].
Portuguese national clinical guidelines regarding the use of NSAIDs and COX-2 inhibitors identify naproxen as the NSAID of choice for patients with a high CV risk or patients on secondary prevention. Selective COX-2 inhibitors are described as those with the most negligible GI impact but greater CV risk. However, this document was last updated in 2013 [15]. Both last recommendations from the International Association on the Study of Pain (IASP) and the United Kingdom National Health System (NHS) suggest starting with naproxen or ibuprofen plus proton pump inhibitor (PPI) in patients with CV risk [16,17]. Nevertheless, a recent study suggests that the risk of GI, CV, and renal adverse drug reactions is significantly reduced with the use of selective COX-2 inhibitors compared to non-selective NSAIDs [18].
Understanding the safety profiles of these NSAIDs is crucial for guiding clinical decision-making in the elderly, where balancing therapeutic benefits with potential risks is paramount.
Bearing this in mind, the main purpose of this work is to perceive the CV, GI, and renal safety profiles of ibuprofen, naproxen, acemetacin, diclofenac, celecoxib, and etoricoxib in elderly patients. Therefore, we performed a systematic review aimed at systematizing the available data about the safety profiles of these drugs to provide clinicians with evidence-based information regarding the preferred NSAID options for this population. The authors intend to contribute to a more informed, patient-adapted choice, while minimizing potential adverse events and increasing the efficiency of care.

2. Methods

A comprehensive literature search was conducted in PubMed and the Cochrane Library. For the selection of articles, we used Medical Subject Headings (MeSH) terms “aged” (A person 65 years of age or older) sequentially and together with “ibuprofen”, “diclofenac”, “naproxen”, “acemetacin”, “celecoxib”, and “etoricoxib”, published from January 2003 to January 2023.
Studies were included if they met the following criteria: participants were individuals aged 65 years or older, or the study included a subgroup analysis focusing on the elderly. Compared with non-use or placebo, the interventions involved using ibuprofen, naproxen, acemetacin, diclofenac, celecoxib, or etoricoxib. The outcomes assessed, either as primary or secondary, were renal, GI, and CV adverse events. We included meta-analyses, systematic reviews, and original research articles reporting observational studies or randomized controlled trials (RCTs).
Exclusion criteria were applied to studies in languages other than Portuguese or English, studies focusing on pain in a surgical context, and studies using the selected NSAIDs administered by routes other than oral.
To assess the quality and interest of the articles, four independent reviewers screened titles and abstracts to identify potentially eligible studies. Full-text articles were retrieved and assessed for eligibility based on the inclusion criteria and contributions with relevant information to the aim of this review.
Strength of Recommendation Taxonomy (SORT) was used to rate the quality of individual studies and establish recommendation strengths [19]. In line with the defined inclusion criteria on study design, only studies classified as level one and two were selected. Level of evidence one means the study is a meta-analysis or a systematic review with consistent findings or a high-quality randomized control trial. Level of evidence two means the study is a meta-analysis or a systematic review of lower quality or clinical trials with inconsistent findings, cohort study, or case-control study. Regarding the recommendation strength, C is assigned to expert opinions, bench research, a consensus guideline, clinical experience, usual practice, or a case series study; A is assigned to Cochrane reviews with a clear recommendation, a clinical evidence rating of beneficial, consistent findings from at least two good-quality randomized control trials or two good-quality diagnostic cohort studies, or a systematic review/meta-analysis of same [19].
This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for transparent reporting of systematic reviews [20].

3. Results

Overall, 3423 abstracts were obtained, 2308 from PubMed and 1115 from Cochrane Library. After removing duplicates, a total of 2086 studies were screened. Of those, 1513 studies were excluded based on titles not meeting inclusion criteria. Of 469 abstracts, 233 were selected for full-length reading based on the potentially relevant results listed in the abstract. One was not retrieved due to incapacity of access.
As shown in Figure 1, after full reading, a final group of 39 studies was reached and those were included in this systematic review. Selection was based on a clear focus on our study population, a comparison between drugs of interest or placebo, and with main outcomes being CV, GI or renal safety.
Twenty studies analyzed CV safety (Table 1). One study considered CV and GI safety simultaneously and fourteen considered GI safety only (Table 2). The remaining four studies investigated the renal safety of the NSAIDs of interest (Table 3). There were no studies about acemetacin safety that fulfilled the inclusion criteria.
Some of the final selected articles provide data supporting a higher CV and GI risk in the elderly population. In the MEDAL program study, patients were randomized to etoricoxib 60 or 90 mg or diclofenac 150 mg once daily [21]. In two different analyses of the MEDAL program, Krum et al. aimed to assess the impact of these drugs on the risk of congestive heart failure (CHF) and their hypertensive effects. Despite the used drugs, an age of at least 65 was strongly associated with CHF hospitalization and increased blood pressure [22,23].
In a cohort of patients taking either celecoxib or naproxen, the strongest predictor of thrombotic cardiac events was an age of 65 years or older [24]. The same age group in an RCT of patients taking celecoxib 200–400 mg bid showed higher absolute risk for CV events [25].
Laine L. et al. identified age ≥ 65 years as a significant predictor of discontinuation of diclofenac or etoricoxib due to GI side effects [26]. Chan FK. et al. and Lai KC. et al. found age as an independent risk factor for ulcer recurrence [27,28]. On the other hand, Kyeremateng K. et al. and Hsiang KW. et al. did not find any difference in the overall rate or type of adverse events between elderly and younger participants, did not find age > 70 years to be a risk factor for symptomatic ulcers in patients taking the studied NSAIDs [29,30].
In terms of CV safety, in the Solomon DH et al. study, naproxen showed a protective effect against CV events, when compared to diclofenac and ibuprofen [31]. Schneeweiss S. et al.’s results suggest an equivalent risk for acute myocardial infarction (AMI) between ibuprofen and celecoxib, but a more favorable CV safety profile of naproxen compared to celecoxib [32]. On the other hand, Lévesque LE et al. found a neutral effect of naproxen on CV risk, same as celecoxib [33]. Likewise, Hudson M. et al. found no statistically significant differences between celecoxib, naproxen, and ibuprofen in the risk of CHF [34], and Mamdani M. et al. found no statistically significant differences between celecoxib and naproxen for AMI [35].
In turn, diclofenac demonstrated an increased risk of major adverse CV events when compared to ibuprofen, naproxen, and non-use [36]. It also showed a higher risk for thromboembolic events, namely stroke and venous thromboembolism [37,38].
CV risks of etoricoxib are comparable to those of diclofenac [21].
Evaluating GI safety, according to Schneeweiss S. et al. celecoxib produces a significant reduction in GI complications compared with naproxen, diclofenac, and ibuprofen [32]. In spite of that, celecoxib, as all NSAIDs, does not appear to be free of risks, showing a modest but still statistically significant risk of upper GI events as compared with non-use as stated in Chang CH et al.’s work [39]. In RCTs, diclofenac showed a worst GI safety profile when compared to celecoxib, even when added to PPI [40]. Etoricoxib may offer a GI safety advantage over diclofenac [21].
Concerning renal safety, a single 50 mg daily dose of diclofenac demonstrates a significant reduction in glomerular filtration rate, urine flow, and excretion rates of sodium and potassium. Pre-treatment with diuretics and angiotensin-converting enzyme inhibitors (drugs frequently used by elderly patients) exacerbated the renal impairment caused by diclofenac [41]. Higher doses of NSAIDs were associated with a higher risk of acute kidney failure (AKF). Both celecoxib and naproxen show a dose-dependent increase in the risk of AKF. However, the risk increase is more pronounced with higher doses of naproxen [42].
Table 1. Main characteristics of the systemically reviewed studies on CV safety of NSAIDs on a geriatric population.
Table 1. Main characteristics of the systemically reviewed studies on CV safety of NSAIDs on a geriatric population.
ReferencesYearStudy DesignPopulation
n (%)		Studied Drug of Interest (Dosage)Main Findings in Population of InterestSORT Evidence Level
Cannon CP et al. [21]2006RCTOverall = 34,701
≥65 y = 14,397 (41.5%)		Diclofenac (150 mg/day)
Etoricoxib (60 mg or 90 mg/day)		For elderly patients, the study suggests that the CV risk of etoricoxib is comparable to diclofenac.1
Bertagnolli MM et al. [25]2009RCTOverall = 2035
≥65 y = ND		Celecoxib (200 mg 2id or 400 mg bid)Patients aged 65 or older showed higher absolute risk for CV events. 1
Krum H, et al. [22]2009RCTOverall = 34,695
≥65 y = 14,386 (41.5%)		Diclofenac (150 mg id)
Etoricoxib (60 or 90 mg id)		Older age increased the risk of CHF hospitalization.1
Krum H, et al. [23]2009RCTOverall = 23,498
≥65 y = 9998 (42.5%)		Diclofenac (150 mg id)
Etoricoxib (60 or 90 mg id)		Age at least 65 years was strongly associated with increased BP.1
Mamdani M et al. [35]2003Retrospective Cohort StudyOverall = 593,808
≥65 y = 593,808 (100%)		Celecoxib (ND)
Naproxen (ND)		No significant differences in AMI rates were observed between celecoxib and naproxen. The findings do not support a short-term reduced risk of AMI with naproxen.2
Lévesque LE et al. [33]2005Retrospective Cohort StudyOverall = 113,927
≥65 y = 113,927 (100%)		Celecoxib (≤200 mg or >200 mg/day)
Naproxen (ND)		The study found no increased risk among users of celecoxib, regardless of the dose prescribed. Naproxen was not associated with an increased CV risk or benefit.2
Hudson M et al. [43]2005Retrospective Cohort StudyOverall = 18,503
≥65 y = 18,503 (100%)		Ibuprofen (ND)
Naproxen (ND)		Trend toward an increase in the rate of recurrent AMI with longer duration of ibuprofen exposure. Trend toward a lower rate of recurrent AMI in patients taking naproxen and AAS compared to AAS alone.2
Solomon DH, et al. [31]2006Longitudinal CohortStudyOverall = 74,838
≥65 y = 74,838
(100%)		Celecoxib
low ≤ 200 mg, high > 200 mg
Ibuprofen,
Diclofenac and
Naproxen (low ≤ 75% of the
maximum anti-inflammatory dosage,
high > 75%)		Naproxen showed a protective effect against CV events, particularly compared to diclofenac and ibuprofen.Diclofenac was associated with a higher risk of AMI, though not significantly different for overall CV events.2
Lévesque LE et al. [44]2006Population-Based Cohort StudyOverall = 113,927
≥65 y = 113,927 (100%)		Celecoxib (ND)The risk increase for first-time use of celecoxib was not statistically significant. 2
Rahme E et al. [45]2007Retrospective Cohort StudyOverall = 283,799
≥65 y = 283,799 (100%)		Celecoxib (≤200 mg/day vs. >200 mg/day OR 400 mg/day vs. >400 mg/day)
Diclofenac (≤150 mg/day vs. >150 mg/day) and Ibuprofen (≤1600 mg/day vs. >1600 mg/day)
Study suggests that celecoxib does not confer a higher CV risk compared to ibuprofen and diclofenac.2
Hudson M et al. [34]2007Case-Control StudyOverall = 42,560
≥65 y = 42,560 (100%)		Celecoxib (≤200 mg id and >200 mg/day)
Diclofenac (≤100 mg id and >100 mg/day)
Ibuprofen (≤1200 mg id and >1200 mg/day)
Naproxen (≤500 mg id and >500 mg/day)		Risks of recurrent CHF in patients exposed to naproxen, diclofenac, and ibuprofen were not significantly different compared with those of patients exposed to celecoxib at target doses. 2
Abraham NS et al. [46]2007Retrospective Cohort StudyOverall = 384,322
≥65 y = 384,322 (100%)		Celecoxib (200 mg median daily dose)
Ibuprofen (1800 mg median daily dose)
Naproxen (1000 mg median daily dose)		Celecoxib was associated with a non-significant increase in the risk of AMI or cerebrovascular accident compared to naproxen. Ibuprofen showed a slightly higher risk of AMI compared to naproxen but had a similar risk for cerebrovascular accident compared to naproxen.2
Solomon DH, et al. [47]2008Retrospective Cohort StudyOverall = 76,082
≥65 y = 76,082 (100%)		Celecoxib (ND)
Diclofenac (ND)
Ibuprofen (ND)
Naproxen (ND)		Ibuprofen appeared to confer an increased CVR in patients aged ≥80 years.2
Cunnington M et al. [24]2008Retrospective Cohort StudyOverall = 80,826
≥65 y = 39,048
(48.3%)		Celecoxib (ND)
Naproxen (ND)		One of the strongest predictors of AMI/ ischemic stroke risk was age >65 years.2
Mangoni AA, et al. [48]2010Retrospective Case-Control StudyOverall = 138,774
≥65 y = 138,774 (100%)		Celecoxib (ND)
Diclofenac (ND)
Ibuprofen (ND)
Naproxen (ND)		Neither naproxen or celecoxib showed a significant association with the risk of ischemic or hemorrhagic stroke. Low to moderate use of ibuprofen and diclofenac may be associated with a reduced risk of ischemic stroke.2
Mangoni AA, et al. [49]2010Retrospective Case-Control StudyOverall = 138,774
≥65 y = 138,774 (100%)		Celecoxib (ND)
Diclofenac (ND)
Ibuprofen (ND)
Naproxen (ND)		There was an increase in the risk of AMI with increasing supplies of the individual NSAIDs naproxen and ibuprofen, but not for diclofenac.Analysis of the individual NSAIDs showed a reduced risk of cardiac arrest associated with low exposure to diclofenac and an increased risk of arrhythmias associated with moderate-high exposure to naproxen.2
Schjerning et al. [50]2011Retrospective Cohort StudyOverall = 83,677
≥65 y = ND		Celecoxib (ND)
Diclofenac (ND)
Ibuprofen (ND)
Naproxen (ND)		Age-stratified analysis found that patients ≥80 years of age had a higher risk of death during the first week of treatment when taking diclofenac compared to younger patients. 2
Caughey GE, et al. [38]2011Retrospective Cohort StudyOverall = 162,065
≥65 y = 162,065 (100%)		Diclofenac (ND)
Ibuprofen (ND)		An increased risk of stroke was observed with diclofenac. Ibuprofen was not associated with ischemic or hemorrhagic stroke. 2
Lee T, et al. [37]2016Case-control StudyOverall = 24,079
≥70 y = 15,435 (64.1%)		Celecoxib (ND)
Diclofenac (ND)
Ibuprofen (ND)
Naproxen (ND)		Among current users, risk of venous thromboembolism was increased in diclofenac and ibuprofen. However, such association was not observed among current naproxen users.2
Schmidt M, et al. [36]2018Emulated TrialOverall = 7,608,766
≥70 y = 779,250 (10.2%)		Diclofenac (ND)
Ibuprofen (ND)
Naproxen (ND)		The increased risk of major adverse CV events with diclofenac initiation was consistent in the elderly subgroups compared to ibuprofen, naproxen, and non-use.2
AAS: Acetylsalicylic Acid; AMI: Acute myocardial infarction; BP: Blood Pressure; CHF: Cardiac Heart Failure; CI: Cardiovascular; OA: Osteoarthritis; ND: No Data; NSAID: Non-steroidal Anti-Inflammatory Drugs; RCT: Randomized Controlled Trial.
Table 2. Main characteristics of the systemically reviewed studies on GI safety of NSAIDs on a geriatric population.
Table 2. Main characteristics of the systemically reviewed studies on GI safety of NSAIDs on a geriatric population.
ReferencesYearStudy DesignPopulation
n (%)		Studied Drugs of Interest (Dosage)Main Findings in Population of InterestSORT Evidence Level
Goldstein JL et al. [51]2003RCTOverall = 186
≥65 y = 186
(100%)		Naproxen (500 mg bid)Naproxen use was associated with a significantly higher incidence of gastroduodenal ulcers and erosions compared to placebo.1
Laine L et al. [52]2004RCTOverall = 1519
≥65 y = 467
(30.7%)		Ibuprofen (800 mg bid)No significant treatment-by-subgroup interaction was seen for ulcer risk factors, including age ≥ 65 years. Rates of discontinuation and gastroduodenal ulcers and erosions were significantly higher in the ibuprofen group compared with placebo group. 1
Chan FK et al. [27]2004RCTOverall = 287
≥65 y = ND		Celecoxib (200 mg bid)
Diclofenac (75 mg bid)		Age ≥ 75 years was an independent riskfactor predicting ulcer recurrence.1
Lai KC et al. [28]2005RCTOverall = 242
≥65 y = 81
(33.5%)		Celecoxib (200 mg/day)
Naproxen (750 mg/day)		Celecoxib was not inferior to lansoprazole plus naproxen in preventing GI ulcer complications, including those aged 65 or older. Age 65 years or more was an independent risk factor for ulcer recurrence. 1
Laine L et al. [53]2008Prospective Cohort TrialOverall = 34,701
≥65 y = 14,396
(41.5%)		Diclofenac (150 mg/day)
Etoricoxib (60 or 90 m/day)		Older age was a significant predictor for lower GI clinical events, with a 2-fold increase in risk. 1
Laine L e at. [26]2010RCTOverall = 34,701
≥65 y = 14,227 (41.0%)		Diclofenac (150 mg/day)
Etoricoxib (60 or 90 mg/day)		Age ≥ 65 years was a significant predictor of discontinuation due to dyspepsia, clinical events, and complicated events.1
Arber N et al. [54]2012RCTOverall = 3588
≥65 y = 29.7% (APC Study); 37.9% (PreSAP study)		Celecoxib (200 mg/400 mg bid or 400 mg id)Age ≥65 years was associated with an increased risk of GI events in both celecoxib and placebo groups. The noninferiority of celecoxib to placebo was not established.1
Kellner HL et al. [40]2012RCTOverall = 2446
≥65 y = 2446 (100%)		Celecoxib (200 mg bid)
Diclofenac (75 mg bid)		Celecoxib was associated with significantly fewer clinically significant upper and lower GI events compared with diclofenac plus omeprazole in patients aged ≥65 years.1
Couto A et al. [55]2018RCTOverall = 818
≥65 y = 358 (43.7%)		Naproxen (220 mg bid)The rate of reported GI AE was comparable in the naproxen and placebo groups for all age groups.1
Kyeremateng K et al. [29]2019Retrospective Pooled Analysis of RCTsOverall = 1494
≥65 y = 544 (36.4%)		Naproxen (440 mg/day)
Ibuprofen (600–1200 mg/day)		In ≥65 years there was no difference in the overall rate or type of AE compared with younger participants. There were no significant differences in overall adverse events between naproxen, placebo or ibuprofen.
1
Biskupiak JE et al. [56]2006Retrospective Cohort StudyOverall = 60,212
≥65 y = ND		Ibuprofen (ND)
Naproxen (ND)		Elderly patients had a higher incidence of serious GI toxicities compared to younger adults both with naproxen and ibuprofen.2
Schneeweiss S et al. [32]2006Population-Based Cohort StudyOverall = 49,711
≥65 y = 49,711
(100%)		Celecoxib (ND)
Diclofenac (ND) Naproxen (ND) Ibuprofen (ND)		Celecoxib produces a significant short-term reduction in GI complications compared with all nonselective NSAIDs combined. Diclofenac appears to have the least favorable safety profile among individual NSAIDs. The risk of AMI was significantly higher for diclofenac compared to celecoxib, while ibuprofen did not show a significant difference in AMI risk when compared to celecoxib. Naproxen may have a more favorable CV safety profile compared to celecoxib, indicated by the lowest risk difference for MI among the NSAIDs studied, although this difference was not statistically significant.2
Hsiang KW et al. [30]2010Prospective Observational Cohort StudyOverall = 933
≥70 y = 490 (49.3%)		Celecoxib (100–400 mg/day)
Etoricoxib (60 mg/day)		Age >60 or >70 years was not a risk factor for symptomatic ulcers and ulcer complications in COX-2 inhibitor users. Use of COX-2 inhibitors was well tolerated in regard to the upper GI tract in patients aged >70 years.2
Sostek MB et al. [57]2011Open-label, Multicenter, Phase III StudyOverall = 239
≥65 y = 78 (32.6%)		Naproxen (500 mg bid)Twice-daily dosing with naproxen/esomeprazole was not associated with any new or unexpected safety issues. Subgroup analysis suggest that the safety profile of naproxen/esomeprazole is similar in <65 vs. ≥65 years old patients.2
Chang CH et al. [39]2011Case-Crossover StudyOverall = 40,635
≥65 y = ND		Celecoxib (ND)Celecoxib was associated with higher risk of upper GI events vs. non-use. Elderly were at higher risk for upper GI adverse events.2
AE: Adverse Events; CI: Cardiovascular; GI: Gastrointestinal; PPI: Proton Pump Inhibitors; OA: Osteoarthritis; ND: No Data; NSAID: Non-steroidal Anti-Inflammatory Drugs; RCT: Randomized Controlled Trial; AMI: Acute myocardial infarction.
Table 3. Main characteristics of the systemically reviewed studies on renal safety of NSAIDs on a geriatric population.
Table 3. Main characteristics of the systemically reviewed studies on renal safety of NSAIDs on a geriatric population.
ReferencesYearStudy DesignPopulation
n (%)		Studied Drug (Dosage)Main Findings in Population of InterestSORT Evidence Level
Juhlin T et al. [41]2004RCTOverall = 14
≥65 y = 14 (100%)		Diclofenac (50 mg id)Diclofenac caused significant reductions in GFR, urine flow, and excretion rates of sodium and potassium. Pre-treatment with diuretics and ACE-inhibitors exacerbated this impact.2
Schneider V et al. [42]2006Case-Control StudyOverall = 121,722
≥65 y = 121,722 (100%)		Celecoxib (low dose 200 mg id // high dose >200 mg id)
Naproxen (low dose 750 mg id // high dose >750 mg id)		Both celecoxib and naproxen show a dose-dependent increase in the risk of AKI. However, the risk increase is more pronounced with higher doses of naproxen. The study suggests that celecoxib is associated with a lower risk of AKI compared to naproxen, especially at lower doses.2
Winkelmayer WC et al. [58]2008Retrospective Cohort StudyOverall = 183,446
≥65 y = 183,446 (100%)		Celecoxib (ND)
Diclofenac (ND)
Naproxen (ND)
Ibuprofen (ND)		Ibuprofen seemed to have a greater rate of AKI compared with celecoxib.2
Benson P et al. [59]2012Prospective observational studyOverall = 44
≥65 y = 44 (100%)		Celecoxib (400 mg bid)High-dose celecoxib was relatively well-tolerated by elderly patients, with stable renal function and minor electrolyte alterations.
2
ACE: Angiotensin-converting enzyme; AKI: Acute kidney injury; GFR: Glomerular filtration rate; ND: No Data; NSAID: Non-steroidal anti-inflammatory drugs; RCT: Randomized controlled trial.

4. Discussion

Recommendations about NSAID prescriptions are frequently based on COX selectivity, but there are marked differences in each NSAID’s molecular and chemical properties, which confer different pharmacological results [5].
Age is widely described in the literature as an important CV risk factor, with a high prevalence of hypertension, ischemic heart disease, atrial fibrillation, and heart failure (level of evidence 1). Reduced gastric and intestinal motility, decreased splanchnic blood flow, impaired mucosal protective mechanisms and enzyme secretion, hypochlorhydria, and mucosal atrophy are some of the age-related GI changes [60,61].
Our results show that older age acts as an independent CV risk factor and that the elderly have a higher baseline risk for GI complications (level of evidence 2). Both can be exacerbated by NSAID use. Even though two studies do not find age as a risk factor for symptomatic peptic ulcer disease (PUD) [29,30], a manifestation of PUD in the elderly is often atypical [60]. Also, these studies, like many others in this matter, did not account for H. pylori infection, one of the most frequent causes of PUD [60], which might be an important confounder.
Most existing orientations are targeted at the adult population and usually divide recommendations into CV risk vs. GI risk to direct the choice of NSAID [15,16,17]. Nevertheless, the elderly frequently fulfill both risks plus the expected decline in kidney function, making drug selection particularly challenging [5].
Both the United Kingdom NHS and IASP recommend starting with naproxen or ibuprofen plus PPI [16,17]. IASP proposes low doses of celecoxib as an alternative option in high CV risk patients [16].
In the results of this systematic review, two studies support the potential superiority of naproxen in terms of CV risk [31,32]. When analyzing these publications, no statistical significance is reached on one of them [32], and in the other, the doses of the drugs used in the analysis are not clearly presented [31]. Other studies suggest a neutral impact of naproxen in thromboembolic events [37,48]. Once again, these studies also do not clearly present the doses used for each drug, which can be an important bias. Consequently, in light of the results gathered in this systematic review, opting for first-line naproxen in the elderly high CV risk population is not supported by scientific evidence (level of evidence 1). When comparing ibuprofen with naproxen, our results suggest a modest inferiority of ibuprofen to naproxen based on two studies that document a higher risk for AMI and venous thromboembolic events [37,46]. Therefore, ibuprofen should be considered as a second-line therapy compared to naproxen in elderly patients with high CV risk (level of evidence 1).
When celecoxib is only compared with naproxen, it shows no inferiority regarding AMI, CHF, and cerebrovascular events risk [34,35,46,48]. Taking this into consideration, in high CV risk elderly patients, in studies that compare one to another, celecoxib shows a similar safety profile to naproxen (level of evidence 2).
It is important to acknowledge that all the mentioned studies are based on prescription records, and lack direct measures of adherence, dosage, duration of treatment or nonprescription NSAID use.
As previously mentioned, COX-2 inhibitors are designed to prevent GI issues, and therefore, celecoxib is expected, right from the start, to show a better safety profile when it comes to GI events. Despite this theoretical advantage, data from our review continue to find that the use of celecoxib is not without harm, showing a modest risk of superior GI effects when compared with placebo (level of evidence 2) [39].
However, when compared to diclofenac, naproxen, and ibuprofen, celecoxib showed a better GI safety profile (level of evidence 2), including greater safety compared to diclofenac in combination with PPIs [32,40]. When compared only with naproxen plus lansoprazole, celecoxib alone was not inferior in preventing GI ulcer complications [28]. Regarding the use of naproxen alone, it was associated with a significantly higher incidence of gastroduodenal ulcers and erosions compared to placebo (level of evidence 1). Consequently, in light of the results gathered in this systematic review, we consider that celecoxib has a better GI safety profile (level of evidence 2), followed by naproxen plus PPI (level of evidence 2).
Celecoxib demonstrates a better safety profile when compared with naproxen and ibuprofen (level of evidence 2).
A study comparing naproxen and celecoxib concluded that both show a dose-dependent increase in the risk of AKF. Still, the risk increase was more pronounced with higher doses of naproxen [42]. Celecoxib also had a lower rate of AKF compared to ibuprofen [58].
When celecoxib was compared with placebo, it showed a stable renal function and minor electrolyte alterations [59].
All these studies advocate for a better safety profile for celecoxib (level of evidence 1).
Acemetacin was one of the drugs this systematic review intended to study. A promising safety profile was expected due to its specific pharmacokinetic characteristics. Being a prodrug and bearing a weak reduction of prostaglandin synthesis might reduce the damage of the GI mucosa [62] (level of evidence 3). Of all the drugs included in our study, acemetacin has the lowest renal excretion, which may be better suited for the elderly with compromised renal function [5] (level of evidence 3). Despite its theoretical potential, no papers were identified that evaluated its use in the elderly.
Diclofenac presents a lower renal excretion compared with most NSAIDs and a phase 2 liver biotransformation, making it theoretically a good choice for elderly patients [5]. Nevertheless, IASP and NHS advise against the use of diclofenac in high CV risk patients [16,17]. In our findings, diclofenac showed an overall poorer CV safety profile compared to naproxen and ibuprofen (level of evidence 2). Diclofenac also showed a worse GI safety profile when compared to celecoxib, even when added to PPI (level of evidence 2) [32,40]. Additionally, a single low dose of 50 mg daily had a significant impact on renal function (level of evidence 2) [41].
Findings on etoricoxib were also very scarce. Of the studies retrieved in this systematic review, the MEDAL trial was the only one that allowed comparison between this drug and the other NSAIDs studied [21]. It suggests that the cardiovascular risks of etoricoxib are comparable to those of diclofenac (level of evidence 2), which, as discussed above, showed a poorer CV safety profile.
A prior pharmacovigilance and literature review study [18] concluded that the risk of GI, CV, and renal adverse drug reactions was significantly lower with the use of selective COX-2 inhibitors compared to non-selective NSAIDs. Although this is one of the populations with higher needs and prescriptions for NSAIDs, few studies focus on geriatric patients.
Our study has some limitations. The search was limited to certain databases, which might have excluded relevant studies that were not indexed. A global assessment of the results obtained leads us to reflect on their heterogeneity. The multiplicity of study types, drug comparisons, doses, and treatment periods limit the achievement of solid recommendations. Also, the determination of the strength of recommendations is affected by inherent subjectivity.

5. Conclusions

When CV risk is the main concern, according to our findings, celecoxib or naproxen are a suitable choice (recommendation strength B). Acemetacin can be considered (recommendation strength C). Etoricoxib and diclofenac should be avoided in these patients (recommendation strength B).
Regarding the GI safety profile, celecoxib remains the first-line choice, as does naproxen plus PPI (recommendation strength B).
When renal function is in focus, celecoxib remains the first-line therapy (recommendation strength A). Naproxen can be considered a second-line therapy in these patients (recommendation strength B). Acemetacin can also be considered (recommendation strength C). Ibuprofen and diclofenac should be used with caution in these patients (recommendation strength B).
These results will assist in making tailored treatment decisions for patients, reducing the risk of adverse events, and enhancing care efficiency.

Author Contributions

Conceptualization, C.C. and H.R.; methodology, C.C., J.P.A. and H.R.; validation, A.B., A.G., J.P.A. and H.R.; formal analysis, C.C., D.S., A.B. and A.G.; investigation, C.C., D.S., A.G. and A.B.; resources, H.R.; data curation, C.C. and D.S.; writing—original draft preparation, C.C.; writing—review and editing, J.P.A. and H.R.; visualization, D.S., A.B. and A.G.; supervision, H.R.; project administration, J.P.A.; funding acquisition, H.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data Availability Statement

Dataset available on request from the authors.

Conflicts of Interest

The authors declare no conflict of interest.

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Biochem 04 00015 g001
Figure 1. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols used in this study.
Figure 1. Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) protocols used in this study.
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Costa, C.; Soares, D.; Borges, A.; Gonçalves, A.; Andrade, J.P.; Ribeiro, H. Appropriate Prescription of Non-Steroidal Anti-Inflammatory Drugs in Geriatric Patients—A Systematic Review. BioChem 2024, 4, 300-312. https://doi.org/10.3390/biochem4040015

AMA Style

Costa C, Soares D, Borges A, Gonçalves A, Andrade JP, Ribeiro H. Appropriate Prescription of Non-Steroidal Anti-Inflammatory Drugs in Geriatric Patients—A Systematic Review. BioChem. 2024; 4(4):300-312. https://doi.org/10.3390/biochem4040015

Chicago/Turabian Style

Costa, Carolina, Diana Soares, Ana Borges, Ana Gonçalves, José Paulo Andrade, and Hugo Ribeiro. 2024. "Appropriate Prescription of Non-Steroidal Anti-Inflammatory Drugs in Geriatric Patients—A Systematic Review" BioChem 4, no. 4: 300-312. https://doi.org/10.3390/biochem4040015

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