By Mereyem Toppa, Esther Udo, Jordan Villaruel and Jessica Zhu
Clinical Scenario
Patient is a 95-year-old who is generally in good health but has chronic knee pain despite having a knee replacement 10 years ago. She tells you that taking Aleve twice a day helps her with the pain, but you are concerned about the risks to her of using an NSAID on a regular basis. She says, “I’m an old woman, how serious a risk is it?” What can you tell her about the degree of risk of chronic NSAID use for her?
Clinical Question:
In geriatric patients, is there significant risk of adverse outcomes with chronic NSAID use?
PICO elements:
P→ elderly patients
I→ chronic NSAID use
C→ patients not taking NSAIDs
O→ Risks / Complication of NSAID use
Search Strategy/ Databases:
- PubMed
“Risk of Chronic NSAID Use” / Limits: 10 years → 25,130
“Risk of Chronic NSAID use in Elderly” / Limits: 10 years, meta-analysis→ 8431
“Risk of Chronic NSAID use in Elderly” / Limits: 10 years, meta-analysis, systematic review→ 6911
Articles Chosen for Inclusion:
#1 Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies
Abstract: 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. 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
#2 “Systematic review: ibuprofen-induced liver injury”
Abstract: Ibuprofen is one of the most commonly used and safest NSAIDs, nevertheless reports on ibuprofen-induced hepatotoxicity are available. A systematic search was performed and information on ibuprofen-induced liver injury included in case series and case reports, in terms of demographic, clinical, biochemical and outcome data, was analyzed. Twenty-two idiosyncratic ibuprofen hepatotoxicity cases were identified in the literature, suggesting a very low prevalence of this type of DILI. These patients had a mean age of 31 years and 55% were females. Mean cumulative dose of ibuprofen and time to onset were 30 g and 12 days, respectively. Hepatocellular injury was the most frequently involved liver injury pattern. Six cases developed vanishing bile duct syndrome. Full recovery occurred in 11 patients after a mean time of 14 weeks, whereas five cases evolved to acute liver failure leading to death/liver transplantation. When assessing potential hepatotoxicity cases, physicians should keep in mind that ibuprofen has been associated with hepatotoxicity in the literature. Ibuprofen-associated DILI presents commonly as hepatocellular damage after a short latency period. Published reports on ibuprofen hepatotoxicity leading to liver failure resulting in liver transplantation or death are available. However, due to the apparent low absolute risk of ibuprofen-induced liver complications, ibuprofen can be regarded as an efficacious and safe NSAID.
#3 Risk of acute myocardial infarction with NSAIDs in real world use: Bayesian meta-analysis of individual patient data
Abstract: A systemic review and meta-analysis from Canadian and European healthcare databases looking at risk of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs(NSAIDS). The studies were conducted in the general and elderly population using selective cyclooxygenase-2 inhibitors and traditional NSAIDS. The studies compared risk of acute myocardial infarction in NSAID users with non-users. A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. The results found that taking any dose of NSAIDS for one week, one month, or more than a month was associated with an increased risk of MI. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations. All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.
#4 Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials
Abstract: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (NSAIDs), are not well characterized, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomized trials.
We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making.
Summary of the Evidence:
| Author (Date) | Level of Evidence | Sample/Setting(# of subjects/ studies, cohort definition etc.) | Outcome(s) studied | Key Findings | Limitations and Biases |
| 1. Ungprasert P, et al. (April 2015) | Systematic Review,Meta-Analysis | 4 case control 1 cohort28,992 patients | Risk of AKI among patients who use the following NSAIDs and COX-2 inhibitors: indomethacin, piroxicam, ibuprofen, naproxen, sulindac, diclofenac, meloxicam, rofecoxib and celecoxib | A statistically significant elevated AKI risk among traditional NSAID users has been demonstrated. The highest risk ratio was observed among indomethacin users while the lowest risk was found in subjects who used sulindac. | – Most of the included studies were conducted using medical registry-based databases, raising a concern of coding inaccuracy and incompleteness. – Exposure to NSAIDs was defined by prescription, over-the-counter use of NSAIDs was not recorded |
| 2. Zoubek M, et al. (January 2020) | Systematic Review | Done in accordance with the “Preferred Reporting Items for Systematic review and Meta-Analysis guidelines.” Electronic searches done on Pubmed, Cochrane and Web of science for reported cases and case series. Search terms used were “Hepatotoxicity”, “Drug induced liver injury”, “ibuprofen”, and “Vanishing Bile duct Syndrome.” 22 articles were included in the final review out of 131 originally published works. Of the 22 articles, 17 were case reports, 2 were case series of idiosyncratic ibuprofen induced liver injury while 3 cases were of ibuprofen overdose related liver injury. | The occurrence of drug-induced liver injury with ibuprofen use only (a commonly used NASAID) or in concomitant treatment. Demographic, clinical, and biochemical data. Also observed in patients with certain chronic conditions like Rheumatic disorders. | I. The mean onset of DILI episodes was 12 days (range 1-42 daysii.. Prevalent symptoms include Rash (56%), Vomiting (38%). Abdominal pain (22%), fever (56%), Jaundice (50%) and Choluria (39%)iii. 4 Patients were asymptomatic and liver injury was incidental finding on routine blood tests)Iv. Liver histology was done in 15 patients after DILI was recognized and necrosis was found in 3 cases, cholestasis in 5 cases, and fatty changes in 3 cases. V. Hepatocellular injury was the most observed pattern. 11 cases had biochemical and or/ histopathological criteria for hepatocellular injury.3 cases had cholestatic injury and 3 cases had mixed liver injury. 5 cases provided insufficient data to assess the type of liver injury Vi. Most of the cases of DILI were female. | I. Fewer number of cases. Not enough to establish causality. ii. Publication bias as more novel reports may be preferred over others. iii. Lack of data for concomitant drug use in some of the reported cases included in the review. |
| 3. Bally M, et al. (May 2017) | Systematic Review, Meta-analysis of Randomized controlled trials | A cohort of 446,763 including 61,460 with acute myocardial infarction was acquired | Outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date | All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses. | Myocardial infarction can be caused by many factors and comorbidities especially in the elderly population. In a large elderly cohort, comorbidities can vary largely, increasing myocardial infarction even without NSAID use. |
| 4. Bhala N, et al. (May 2013) | Meta-analyses of randomized trials | Meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68, 342 person-years) and 474 trials of one NSAID versus another NSAID (229, 296 participants, 165, 456 person-years) | Major vascular events (non-fatal MI, non-fatal stroke, vascular death); major coronary events (non-fatal MI or coronary death); stroke; mortality; HF; upper GI complications (perforation, obstruction, bleed) | Major vascular events were increased by about a third by a coxib or diclofenac mainly due to an increase in major coronary events. Ibuprofen also significantly increased major coronary events but not major vascular events. Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events compared to coxibs, diclofenac and possibly ibuprofen. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper GI complications. | Individual participant data was provided from unpublished trials in addition to published trials. High dose coxibs and NSAIDs were analyzed in which high dose naproxen was associated with less vascular hazard. However, there is unawareness if this applies to low dose naproxen as well. |
Conclusion(s):
- Ungprasert P, et al. – A statistically significant elevated AKI risk among traditional NSAID users has been demonstrated in this meta-analysis. Clinicians must weigh the possible risks of AKI and other NSAID related adverse events, including chronic kidney injury, hypertension, and gastrointestinal bleeding against their potential benefit. Wherever possible, strategies using the minimum amount of drug for the shortest duration possible are preferred over long-term treatment.
- Zoubek M, et al. show that based on the reports from their systematic review the findings show support that ibuprofen -induced liver injury can occur in some cases, but the absolute risk of hepatotoxicity is lower than the risk of vascular and gastrointestinal complications that have been associated with NSAID use. In addition, Ibuprofen induced liver injury appears as hepatocellular type of liver injury pattern in most cases.
- Bally M, et al. (May 2017) – All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.
- Bhala N, et al. – The use of coxibs and NSAIDs were associated with an increased risk of cardiovascular disease and upper gastrointestinal complications. Vascular risks of diclofenac and possibly ibuprofen were similar to coxibs, however, naproxen was found to have less risk of vascular events.
With the research we found, we were able to evaluate if the geriatric population is at an increased risk for adverse outcomes with chronic NSAID use. According to the articles gathered, data was statistically significant enough to demonstrate a positive association between adverse outcomes such as cardiovascular, AKI, GI, liver injury and vascular complications and long-term administration of NSAIDs. The NSAIDs analyzed were found to have increased risk of vascular effects, however, naproxen was associated with less risk which relates to the clinical question. High dose naproxen may be the safest choice for chronic NSAID use in terms of vascular risk but there are still additional risks to consider in addition to requiring more research to see if this applies to low dose naproxen as well. Although NSAIDs increase risk for adverse outcomes, the size of these risks can be predicted with the aid of meta-analysis and systematic review, which allows for guidance of clinical decision making.
