Safety Comparison of NSAIDs

−This Clinical Resource gives subscribers
additional insight related to the Recommendations published in−
January 2017 ~ Resource #330101
Safety Comparison of NSAIDs

The following chart compares COX-2 selectivity, GI risk, and cardiovascular risk of available NSAIDs. Also keep in mind that NSAIDs carry
varying risks of rare hepatotoxicity (diclofenac poses the highest risk). Also, NSAIDs can cause renal injury by reducing renal blood flow or
through other mechanisms.11 In older patients, theoretically, COX-2 inhibitors may be safer from a renal standpoint because in the elderly renal blood
flow is mostly COX-1 dependent.12 Other options that may have relatively low renal risk are nabumetone or nonacetylated salicylates (e.g.,
diflunisal).13,14 COX-2 selectivity is not necessarily associated with better GI safety or worse CV outcomes.
Drug COX-2 selectivity (in vitro)b,1-3 GI Risk4-7,15 Cardiovascular Riska,4,8-10,16

Aspirin Low Moderate Low
Celecoxib (Celebrex) High Low Moderate to High
Diclofenac (Voltaren [Canada], High Moderate High

generics)
Diflunisal Moderate Moderate Data not availablea
Etodolac High Low Moderate
Fenoprofen (U.S. only)(Nalfon, Moderate Moderate Data not availablea

generics)
Flurbiprofen Low High Data not availablea
Ibuprofen Moderate Low Moderate to High
Indomethacin (Indocin [U.S.], Low Moderate to High Moderate

generics)
Ketoprofen (Anafen [Canada], Low Moderate Data not availablea

generics)
Ketorolac (Toradol [Canada], Low High Data not availablea

generics)
More. . .
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(Clinical Resource #330101: Page 2 of 3)
Drug COX-2 selectivity (in vitro)b,1-3 GI Risk4-7,15 Cardiovascular Riska,4,8-10,16

Meclofenamate (U.S. only) Moderate High Data not availablea
Mefenamic acid (Ponstel [U.S.], High Low to Moderate Data not availablea
Ponstan [Canada], generics)
Meloxicam (Mobic [U.S.], High Low Moderate

Mobicox [Canada], generics)
Nabumetone Moderate Low Data not availablea
Naproxen (Anaprox DS, etc, Low Moderate Low to Moderate

generics)
Oxaprozin (Daypro, generics) Low High Data not availablea
Piroxicam (Feldene [U.S.], Moderate High Low

generics)
Salsalate (U.S. only) Unavailable Low Data not availablea
Sulindac Moderate Moderate Data not availablea
Tolmetin (U.S. only) Low Moderate Data not availablea
a. For patients with cardiovascular disease or risk factors for ischemic heart disease, the American Heart Association recommends for pain (in the
order listed): acetaminophen, aspirin, tramadol, opioids (short-term), nonacetylated salicylates (e.g., diflunisal), NSAIDs with low COX-2
selectivity, NSAIDs with some COX-2 selectivity, and COX-2 selective agents.8
b. Note that the selectivity ratio in the table above is based on in vitro assay studies and should be interpreted with caution as different assay
methods give different results. Moreover, no assay method can predict what will happen when the drug is given to patients. Clinical studies are
the best way to determine the effects of NSAIDs in patients.1
Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical
judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
organizations. Information and internet links in this article were current as of the date of publication.
More. . .
Project Leader in preparation of this clinical clinicians: a scientific statement from the American
resource (330101): Melanie Cupp, Pharm.D., Heart Association. Circulation 2007;115:1634-42.
9. Fosbol EL, Folke F, Jacobsen S, et al. Cause-
BCPS specific cardiovascular risk associated with
nonsteroidal antiinflammatory drugs among healthy
References individuals. Circ Cardiovasc Qual Outcomes
1. Chou R, Helfand M, Peterson K, et al. Drug class 2010;3:395-405.
review on cyclo-oxygenase (COX)-2 inhibitors and 10. McGettigan P, Henry D. Cardiovascular risk with
non-steroidal anti-inflammatory drugs (NSAIDs). non-steroidal anti-inflammatory drugs: systematic
Final report update 3. Oregon evidence-based review of population-based controlled observational
practice center, Oregon Health & Sciences studies. PLoS Med 2011;8:e1001098. Epub 2011
University. Portland, Oregon 97201. November Sep 27.
2006. 11. Clinical Resource, Lab monitoring for common
2. Warner TD, Mitchell JA. Cyclo-oxygenases: new medications. Pharmacist’s Letter/Prescriber’s Letter.
forms, new inhibitors, and lessons from the clinic. June 2014.
FASEB J 2004;18:790-804. 12. Barkin RL, Beckerman M, Blum SL, et al. Should
3. Kawai S. Cyclo-oxygenase selectivity and the risk of nonsteroidal anti-inflammatory drugs (NSAIDs) be
gastro-intestinal complications of various non- prescribed to the older adult? Drugs Aging
steroidal anti-inflammatory drugs: a clinical 2010;27:775-89.
consideration. Inflamm Res 1998;47(Suppl 2):S102- 13. Bergamo RR, Cominelli F, Kopple JD, Zipser RD.
6. Comparative acute effects of aspirin, diflunisal,
4. Clinical Resource, Managing NSAID Risks. ibuprofen and indomethacin on renal function in
Pharmacist’s Letter/Prescriber’s Letter. January healthy man. Am J Nephrol 1989;9:460-3.
2017. 14. Cook ME, Wallin JD, Thakur VD, et al. Comparative
5. Henry D, Lim LL, Garcia Rodriguez LA, et al. effects of nabumetone, sulindac, and ibuprofen on
Variability in risk of gastrointestinal complications renal function. J Rheumatol 1997;24:1137-44.
with individual non-steroidal anti-inflammatory drugs: 15. MacDonald TM, Morant SV, Robinson GC, et al.
results of a collaborative meta-analysis. BMJ Association of upper gastrointestinal toxicity of non-
1996;312:1563-6. steroidal anti-inflammatory drugs with continued
6. Singh G. Recent considerations in nonsteroidal anti- exposure: cohort study. BMJ 1997;315:1333-7.
inflammatory drug gastropathy. Am J Med 16. Nissen SE, Yeomans ND, Solomon DH, et al.
1998;105(1B):31-8S. Cardiovascular safety of celecoxib, naproxen, or
7. Clinical Resource, NSAIDs and the Risk of GI ibuprofen for arthritis. N Engl J Med Nov 13, 2016
Effects. Pharmacist’s Letter/Prescriber’s Letter. [Epub ahead of print].
February 1998.
8. Antman EM, Bennett JS, Daugherty A, et al. Use of
nonsteroidal antiinflammatory drugs: an update for
Cite this document as follows: Clinical Resource, Safety Comparison of NSAIDs. Pharmacist’s Letter/Prescriber’s
Letter. January 2017.
Evidence and Recommendations You Can Trust…
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Copyright  2017 by Therapeutic Research Center
Subscribers to the Letter can get clinical resources, like this one,
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−This Clinical Resource gives subscribers
additional insight related to the Recommendations published in−
July 2018 ~ Resource #340702
Managing NSAID Risks

NSAIDs are useful in the treatment of several different types of pain. Unfortunately, NSAIDs can cause GI ulceration and bleeding and CV events.
They can also harm the kidneys and the liver. Although the chance of a serious adverse event is relatively small, the consequences can be
devastating. Certain NSAIDs may have more of a propensity to cause given adverse effects. Although no single NSAID is free of risk, risk can be
minimized by selecting an NSAID based on patient risk factors. In addition, gastroprotective agents such as proton pump inhibitors (PPIs) can be
used to decrease GI risk. This chart provides information to help healthcare professionals manage NSAID risks, and avoid aspirin/NSAID
interactions, in a “frequently asked questions” format.
Abbreviations: BID = twice daily; CV = cardiovascular; COX = cyclo-oxygenase; GI = gastrointestinal; MI = myocardial infarction; NSAIDs =
nonsteroidal anti-inflammatory drugs; SBP = systolic blood pressure; TID = three times daily
Clinical Question Pertinent Information
Gastrointestinal Risk
How do NSAIDs • Prostaglandins produced by COX-2 mediate inflammation, pain, and fever. This enzyme is the main therapeutic target of
cause GI ulceration NSAIDs.1
and bleeding? • NSAIDs also inhibit the COX-1 pathway to varying degrees. Prostaglandins produced by the COX-1 pathway increase
GI mucosal blood flow, mucus and bicarbonate production, and epithelial growth. NSAIDs harm the mucosa by
inhibiting production of protective prostaglandins via inhibition of the COX-1 pathway. Inhibition of COX-1 by
NSAIDs deprives the gastroduodenal mucosa of prostaglandins’ protections against acid, enzymes, and bile salts, thus
increasing the risk of ulcers.1
• NSAIDs also harm the GI mucosa by direct irritation.1
What is the magnitude • The relative risk for a GI bleed or perforation increases about four-fold in patients who use NSAIDs compared to those
of the risk of NSAID- who don’t use NSAIDs.2,3
associated GI harm?
What are the risk • Risk factors for an NSAID-associated GI event includes male gender, history of peptic ulcer (especially bleeding ulcer),
factors for an NSAID- dyspepsia, and CV disease.1,4
associated GI event? • Age is a significant risk factor; increased risk begins at age 60 years and rises thereafter.1
• Risk is also increased with the use of antiplatelets (e.g., aspirin), anticoagulants (e.g., warfarin), corticosteroids, or high
NSAID doses.1,4
More. . .

Gastrointestinal Risk, continued
What is the time • Events can occur within the first month of use.4
course of NSAID- • Risk decreases after the first few months of NSAID use, but never goes away.4
associated GI risk?
How do NSAIDs • The bulk of evidence suggests that lower doses of ibuprofen and celecoxib have the lowest GI risk, and piroxicam and
compare in regard to ketorolac have the highest risk [Evidence level B-3,4].2,5-9 Naproxen seems to have moderate risk.2,6,7
GI risk, and what may • Risk may be high with some of the longer-acting NSAIDs such as sustained-release formulations, piroxicam, and
account for these ketorolac due to longer mucosal exposure.4,5
differences? • Ibuprofen may be a lower-risk NSAID in regard to GI events because low doses are typically used (perhaps due to
nonprescription availability), or because it has a short half-life (about two hours).4,10 Note that at high doses
(2,400 mg daily), ibuprofen’s GI risk approached that of naproxen and was about twice that of celecoxib or
diclofenac in the Coxib and Traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled
trials.11
• COX-2 selectivity also affects risk. A selective COX-2 inhibitor should provide pain relief with lower GI risk.1
• Among “traditional” NSAIDs, meloxicam, nabumetone, and etodolac have some COX-2 selectivity, but there’s
not much evidence they are less likely than less selective NSAIDs to cause GI events.2,4,5,9,12,13
• The selective COX-2 inhibitor celecoxib may be associated with a 20% lower relative risk of bleeding or perforation
compared to traditional NSAIDs.5 But absolute difference in risk of a GI event is low short-term (e.g., 1.1% in a six-
month study).14 Celecoxib may not be safer than nonselective NSAIDs past six months of use, or in patients taking
low-dose aspirin.15-17 In PRECISION (see footnote a), celecoxib was not associated with a lower risk of hemorrhage
or ulceration.8
What is the GI safety • Diflunisal seems to have moderate GI risk, although it has been included in only a few studies.6
of salicylates? • Salsalate seems to pose low GI risk based on endoscopic data.18.19
• The GI risk of choline magnesium salicylate is also not well characterized.
• Aspirin poses moderate GI toxicity.6,20 For help with decisions regarding aspirin use for primary CV prevention, see our
chart, Aspirin for Primary Prevention.
Do gastroprotective • Misoprostol reduces the relative risk of gastroduodenal complications by about 40% among patients at higher than
agents reduce the risk average risk.21
of NSAID-associated • The recommended dose is 200 mcg four times daily, but adverse effects (e.g., diarrhea, cramping) may require dose
GI toxicity? reduction.15 However, lower doses may also cause GI symptoms and have not been shown to reduce ulcer
complications.22
Continued… • Proton pump inhibitors are well tolerated and have been shown to reduce the risk of bleeding ulcers associated with
More. . .

Gastroprotective celecoxib in high-risk patients (NNT=11).23 Furthermore, PPIs can reduce the risk of NSAID-associated ulcer bleeding
agents, in patients with H. pylori and a history of ulcer bleeding. They also seem protective against NSAID-associated ulcer
continued bleeding in epidemiologic studies and in secondary analysis of prospective studies.4
• Standard-dose H2-blockers reduce the risk of NSAID-associated duodenal ulcers.15,22 But high-dose H2-blockers (e.g.,
80 mg/day famotidine) reduce the risk of both duodenal and gastric ulcers.15,22,24 Benefit is highest in patients with H.
pylori.15 Note that H2-blockers have not been shown to reduce the risk of serious GI events in NSAID users.
How do I choose an • For purposes of management of GI risk, the American College of Gastroenterology categorizes patients as high,
NSAID based on a moderate, and low risk (see footnote b):4
patient’s GI risk? • For patients with high GI risk (see footnote b) and low CV risk, avoid NSAIDs if possible.4 Or use celecoxib with
a proton pump inhibitor or misoprostol [Evidence level B-1].4,21,23 Patients with both high GI risk and high CV risk
should not receive an NSAID (including celecoxib).4
• For patients with moderate GI risk (see footnote b) and low CV risk, use celecoxib or add a proton pump inhibitor
or misoprostol to a less COX-2 selective NSAID.4 For patients with moderate GI risk but high CV risk (e.g., history
of CV event, diabetes, hypertension, hyperlipidemia, obesity), choose naproxen [Evidence level A-2].4,25-27 These
patients will also require a proton pump inhibitor or misoprostol.4 PRECISION (see footnote a) results suggest
low-dose celecoxib is an option.8
• Low GI risk patients are those without risk factors (see footnote b).4 For patients with low GI risk and low CV
risk, choose an NSAID with the least GI risk at the lowest effective dose (e.g., celecoxib).4,8 For patients with low
GI risk but high CV risk (e.g., history of CV event, diabetes, hypertension, hyperlipidemia, obesity), choose
naproxen [Evidence level A-2].4,25-27 Add gastroprotection if on aspirin.4 PRECISION (see footnote a) results
suggest low-dose celecoxib is an option.8
• These recommendations are summarized in the following table:4,8
Low GI risk Moderate GI risk High GI risk
Low CV risk Celecoxib or other 1. Celecoxib alone 1. Avoid NSAIDs if
low-GI risk NSAID 2. NSAID plus PPI, possible
misoprostol, or double-dose 2. Celecoxib plus PPI or
H2-blocker (second line) misoprostol
High CV risk Naproxen or low-dose 1. Naproxen PPI, misoprostol, Avoid NSAIDs
celecoxib (if on aspirin, or double-dose H2-blocker
naproxen plus (second line)
gastroprotection) 2. Low-dose celecoxib
***Patients with a history of ulcers should be tested for H. pylori and treated if positive.4***
More. . .

Cardiovascular Risk
What are the CV risks • In addition to the hypertension and heart failure concerns with all NSAIDs, NSAIDs seem to increase the risk of CV
of NSAIDs? events (MI, stroke, death) to varying degrees, even in healthy people.28
• In one meta-analysis, CV risk conferred by NSAIDs was proportional regardless of baseline CV risk, meaning that
absolute risk was higher in patients with high baseline CV risk. Heart failure risk was doubled by all NSAIDs.11
• A nested case-control study also showed that the odds of heart failure admission is doubled in users of high-dose
diclofenac, indomethacin, or piroxicam.38 For NSAIDs overall, current use increased risk by 20% vs previous use.29
• U.S. NSAID labeling has been revised to reflect that NSAIDs can increase the risk of heart attack or stroke in patients
with or without heart disease or risk factors for heart disease, and that there is an increased risk of heart failure with
NSAID use.30
Why might NSAIDs • Adverse CV events associated with NSAIDs are thought to be caused by NSAIDs upsetting the balance between
increase the risk of CV vasoconstricting, platelet aggregating thromboxane A2 (produced by COX-1) and opposing vasodilating prostacyclin
events? (produced by COX-2). This may lead to vasoconstriction, platelet aggregation, and thrombosis.20
• NSAID-associated heart failure is thought to be due to increased peripheral vascular resistance and reduced renal
perfusion caused by prostaglandin inhibition.29
• NSAIDs that tend to be more COX-2 selective could therefore be assumed to have more CV risk. In fact, the COX-2
selective agents rofecoxib (Vioxx) and valdecoxib (Bextra) were withdrawn from the market due to CV risk.20 But not all
COX-2 inhibitors are the same. For example, rofecoxib causes higher blood pressure and more edema than celecoxib.
Celecoxib, but not rofecoxib, seems to improve endothelial function and reduce oxidative stress.31
• NSAIDs that provide sustained COX-1 inhibition (e.g., naproxen) may pose less CV risk.32
• NSAIDs that are the safest from a CV standpoint tend to have higher GI toxicity and vice versa. See our chart, Safety
Comparison of NSAIDs. Keep in mind that risk rankings are not absolute and are based on epidemiologic data.
What do we know • In the U.S., NSAID labeling has been revised to reflect that although current information suggests that CV risk may not
about specific NSAIDs be equal among all NSAIDs, there is insufficient evidence to definitively say that the risk of any particular NSAID is
and CV risk? higher or lower than that of any other particular NSAID.30
Celecoxib
• In a randomized study of celecoxib for prevention of colorectal adenomas, celecoxib 400 mg BID more than doubled the
risk of a composite endpoint of CV death, MI, stroke, or heart failure compared to placebo (HR 3.4, 95% CI 1.4 to 7.8). 33
• In PRECISION (see footnote a), celecoxib 209 mg, naproxen, and ibuprofen had similar impact on CV death, MI, and
stroke.8 Study weaknesses included lack of a placebo group and low CV event rate. Almost 70% of patients stopped
Continued… taking the study drug.
More. . .

Specific NSAIDs and • In a prespecified substudy of PRECISION (see footnote a), ambulatory blood pressure monitoring revealed a 4 mmHg
CV risk, increase in SBP in ibuprofen users, but no significant change in celecoxib or naproxen users (p=0.0009 for ibuprofen vs
Continued celecoxib). Celecoxib users also had lower odds of a new diagnosis of hypertension vs ibuprofen users (OR 0.39,
p=0.004).34
• Arthritis patients 60 years of age and older without CV disease were randomized to switch to celecoxib or continue their
previous NSAID and followed for a median of three years.9 The incidence of CV events was similar in both groups.
Study weaknesses included a low CV event rate in both groups, and an over 50% dropout rate in the celecoxib group.
• In a nested case-control study, celecoxib appeared to pose a lower risk of heart failure hospitalization than other NSAIDs,
at least at low doses.29
Diclofenac
• Diclofenac 100 to 150 mg daily carries CV risk similar to that of rofecoxib.11,27,35 However, unlike coxibs, diclofenac
offers no GI advantage.27 Given the availability of safer alternatives, oral diclofenac should be avoided.27
Ibuprofen
• A Danish cohort study examined the risk of specific CV events in healthy users vs nonusers of NSAIDs.28 Ibuprofen was
associated with an increased odds ratio of coronary death or nonfatal MI (OR 1.52) and fatal or nonfatal stroke (OR
1.29).28
• The Coxib and Traditional NSAID Trialists’ Collaboration meta-analysis of individual participant data from randomized
controlled trials found a 2.2-fold risk of a major coronary event among participants taking ibuprofen 2400 mg/day
compared to placebo.11
• See Celecoxib, above, for information on ibuprofen in the PRECISION trial.
Naproxen
• A Danish cohort study examined the risk of specific CV events in healthy users vs nonusers of NSAIDs.28 Naproxen
increased the risk of fatal and nonfatal stroke (OR 1.91).28 But naproxen was previously found to have a neutral CV
effect in meta-analyses of observational and randomized trials.25,26
• See Celecoxib, above, for information on naproxen in the PRECISION trial.
More. . .

Cardiovascular Risk, continued
Is NSAID-associated • In the U.S., NSAID labeling has been revised to reflect that higher doses appear to confer greater risk. 30
CV risk dose- • Risk of NSAID-associated heart failure hospital admission appears to be dose-dependent.29
dependent? • Not surprisingly, a dose-dependent risk has not been obvious in healthy individuals.28.36 In an analysis of patients
following hospitalization for a first MI, the risk of death with ibuprofen was increased 2.2-fold at doses higher than
1,200 mg/day, while re-infarction was increased at doses below and above 1,200 mg/day.37
• Celecoxib about doubled the odds of coronary death or nonfatal MI in healthy individuals, but interestingly, only at
200 mg daily or less.28 Previous studies had indicated that celecoxib increases the risk of CV events in a dose-dependent
manner. In a case-control study (n=486,378), an increased risk for MI was reported with celecoxib (RR 1.56, 95% CI,
1.22-2.00; at ≤200 mg/day, RR 1.44, 95% CI 1.12-1.87; and at >200 mg/day, RR 2.45, 95% CI 2.41-3.25).38 Gislason et
al found an association between celecoxib and increased risk for death (HR 2.57, 95% CI 2.15-3.08) and reinfarction (HR
1.50, 95% CI 1.10-2.05) in patients following hospitalization for first MI. Higher risks were observed in patients taking
higher doses of celecoxib. There was a 1.9-fold increased risk for death in patients taking ≤200 mg/day compared to
4.7-fold increase in patients taking >200 mg/day of celecoxib. The risk for reinfarction was increased by 1.5-fold in the
patients taking ≤200 mg/day compared to a 1.6-fold risk in patients taking >200 mg/day.37 In a randomized study of
celecoxib for prevention of colorectal adenomas, celecoxib 400 mg BID more than doubled the risk of a composite
endpoint of CV death, MI, stroke, or heart failure compared to placebo (HR 3.4, 95% CI 1.4 to 7.8).33 Risk was lower for
the 200 mg BID arm (HR 2.3, 95% CI 0.9 to 5.5).33 In PRECISION (see footnote a), lower-dose celecoxib (mean daily
dose 209 mg) did not pose more CV risk than ibuprofen (mean daily dose 2,045 mg) or naproxen (mean daily dose
852 mg).8
What is the • In the U.S., NSAID labels have been revised to reflect that NSAID-associated CV risk can occur in the first weeks of use,
relationship between and the risk may increase with duration of use.30 Patients treated with an NSAID following the first year after a
duration of NSAID use myocardial infarction are more likely to die than patients who do not take an NSAID.30
and CV risk? • Cohort data suggests that risk begins early and continues throughout treatment. Diclofenac risk started at the beginning
of treatment, whereas ibuprofen risk began after one week of treatment, and celecoxib risk started after 14 to 30 days of
treatment. Diclofenac posed the highest risk (HR 3.26, 95% CI 2.57 to 3.86 for death or MI during the first week of
treatment).39 These same investigators assessed the risk of death by year after a first MI. The risk was highest in the first
year, and although risk declined, it remained elevated for at least four years.40
More. . .

Cardiovascular Risk, continued
Can NSAIDs be used • For patients with CV disease or risk factors for ischemic heart disease, acetaminophen, aspirin, tramadol, opioids (short-
in patients with CV term), or nonacetylated salicylates (e.g., diflunisal, salsalate [U.S. only], choline magnesium trisalicylate [U.S. only])
risk? may be considered before moving to an NSAID.20
• Data on the CV risk of nonacetylated salicylates is lacking.
• After a myocardial infarction, there does not seem to be a safe time frame for using an NSAID.39
• If an NSAID is necessary, use the lowest dose necessary for the shortest time needed.20 Consider adding aspirin 81 mg
and a proton pump inhibitor in patients with increased CV risk.20 (Note: aspirin is not proven to mitigate NSAID-
associated CV risk.)20,27 Monitor renal function and blood pressure.20 Watch for edema and GI toxicity.20
• For patients with low GI risk (see above) but high CV risk (e.g., history of CV event, diabetes, hypertension,
hyperlipidemia, obesity), choose naproxen.4,25-27 Add gastroprotection if on aspirin.4 Consider limiting the dose to
500 mg BID [Evidence level B-1].8 PRECISION (see footnote a) results suggest low-dose celecoxib is an option.8
• For patients with moderate GI risk (see above) but high CV risk (e.g., history of CV event, diabetes, hypertension,
hyperlipidemia, obesity), choose naproxen.4,25-27 These patients will also require a proton pump inhibitor or misoprostol.4
Consider limiting the naproxen dose to 500 mg BID [Evidence level B-1].8 PRECISION (see footnote a) results suggest
low-dose celecoxib is an option.8
• Patients with both high GI risk (see above) and high CV risk should not receive an NSAID (including celecoxib).4
Aspirin Considerations
Is there an interaction • Aspirin inhibits platelet function by inhibiting platelet COX-1. NSAIDs can compete with aspirin for this receptor, and
between NSAIDs and NSAIDs do not completely and persistently inhibit COX-1 irreversibly like aspirin does.59
aspirin? • Taking an NSAID may interfere with aspirin’s antiplatelet effect in some patients/circumstances.59-61 Taking the NSAID
after aspirin has exerted its antiplatelet effect or allowing the NSAID to clear the system before aspirin is taken may
minimize or avoid the interaction.60
• There is no proof that the impact of chronic NSAID use is large enough to decrease aspirin’s cardioprotective effect.
Observational studies and a post-hoc analysis of a large randomized study seem to suggest this interaction doesn’t reduce
aspirin’s benefit on CV outcomes.58,62,63 However, no randomized studies have been designed to prospectively test the
clinical significance of the interaction.
• Occasional NSAID use should not interfere with chronic aspirin therapy.60,61
• Most evidence for this interaction comes from studies of ibuprofen and naproxen, but is likely with other nonselective
NSAIDs. If the interaction is concerning, advising aspirin patients who regularly take any NSAID to wait 30 minutes
after they take their immediate-release aspirin before taking their NSAID may allow aspirin time to bind to platelet
COX-1 before the NSAID.60,61
Continued… • Due to lack of data about the impact of NSAIDs on the antiplatelet effects of enteric-coated aspirin, it may be prudent to
More. . .

NSAID/Aspirin use immediate-release aspirin instead in patients who need a chronic NSAID.60
interaction, continued • Durlaza (extended-release aspirin) labeling recommends waiting two to four hours after taking Durlaza to take a
nonselective NSAIDs such as ibuprofen.41
How do various • Durlaza is a formulation of low-dose aspirin designed to release over 24 hours.41 There is no evidence it is superior or
aspirin formulations safer than other low-dose aspirin formulations for prevention of CV events. It cannot be used in place of immediate-
compare? release aspirin when rapid action is needed (e.g., treatment of acute MI).41
• Although powdered or effervescent aspirin may be absorbed more quickly than immediate-release tablets,42 there is no
proof they are safer.
• Yosprala (aspirin 81 mg or 325 mg/omeprazole 40 mg) is much more expensive than the two drugs purchased separately.
• For information on plain, enteric-coated, and buffered aspirin, see our chart, The Truth About Aspirin.
Hepatotoxicity
How common is • About 10% of all cases of drug-induced hepatotoxicity are associated with use of an NSAID.43 This is probably a
hepatotoxicity with reflection of how commonly they are prescribed.44 Most studies have found an incidence of one to nine cases per
NSAIDs, what are the 100,000 patients.43 This is about 100 times lower than the incidence of GI, CV, or renal side effects.43
risk factors and • Risk factors may include metabolic syndrome, hepatic steatosis, and age over 75 years.43
mechanism, and is it • The mechanism may involve hypersensitivity or formation of a toxic metabolite.43,44
more/less common • Oral diclofenac carries a higher risk of hepatotoxicity than other NSAIDs, with a risk of 11/100,000 patients in one
with certain NSAIDs? study.45 Most cases occur within the first six months of use.43 Sulindac also seems to carry a relatively high risk.43
Ibuprofen seems relatively safe, perhaps due to its short half-life and lack of formation of toxic metabolites.43
Nephrotoxicity
How common is • NSAIDs reduce blood flow to the glomerulus by inhibiting production of vasodilating prostaglandins.48
nephrotoxicity with • The American Board of Internal Medicine’s Choosing Wisely site (www.choosingwisely.org), in partnership with the
NSAIDs, what are the American Society of Nephrology, advises avoiding NSAIDs in patients with hypertension, heart failure, or diabetic or
risk factors and other chronic kidney disease.46 NSAIDs can increase blood pressure, cause fluid retention, and worsen renal function in
mechanism, is it these patients.46 Among patients with hypertension, those who take NSAIDs for three months or longer are about 32%
more/less common more likely to have chronic kidney disease than nonusers.47
with certain NSAIDs, • Consider NSAID alternatives such as acetaminophen, tramadol, or short-term use of an opioid.46 If an NSAID must be
and how can risk be used, monitor renal function and avoid ketorolac (a high-potency NSAID) and NSAIDs with half-lives over 12 hours,
managed? such as oxaprozin (Daypro), nabumetone, naproxen, meloxicam, or piroxicam.47-50 An occasional dose of OTC
ibuprofen or naproxen, or daily low-dose aspirin, should be safe for most patients.51,52
Continued… • If an NSAID must be used in a high-risk patient, including those taking an ACEI, ARB, or diuretic, consider checking
More. . .

Nephrotoxicity, serum creatinine and potassium within the first three weeks.53 Prescription NSAID labeling generally recommends
continued checking a chemistry profile periodically in all patients.
• In PRECISION (see footnote a), the risk of serious renal events was lower with celecoxib vs ibuprofen (0.7% vs 1.1%,
p=0.004).8 The addition of aspirin attenuates this celecoxib advantage, but does not negate it.58 Study weaknesses
included lack of a placebo group and high dropout rate; almost 70% of patients stopped taking the study drug during the
10-year study. Also, nephrotoxicity was not a primary outcome measure of this trial.
Nonoral NSAID Safety

Do topical or • Little topical diclofenac is absorbed systemically, probably <5% of the amount absorbed after oral administration.54 It
injectable NSAIDs appears to have a systemic safety profile comparable to placebo in studies of up to 12 weeks’ duration.44,54
pose lower systemic • Topical NSAIDs, including topical diclofenac, posed a lower risk of GI side effects compared to oral NSAIDs in studies
risks than oral of up to 12 weeks in length.54
NSAIDs? • Topical diclofenac does not appear to carry CV risk, at least short-term, and can be considered for patients with hand or
knee osteoarthritis.44,55
• In studies of up to 12 weeks’ duration, mean change from baseline in liver transaminases was similar with topical
diclofenac and placebo.44
• The American College of Rheumatology suggests use of topical NSAIDs over oral NSAIDs as a first-line
pharmacotherapy option in patients over 75 years of age with hand osteoarthritis.56
• Regardless, labeling of topical diclofenac products carries warnings about CV and GI risks, and recommendations for
liver function monitoring.
• Although use of a topical NSAID plus an oral NSAID might be an attractive idea, the combination has not been shown to
be more effective than an oral NSAID alone.57
• Injectable NSAIDs cannot be assumed to have better risk profiles than their oral counterparts. Labeled warnings are the
same.
a. The PRECISION trial was a randomized head-to-head CV safety comparison of NSAIDs (mean daily doses of celecoxib 209 mg, naproxen
852 mg, and ibuprofen 2,045 mg) in arthritis patients with CV risk factors or CV disease.8
b. GI Risk: patients at highest GI risk are those with a history of complicated ulcer, especially recent; those using anticoagulants or
corticosteroids; and those with more than two risk factors: age over 65, high-dose NSAID, history of uncomplicated ulcer, or use of aspirin
or other antiplatelet agent (e.g., clopidogrel [Plavix]).4 Moderate GI risk patients have one or two of these risk factors.4
Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical
judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national
organizations. Information and internet links in this article were current as of the date of publication.
More. . .
Levels of Evidence 5. Garcia Rodriguez LA, Barreales Tolosa L. Risk of

In accordance with our goal of providing Evidence- upper gastrointestinal complications among users of
traditional NSAIDs and COXIBs in the general
Based information, we are citing the LEVEL OF population. Gastroenterology 2007;132:498-506.
EVIDENCE for the clinical recommendations we 6. Henry D, Lim LL, Garcia Rodriguez LA, et al.
publish. Variability in risk of gastrointestinal complications
Level Definition Study Quality with individual non-steroidal anti-inflammatory drugs:
results of a collaborative meta-analysis. BMJ
A Good-quality 1. High-quality RCT 1996;312:1563-6.
patient-oriented 2. SR/Meta-analysis of 7. MacDonald TM, Morant SV, Robinson GC, et al.
evidence.* RCTs with consistent Association of upper gastrointestinal toxicity of non-
findings steroidal anti-inflammatory drugs with continued
3. All-or-none study exposure: cohort study. BMJ 1997;315:1333-7.
B Inconsistent or 1. Lower-quality RCT 8. Nissen SE, Yeomans ND, Solomon DH, et al.
limited-quality Cardiovascular safety of celecoxib, naproxen, or
2. SR/Meta-analysis
patient-oriented ibuprofen for arthritis. N Engl J Med 2016;375:2519-
with low-quality
evidence.* 29.
clinical trials or of
9. MacDonald TM, Hawkey CJ, Ford I, et al.
studies with
Randomized trial of switching from prescribed non-
inconsistent findings
selective non-steroidal anti-inflammatory drugs to
3. Cohort study
prescribed celecoxib: the Standard care vs.
4. Case control study
Celecoxib Outcome Trial (SCOT). Eur Heart J
C Consensus; usual practice; expert opinion; 2017;38:1843-50.
disease-oriented evidence (e.g., physiologic or 10. Clinical Pharmacology powered by ClinicalKey.
surrogate endpoints); case series for studies of Tampa, FL: Elsevier. 2018. http://clinicalkey.com.
diagnosis, treatment, prevention, or screening. (Accessed May 25, 2018).
*Outcomes that matter to patients (e.g., morbidity, mortality,
11. Coxib and traditional NSAID Trialists’ (CNT)
symptom improvement, quality of life).
RCT = randomized controlled trial; SR = systematic review Collaboration, Bhala N, Emberson J, et al. Vascular
[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of and upper gastrointestinal effects of non-steroidal
Recommendation Taxonomy (SORT): a patient-centered approach to anti-inflammatory drugs: meta-analyses of individual
grading evidence in the medical literature. Am Fam Physician participant data from randomised trials. Lancet
2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.] 2013;382:769-79.
12. Chen YF, Jobanputra P, Barton P, et al.
Project Leader in preparation of this clinical Cyclooxygenase-2 selective non-steroidal anti-
inflammatory drugs (etodolac, meloxicam, celecoxib,
resource (340702): Melanie Cupp, Pharm.D., rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for
BCPS osteoarthritis and rheumatoid arthritis: a systematic
review and economic evaluation. Health Technol
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More. . .
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Safety Comparison of NSAIDs

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−This Clinical Resource gives subscribers

additional insight related to the Recommendations published in−

January 2017 ~ Resource #330101

Safety Comparison of NSAIDs

Drug COX-2 selectivity (in vitro)b,1-3 GI Risk4-7,15 Cardiovascular Riska,4,8-10,16

Celecoxib (Celebrex) High Low Moderate to High

Diclofenac (Voltaren [Canada], High Moderate High

Diflunisal Moderate Moderate Data not availablea

Etodolac High Low Moderate

Fenoprofen (U.S. only)(Nalfon, Moderate Moderate Data not availablea

Flurbiprofen Low High Data not availablea

Ibuprofen Moderate Low Moderate to High

Indomethacin (Indocin [U.S.], Low Moderate to High Moderate

Ketoprofen (Anafen [Canada], Low Moderate Data not availablea

Ketorolac (Toradol [Canada], Low High Data not availablea

Drug COX-2 selectivity (in vitro)b,1-3 GI Risk4-7,15 Cardiovascular Riska,4,8-10,16

Meloxicam (Mobic [U.S.], High Low Moderate

Nabumetone Moderate Low Data not availablea

Naproxen (Anaprox DS, etc, Low Moderate Low to Moderate

Oxaprozin (Daypro, generics) Low High Data not availablea

Piroxicam (Feldene [U.S.], Moderate High Low

Salsalate (U.S. only) Unavailable Low Data not availablea

Sulindac Moderate Moderate Data not availablea

Tolmetin (U.S. only) Low Moderate Data not availablea

Evidence and Recommendations You Can Trust…

July 2018 ~ Resource #340702

Managing NSAID Risks

Clinical Question Pertinent Information

Clinical Question Pertinent Information

Clinical Question Pertinent Information

Clinical Question Pertinent Information

Clinical Question Pertinent Information

Clinical Question Pertinent Information

Clinical Question Pertinent Information

Clinical Question Pertinent Information

Nonoral NSAID Safety

Levels of Evidence 5. Garcia Rodriguez LA, Barreales Tolosa L. Risk of

Long-term Arthritis Safety Study. JAMA https://www.fda.gov/Drugs/DrugSafety/ucm451800.ht

Evidence and Recommendations You Can Trust…

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