330127

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
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. . .
Copyright 2017 by Therapeutic Research Center
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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. Pharmacists Letter/Prescribers 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
Pharmacists Letter/Prescribers 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. Pharmacists Letter/Prescribers 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. Pharmacists Letter/Prescribers
Letter. January 2017.
Evidence and Recommendations You Can Trust
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Subscribers to the Letter can get clinical resources, like this one,
on any topic covered in any issue by going to PharmacistsLetter.com,
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This Clinical Resource gives subscribers
additional insight related to the Recommendations published in
January 2017 ~ Resource #330101
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 GI or CV events. 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; 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 dont 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?
What evidence A systematic review of observational studies revealed that the risk of upper GI bleeding or perforation was not increased
compares NSAIDs in by celecoxib. Risk was low with ibuprofen (RR 2.69), followed by diclofenac (RR 3.98), meloxicam (RR 4.15),
regard to GI risk? indomethacin (RR 4.15), ketoprofen (RR 5.4), naproxen (RR 5.57), piroxicam (RR 9.94), and ketorolac (RR 14.54).2
Risk in one case-control study, from lowest to highest, was ranked: ibuprofen (twice the risk of non-use), meloxicam and
celecoxib (RR 2.7), diclofenac (RR 3.7), ketoprofen (RR 5.4), indomethacin (RR 7.2), and naproxen (RR 8.1).5
A meta-analysis of case-control studies ranked risk, from lowest to highest, as follows: ibuprofen, followed by
diclofenac, sulindac, diflunisal, naproxen, and indomethacin with around twice the risk of ibuprofen, and highest with
piroxicam and ketoprofen, with around four times the risk of ibuprofen.7
A cohort study found a lower risk with nabumetone, and surprisingly indomethacin, compared to ibuprofen. There was
about a 30% to 40% higher relative risk with ketoprofen, naproxen, and immediate-release diclofenac compared to
ibuprofen; and a 63% higher risk with sustained-release diclofenac. Piroxicam had about three times the risk of
ibuprofen.8
The PRECISION trial was a randomized head-to-head 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.18 All patients
received esomeprazole, but adherence was not assessed. The risk of a serious GI event (a secondary outcome measure)
was lowest with celecoxib (p=0.01 vs naproxen; p = 0.002 vs ibuprofen). Celecoxib was linked to one fewer serious GI
event (mostly anemia) for every 200 patients treated for 20 months. Study weaknesses included lack of a placebo group
and high dropout rate; almost 70% of patients stopped taking the study drug.
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.39 The incidence of GI events (not a primary outcome
measure) was low, and similar in both groups. Over 50% of patients randomized to celecoxib discontinued it, vs about
30% for the other NSAIDs.
In summary, the bulk of evidence suggests that low-dose ibuprofen and the agents with relatively more COX-2
selectivity (see discussion below) have the lowest GI risk, and piroxicam and ketorolac have the highest risk [Evidence
level B; case-control and cohort studies].2,5,7,8 Naproxen seems to have moderate risk.2,7,8
More. . .

Why might different Risk is high with some of the longer-acting NSAIDs such as sustained-release formulations, piroxicam (57-hour half-
NSAIDs confer life), and ketorolac (half-life up to ten hours), perhaps due to longer mucosal exposure.4,5,6
different GI risk? Ibuprofen seems to be a lower-risk NSAID in regard to GI events.2,5,7,8 This might be because low doses are typically
used, possibly owing to nonprescription availability, or because it has a short half-life (two hours).4,6 However, it is
important to note that at high doses (2400 mg daily), ibuprofens 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.52
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 and seem to be
less likely than less selective NSAIDs to cause GI events.2,4,5,8,9
The selective COX-2 inhibitor celecoxib (Celebrex) 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).10 Celecoxib may not be safer than nonselective NSAIDs past six months of use, or in
patients taking low-dose aspirin.11,12,40
What is the GI safety Diflunisal seems to have moderate GI risk, although it has been included in only a few studies.7
of salicylates? Salsalate seems to pose low GI risk based on endoscopic data.60,61
The GI risk of choline magnesium salicylate is also not well characterized.
Aspirin poses moderate GI toxicity.7,37 For help with decisions regarding aspirin use for primary CV prevention, see our
chart, Aspirin for Primary Prevention.
Do gastroprotective Gastroprotective agents that are available to reduce NSAID GI risk include misoprostol, proton pump inhibitors, and H2-
agents reduce the risk blockers.11
of NSAID-associated Misoprostol reduces the relative risk of gastroduodenal complications by about 40% among patients at higher than
GI toxicity? average risk.13
The recommended dose is 200 mcg four times daily, but adverse effects (e.g., diarrhea, cramping) may require dose
reduction.11 However, lower doses may also cause GI symptoms and have not been shown to reduce ulcer
complications.14
Proton pump inhibitors are well tolerated and have been shown to reduce the risk of bleeding ulcers associated with
celecoxib in high-risk patients (NNT=11).15 Furthermore, PPIs can reduce the risk of NSAID-associated ulcer bleeding
in patients with H. pylori and a history of ulcer bleeding. They also seem protective against NSAID-associated ulcer
bleeding in epidemiologic studies and in secondary analysis of prospective studies.4
Standard-dose H2-blockers reduce the risk of NSAID-associated duodenal ulcers.11,14 But high-dose H2-blockers (e.g.,
80 mg/day famotidine) reduce the risk of both duodenal and gastric ulcers.11,14,16 Benefit is highest in patients with H.
pylori.11 It should be noted that H2-blockers have not been shown to reduce the risk of serious GI events in NSAID users.
More. . .

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:4
patients 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
For patients with high GI risk and low CV risk, avoid NSAIDs if possible.4 Alternatively, use celecoxib with a
proton pump inhibitor or misoprostol [Evidence level B; lower quality RCT].4,13,15
Patients with both high GI risk and high CV risk should not receive an NSAID (including celecoxib).4
Moderate GI risk patients have one or two of the above risk factors.4
For patients with moderate GI risk 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 cardiovascular event, diabetes, hypertension,
hyperlipidemia, obesity), choose naproxen [Evidence level A; high-quality meta-analyses].4,23,24,26 These patients
will also require a proton pump inhibitor or misoprostol.4 PRECISION results suggest low-dose celecoxib is an
option.18
Low GI risk patients are those without risk factors.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).4,18
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; high-quality meta-analyses].4,23,24,26 Add gastroprotection if on
aspirin.4 PRECISION results suggest low-dose celecoxib is an option.18
These recommendations are summarized in the following table:4,18
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.17
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.52
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.38
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.57
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.37
NSAID-associated heart failure is thought to be due to increased peripheral vascular resistance and reduced renal
perfusion caused by prostaglandin inhibition.38
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), valdecoxib (Bextra), and lumiracoxib (Prexige, Canada only) were withdrawn from
the market due to CV risk.55
NSAIDs that provide sustained COX-1 inhibition (e.g., naproxen) may pose less CV risk.55
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 Celecoxib
about specific NSAIDs In a randomized study of celecoxib for prevention of colorectal adenomas, celecoxib 400 mg BID more than doubled the
and CV risk? 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).22
naproxen 852 mg, and ibuprofen 2,045 mg) in arthritis patients with CV risk factors or CV disease. These NSAIDs had
similar impact on CV death, MI, and stroke.18 Study weaknesses included lack of a placebo group and low CV event rate.
Almost 70% of patients stopped taking the study drug.
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.39 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,
Continued at least at low doses.38
More. . .

Specific NSAIDs and Diclofenac
CV risk, A Danish cohort study examined the risk of specific CV events in healthy users vs nonusers of NSAIDs.17 These same
continued investigators had previously examined the risk of MI and death in this same cohort.20 All NSAIDs were used for a short
period (about a week to a month), mostly in low doses.17,20 In this study, diclofenac (e.g., Voltaren) at doses of at least
100 mg daily increased the risk of CV death (OR 2.04), coronary death or nonfatal MI (OR 2.01), and fatal or nonfatal
stroke (OR 1.70) in a case-crossover analysis, a method that minimizes the effect of unmeasured confounders. For
comparison, with rofecoxib, the odds ratio for risk of CV death was 1.66. Be aware that few patients in the Danish
cohort study received celecoxib or rofecoxib (1.5% and 1.6% of patients, respectively). Also, this was not a randomized
study, so confounding by indication may have played a role in the results (i.e., patients at high CV risk may have been
more likely to receive diclofenac). However, patients who received rofecoxib tended to be older than those who received
diclofenac.17 The CV risk observed with diclofenac has a pharmacologic basis; it has COX-2 selectivity approaching that
of rofecoxib in vitro.17 Diclofenac has previously been associated with increased CV events (observational trials analysis
RR 1.40, 95% CI 1.16-1.70; randomized trials analysis RR 1.63, 95% CI 1.12-2.37).23,24 An analysis by Gislason et al
found that diclofenac at a daily dose of 150 mg conferred a risk of major coronary events similar to that of the coxibs. 25
In summary diclofenac 100 to 150 mg daily carries cardiovascular risk similar to that of rofecoxib.26,27,52 However,
unlike coxibs, diclofenac offers no GI advantage.26 Given the availability of safer alternatives, oral diclofenac should be
avoided.26
Ibuprofen
In the Danish cohort study, 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).17
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.52
See Celecoxib, above, for information on ibuprofen in the PRECISION trial.
Naproxen
Also in the Danish cohort study, naproxen increased the risk of fatal and nonfatal stroke (OR 1.91).17 But naproxen was
previously found to have a neutral CV effect in meta-analyses of observational and randomized trials.23,24
In the U.S., NSAID labeling has been revised to reflect that although current information suggests that CV risk may not
be equal among all NSAIDs, there is insufficient evidence to definitively say that the risk of any particular NSAID is
higher or lower than that of any other particular NSAID.57
See Celecoxib, above, for information on naproxen in the PRECISION trial.
More. . .

Cardiovascular Risk, continued
Is NSAID-associated In the Danish cohort study described above, a dose-dependent effect was not apparent with ibuprofen.17 In a randomized
CV risk dose- trial analysis there was an increase in CV risk with high-dose ibuprofen which was almost statistically significant (RR
dependent? 1.51; 95% CI 0.96-2.37).20 In the Gislason et al analysis in patients following hospitalization for a first MI, the risk of
death with ibuprofen was increased 2.2-fold at doses higher than 1200 mg/day and re-infarction was increased at doses
below and above 1200 mg/day.25
For rofecoxib in the Danish cohort study, for coronary death or nonfatal MI, the odds ratio was 1.6 at doses <25 mg daily
and 3.02 at doses >25 mg daily.17
Celecoxib about doubled the odds of coronary death or nonfatal MI, but interestingly, only at 200 mg daily or less.17
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).21 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.25 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).22 Risk was lower for the 200 mg
BID arm (HR 2.3, 95% CI 0.9 to 5.5).22 In the PRECISION randomized trial, 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).18
In the U.S., NSAID labeling has been revised to reflect that higher doses appear to confer greater risk.57
Risk of NSAID-associated heart failure hospital admission appears to be dose-dependent.38
What is the A study using data from the Danish National Registry sought to clarify the relationship between NSAID treatment
relationship between duration and CV risk in patients with a previous MI.58 They found that risk began early, and continued throughout
duration of NSAID use treatment. Diclofenac risk started at the beginning of treatment, whereas ibuprofen risk began after one week of
and CV risk? 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). These same investigators then 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.59
In the U.S., NSAID labels have been revised to reflect that NSAID-associated CV risk can occur in the first weeks of use,
and the risk may increase with duration of use.57 Patients treated with an NSAID following the first year after a
myocardial infarction are more likely to die than patients who do not take an NSAID.57
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.37
Data on the CV risk of nonacetylated salicylates is lacking.
If an NSAID is necessary, use the lowest dose necessary for the shortest time needed.37 Consider adding aspirin 81 mg
and a proton pump inhibitor in patients with increased CV risk.37 (Note: aspirin is not proven to mitigate NSAID-
associated CV risk.)26,37 Monitor renal function and blood pressure. Watch for edema and GI toxicity.37
After a myocardial infarction, there does not seem to be a safe time frame for using an NSAID.58
For patients with low GI risk (see above) but high CV risk (e.g., history of CV event, diabetes, hypertension,
hyperlipidemia, obesity), choose naproxen [Evidence level A; high-quality meta-analyses].4,23,24,26 Add gastroprotection
if on aspirin.4 Consider limiting the dose to 500 mg BID [Evidence level B; lower quality RCT].18 PRECISION results
suggest low-dose celecoxib is an option.18
For patients with moderate GI risk (see above) but high CV risk (e.g., history of cardiovascular event, diabetes,
hypertension, hyperlipidemia, obesity), choose naproxen [Evidence level A; high-quality meta-analyses].4,23,24,26 These
patients will also require a proton pump inhibitor or misoprostol.4 Consider limiting the naproxen dose to 500 mg BID
[Evidence level B; lower quality RCT].18 PRECISION results suggest low-dose celecoxib is an option.18
Patients with both high GI risk (see above) and high CV risk should not receive an NSAID (including celecoxib).4
NSAID/Aspirin Interaction
Is there an interaction Some NSAIDs may interfere with aspirins antiplatelet effect. Aspirin exerts its antiplatelet effect by irreversibly
between NSAIDs and acetylating platelet COX-1. This prevents the formation of thromboxane A2 for the life of the platelet.29 Although
aspirin? NSAIDs have antiplatelet effects, the effect is reversible and variable, and therefore cannot be relied upon for
cardiovascular protection.30 If an NSAID is present in the COX-1 channel, it can block aspirins access to its site of
action. An NSAIDs ability to block aspirins action depends on its COX-1 affinity.29 Immediate-release aspirin can
take one hour to cause complete platelet inhibition.30 So taking the NSAID after aspirin has exerted its antiplatelet effect
or allowing the NSAID to clear the system before aspirin is taken will minimize or avoid the interaction. In a landmark
study, Catella-Lawson et al found that ibuprofens interference with aspirins antiplatelet effect could be avoided by
taking aspirin two hours before ibuprofen.31
In another small study, healthy volunteers were given aspirin 81 mg once daily for eight days. 32 Thrice daily ibuprofen
400 mg taken one, seven, and 13 hours after aspirin was added on day nine and continued along with aspirin for ten days.
Ibuprofen taken in this manner did not affect platelet function.32 These investigators assumed nearly complete platelet
inhibition if thromboxane B2 (thromboxane A2s more stable metabolite) inhibition was >90%. 32 Other investigators
have used 95% as the cut-off.30,33
Continued Ibuprofen should be avoided with enteric-coated aspirin taken for cardioprotection. One study showed that the
More. . .

NSAIDs/aspirin antiplatelet effect of enteric-coated low-dose aspirin is attenuated when ibuprofen 400 mg is dosed two, seven, and even
interaction, 12 hours after aspirin, perhaps because the absorption of enteric-coated aspirin is delayed vs immediate-release aspirin.34
continued In a small crossover study in healthy volunteers, naproxen 220 mg twice daily plus aspirin 100 mg once daily was taken
for five days.30 In one phase of the study, the morning dose of naproxen was taken two hours before aspirin. After a
14-day washout, patients were crossed over to take naproxen two hours after aspirin. Taking naproxen two hours after
immediate-release aspirin did not affect aspirins antiplatelet effect, but taking naproxen two hours before aspirin did
slightly reduce aspirins antiplatelet effect.30
In another small study of naproxen 220 mg taken three times daily with daily enteric-coated aspirin 81 mg, mean
thromboxane B2 inhibition was 99.7%.33 This study did not specify timing of the naproxen doses relative to the aspirin
dose. Furthermore, this study did not rule out a naproxen/aspirin interaction; thromboxane B2 inhibition could have been
due to naproxen.
In an additional study, healthy volunteers took enteric-coated aspirin 81 mg once daily for five days.56 Daily enteric-
coated aspirin 81 mg was continued, and patients received either naproxen 500 mg/esomeprazole 20 mg or placebo twice
daily on days six through ten, with the morning dose administered at the same time as aspirin. COX-1 inhibition, as
measured by serum thromboxane B2 inhibition, was not affected by naproxen. As in the previously described study,
these results could have been due to naproxens effect on COX-1. Aspirin pretreatment, the scheduled vs as-needed
administration of naproxen, and lack of measurement of actual antiplatelet activity are further study limitations.
In the PRECISION trial, neither ibuprofen nor naproxen appeared to interfere with the efficacy of aspirin, but the study
was not designed to assess this.18
Until more information is available, it is prudent to advise patients that ibuprofen and naproxen should be taken about
one hour after aspirin to give aspirin time to bind to platelets. Ibuprofen should be taken no sooner than eight hours
before aspirin.34 Also advise aspirin users to take NSAIDs only occasionally, use immediate-release NSAIDs only, and
choose immediate-release (i.e., plain, not enteric-coated) aspirin if they plan to take naproxen or ibuprofen. Consider
using an NSAID alternative (e.g., acetaminophen, tramadol, opioids, topicals) in patients taking low-dose aspirin to
minimize NSAID interference with aspirins antiplatelet effects.
Hepatotoxicity
How common is About 10% of all cases of drug-induced hepatotoxicity are associated with use of an NSAID.35 This is probably a
hepatotoxicity with reflection of how commonly they are prescribed.28 Most studies have found an incidence of one to nine cases per
NSAIDs, what are the 100,000 patients.35 This is about 100 times lower than the incidence of GI, cardiovascular, or renal side effects.35
risk factors and Risk factors may include metabolic syndrome, hepatic steatosis, and age over 75 years.35
mechanism, and is it The mechanism may involve hypersensitivity or formation of a toxic metabolite.28,35
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.36 Most cases occur within the first six months of use.35 Sulindac also seems to carry a relatively high risk.35
Ibuprofen seems relatively safe, perhaps due to its short half-life and lack of formation of toxic metabolites.35
More. . .

Nephrotoxicity
How common is NSAIDs reduce blood flow to the glomerulus by inhibiting production of vasodilating prostaglandins.44
nephrotoxicity with Risk factors for acute kidney injury include older age, diabetes, renal insufficiency, and heart failure.44 The American
NSAIDs, what are the Board of Internal Medicines Choosing Wisely site (www.choosingwisely.org), in partnership with the American Society
risk factors and of Nephrology, advises avoiding NSAIDs in patients with hypertension, heart failure, or diabetic or other chronic kidney
mechanism, is it disease.45 NSAIDs can increase blood pressure, cause fluid retention, and worsen renal function in these patients. 45
more/less common Among patients with hypertension, those who take NSAIDs for three months or longer are about 32% more likely to
with certain NSAIDs, have chronic kidney disease than nonusers.54
and how can risk be Consider NSAID alternatives such as acetaminophen, tramadol, or short-term use of an opioid.45 If an NSAID must be
managed? used, monitor renal function and avoid those with half-lives over 12 hours, such as oxaprozin (Daypro), ketorolac,
nabumetone, naproxen, meloxicam, or piroxicam.46,47,53.54,62 An occasional dose of OTC ibuprofen or naproxen, or daily
low-dose aspirin, should be safe for most patients.48,49
If an NSAID must be used in a high-risk patient, including those taking an ACEI, ARB, or diuretic, consider checking
serum creatinine and potassium weekly for several weeks.50,51 Prescription NSAID labeling generally recommends
checking a chemistry profile periodically in all patients.
naproxen 852 mg, and ibuprofen 2,045 mg) in arthritis patients with CV risk factors or CV disease.18 The risk of serious
renal events was lower with celecoxib vs ibuprofen (0.7% vs 1.1%, p=0.004). 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.41 It
injectable NSAIDs appears to have a systemic safety profile comparable to placebo in studies of up to 12 weeks duration.28,41
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.41
NSAIDs? Topical diclofenac does not appear to carry cardiovascular risk, at least short-term, and can be considered for patients
with hand or knee osteoarthritis.28,42
In studies of up to 12 weeks duration, mean change from baseline in liver transaminases was similar with topical
diclofenac and placebo.28
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.43
Regardless, labeling of topical diclofenac products carries warnings about cardiovascular and GI risks, and
recommendations for liver function monitoring.
Continued
More. . .

Safety of topical or Although use of a topical NSAID plus an oral NSAID might be an attractive idea, the combination has not been shown to
injectable NSAIDs, be more effective than an oral NSAID alone.19
continued Injectable NSAIDs cannot be assumed to have better risk profiles than their oral counterparts. Labeled warnings are the
same.
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 with individual non-steroidal anti-inflammatory drugs:

In accordance with the trend towards Evidence-Based results of a collaborative meta-analysis. BMJ
1996;312:1563-6.
Medicine, we are citing the LEVEL OF EVIDENCE
8. MacDonald TM, Morant SV, Robinson GC, et al.
for the statements we publish. Association of upper gastrointestinal toxicity of non-
Level Definition steroidal anti-inflammatory drugs with continued
A High-quality randomized controlled trial (RCT) exposure: cohort study. BMJ 1997;315:1333-7.
High-quality meta-analysis (quantitative 9. Chen YF, Jobanputra P, Barton P, et al.
systematic review) Cyclooxygenase-2 selective non-steroidal anti-
B Nonrandomized clinical trial inflammatory drugs (etodolac, meloxicam, celecoxib,
Nonquantitative systematic review rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for
Lower quality RCT osteoarthritis and rheumatoid arthritis: a systematic
Clinical cohort study review and economic evaluation. Health Technol
Case-control study Assess 2008;12:1-278.
Historical control 10. Cryer B, Li C, Simon LS, et al. GI-REASONS: a
Epidemiologic study novel 6-month, prospective, randomized, open-label,
C Consensus blinded endpoint (PROBE) trial. Am J Gastroenterol
Expert opinion 2013 2013;108:392-400.
D Anecdotal evidence 11. Chan FK, Graham DY. Review article: prevention of
In vitro or animal study non-steroidal anti-inflammatory drug gastrointestinal
Adapted from Siwek J, et al. How to write an evidence-based clinical complications-review and recommendations based
review article. Am Fam Physician 2002;65:251-8. on risk assessment. Aliment Pharmacol Ther
2004;19:1051-61.
Project Leader in preparation of this clinical resource 12. Strand V. Are COX-2 inhibitors preferable to non-
(330101): Melanie Cupp, Pharm.D., BCPS selective non-steroidal anti-inflammatory drugs in
patients with risk of cardiovascular events taking low-
dose aspirin? Lancet 2007;370:2138-51.
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Cite this document as follows: Clinical Resource, Managing NSAID Risks. Pharmacists Letter/Prescribers Letter.
January 2017.
Evidence and Recommendations You Can Trust
3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249
Subscribers to the Letter can get clinical resources, like this one,
on any topic covered in any issue by going to PharmacistsLetter.com,
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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

January 2017 ~ Resource #330101

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

Clinical Question Pertinent Information

Nonoral NSAID Safety

Clinical Question Pertinent Information

Levels of Evidence with individual non-steroidal anti-inflammatory drugs:

Evidence and Recommendations You Can Trust

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