Safety Comparison of NSAIDs

Transcription

1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in January 2017 ~ Resource # 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 Risk 4-7,15 Cardiovascular Risk a,4,8-10,16 Aspirin Low Moderate Low Celecoxib (Celebrex) High Low Moderate to High Diclofenac (Voltaren [Canada], generics) High Moderate High Diflunisal Moderate Moderate Data not available a Etodolac High Low Moderate Fenoprofen (U.S. only)(nalfon, generics) Moderate Moderate Data not available a Flurbiprofen Low High Data not available a Ibuprofen Moderate Low Moderate to High Indomethacin (Indocin [U.S.], generics) Ketoprofen (Anafen [Canada], generics) Ketorolac (Toradol [Canada], generics) Low Moderate to High Moderate Low Moderate Data not available a Low High Data not available a Copyright 2017 by Therapeutic Research Center

2 (Clinical Resource #330101: Page 2 of 3) Drug COX-2 selectivity (in vitro) b,1-3 GI Risk 4-7,15 Cardiovascular Risk a,4,8-10,16 Meclofenamate (U.S. only) Moderate High Data not available a Mefenamic acid (Ponstel [U.S.], Ponstan [Canada], generics) Meloxicam (Mobic [U.S.], Mobicox [Canada], generics) High Low to Moderate Data not available a High Low Moderate Nabumetone Moderate Low Data not available a Naproxen (Anaprox DS, etc, generics) Low Moderate Low to Moderate Oxaprozin (Daypro, generics) Low High Data not available a Piroxicam (Feldene [U.S.], generics) Moderate High Low Salsalate (U.S. only) Unavailable Low Data not available a Sulindac Moderate Moderate Data not available a Tolmetin (U.S. only) Low Moderate Data not available a 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. Copyright 2017 by Therapeutic Research Center

3 (Clinical Resource #330101: Page 3 of 3) Project Leader in preparation of this clinical resource (330101): Melanie Cupp, Pharm.D., BCPS References 1. Chou R, Helfand M, Peterson K, et al. Drug class review on cyclo-oxygenase (COX)-2 inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs). Final report update 3. Oregon evidence-based practice center, Oregon Health & Sciences University. Portland, Oregon November Warner TD, Mitchell JA. Cyclo-oxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004;18: Kawai S. Cyclo-oxygenase selectivity and the risk of gastro-intestinal complications of various nonsteroidal anti-inflammatory drugs: a clinical consideration. Inflamm Res 1998;47(Suppl 2):S Clinical Resource, Managing NSAID Risks. Pharmacist s Letter/Prescriber s Letter. January Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996;312: Singh G. Recent considerations in nonsteroidal antiinflammatory drug gastropathy. Am J Med 1998;105(1B):31-8S. 7. Clinical Resource, NSAIDs and the Risk of GI Effects. Pharmacist s Letter/Prescriber s Letter. February Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 2007;115: Fosbol EL, Folke F, Jacobsen S, et al. Causespecific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes 2010;3: McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med 2011;8:e Epub 2011 Sep Clinical Resource, Lab monitoring for common medications. Pharmacist s Letter/Prescriber s Letter. June Barkin RL, Beckerman M, Blum SL, et al. Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging 2010;27: Bergamo RR, Cominelli F, Kopple JD, Zipser RD. Comparative acute effects of aspirin, diflunisal, ibuprofen and indomethacin on renal function in healthy man. Am J Nephrol 1989;9: Cook ME, Wallin JD, Thakur VD, et al. Comparative effects of nabumetone, sulindac, and ibuprofen on renal function. J Rheumatol 1997;24: MacDonald TM, Morant SV, Robinson GC, et al. Association of upper gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 1997;315: Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med Nov 13, 2016 [Epub ahead of print]. Cite this document as follows: Clinical Resource, Safety Comparison of NSAIDs. Pharmacist s Letter/Prescriber s Letter. January Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2017 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

4 This Clinical Resource gives subscribers additional insight related to the Recommendations published in July 2018 ~ Resource # 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 of the risk of NSAIDassociated GI harm? What are the risk factors for an NSAIDassociated GI event? The relative risk for a GI bleed or perforation increases about four-fold in patients who use NSAIDs compared to those who don t use NSAIDs. 2,3 Risk factors for an NSAID-associated GI event includes male gender, history of peptic ulcer (especially bleeding ulcer), dyspepsia, and CV disease. 1,4 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

5 (Clinical Resource #340702: Page 2 of 13) Clinical Question Pertinent Information Gastrointestinal Risk, continued What is the time Events can occur within the first month of use. 4 course of NSAIDassociated GI Risk decreases after the first few months of NSAID use, but never goes away. 4 risk? How do NSAIDs compare in regard to GI risk, and what may account for these differences? The bulk of evidence suggests that lower doses of ibuprofen and celecoxib have the lowest GI risk, and piroxicam and ketorolac have the highest risk [Evidence level B-3,4]. 2,5-9 Naproxen seems to have moderate risk. 2,6,7 Risk may be high with some of the longer-acting NSAIDs such as sustained-release formulations, piroxicam, and ketorolac due to longer mucosal exposure. 4,5 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 sixmonth study). 14 Celecoxib may not be safer than nonselective NSAIDs past six months of use, or in patients taking low-dose aspirin In PRECISION (see footnote a), celecoxib was not associated with a lower risk of hemorrhage or ulceration. 8 What is the GI safety of salicylates? Do gastroprotective agents reduce the risk of NSAID-associated GI toxicity? Continued Diflunisal seems to have moderate GI risk, although it has been included in only a few studies. 6 Salsalate seems to pose low GI risk based on endoscopic data 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. Misoprostol reduces the relative risk of gastroduodenal complications by about 40% among patients at higher than average risk. 21 The recommended dose is 200 mcg four times daily, but adverse effects (e.g., diarrhea, cramping) may require dose reduction. 15 However, lower doses may also cause GI symptoms and have not been shown to reduce ulcer complications. 22 Proton pump inhibitors are well tolerated and have been shown to reduce the risk of bleeding ulcers associated with

6 (Clinical Resource #340702: Page 3 of 13) Clinical Question Gastroprotective agents, continued How do I choose an NSAID based on a patient s GI risk? Pertinent Information celecoxib in high-risk patients (NNT=11). 23 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. 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. For purposes of management of GI risk, the American College of Gastroenterology categorizes patients as high, moderate, and low risk (see footnote b): 4 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 High CV risk Celecoxib or other low-gi risk NSAID Naproxen or low-dose celecoxib (if on aspirin, naproxen plus gastroprotection) 1. Celecoxib alone 2. NSAID plus PPI, misoprostol, or double-dose H2-blocker (second line) 1. Naproxen PPI, misoprostol, or double-dose H2-blocker (second line) 2. Low-dose celecoxib 1. Avoid NSAIDs if possible 2. Celecoxib plus PPI or misoprostol Avoid NSAIDs ***Patients with a history of ulcers should be tested for H. pylori and treated if positive. 4 ***

7 (Clinical Resource #340702: Page 4 of 13) Clinical Question Cardiovascular Risk What are the CV risks of NSAIDs? Why might NSAIDs increase the risk of CV events? What do we know about specific NSAIDs and CV risk? Continued Pertinent Information In addition to the hypertension and heart failure concerns with all NSAIDs, NSAIDs seem to increase the risk of CV 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 Adverse CV events associated with NSAIDs are thought to be caused by NSAIDs upsetting the balance between vasoconstricting, platelet aggregating thromboxane A2 (produced by COX-1) and opposing vasodilating prostacyclin (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. 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. 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 taking the study drug.

8 (Clinical Resource #340702: Page 5 of 13) Clinical Question Specific NSAIDs and CV risk, Continued Pertinent Information In a prespecified substudy of PRECISION (see footnote a), ambulatory blood pressure monitoring revealed a 4 mmhg increase in SBP in ibuprofen users, but no significant change in celecoxib or naproxen users (p= for ibuprofen vs 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.

9 (Clinical Resource #340702: Page 6 of 13) Clinical Question Pertinent Information 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 dosedependent? Not surprisingly, a dose-dependent risk has not been obvious in healthy individuals In an analysis of patients Risk of NSAID-associated heart failure hospital admission appears to be dose-dependent. 29 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, ; at 200 mg/day, RR 1.44, 95% CI ; and at >200 mg/day, RR 2.45, 95% CI ). 38 Gislason et al found an association between celecoxib and increased risk for death (HR 2.57, 95% CI ) and reinfarction (HR 1.50, 95% CI ) 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 relationship between duration of NSAID use and CV risk? 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. 30 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. 30 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

10 (Clinical Resource #340702: Page 7 of 13) Clinical Question Pertinent Information Cardiovascular Risk, continued Can NSAIDs be used For patients with CV disease or risk factors for ischemic heart disease, acetaminophen, aspirin, tramadol, opioids (shortterm), or nonacetylated salicylates (e.g., diflunisal, salsalate [U.S. only], choline magnesium trisalicylate [U.S. only]) in patients with CV 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 NSAIDassociated 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 between NSAIDs and aspirin? Continued Aspirin inhibits platelet function by inhibiting platelet COX-1. NSAIDs can compete with aspirin for this receptor, and NSAIDs do not completely and persistently inhibit COX-1 irreversibly like aspirin does. 59 Taking an NSAID may interfere with aspirin s antiplatelet effect in some patients/circumstances 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 Due to lack of data about the impact of NSAIDs on the antiplatelet effects of enteric-coated aspirin, it may be prudent to

11 (Clinical Resource #340702: Page 8 of 13) Clinical Question NSAID/Aspirin interaction, continued How do various aspirin formulations compare? Hepatotoxicity How common is hepatotoxicity with NSAIDs, what are the risk factors and mechanism, and is it more/less common with certain NSAIDs? Nephrotoxicity How common is nephrotoxicity with NSAIDs, what are the risk factors and mechanism, is it more/less common with certain NSAIDs, and how can risk be managed? Continued Pertinent Information use immediate-release aspirin instead in patients who need a chronic NSAID. 60 Durlaza (extended-release aspirin) labeling recommends waiting two to four hours after taking Durlaza to take a nonselective NSAIDs such as ibuprofen. 41 Durlaza is a formulation of low-dose aspirin designed to release over 24 hours. 41 There is no evidence it is superior or safer than other low-dose aspirin formulations for prevention of CV events. It cannot be used in place of immediaterelease 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. About 10% of all cases of drug-induced hepatotoxicity are associated with use of an NSAID. 43 This is probably a reflection of how commonly they are prescribed. 44 Most studies have found an incidence of one to nine cases per 100,000 patients. 43 This is about 100 times lower than the incidence of GI, CV, or renal side effects. 43 Risk factors may include metabolic syndrome, hepatic steatosis, and age over 75 years. 43 The mechanism may involve hypersensitivity or formation of a toxic metabolite. 43,44 Oral diclofenac carries a higher risk of hepatotoxicity than other NSAIDs, with a risk of 11/100,000 patients in one 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 NSAIDs reduce blood flow to the glomerulus by inhibiting production of vasodilating prostaglandins. 48 The American Board of Internal Medicine s Choosing Wisely site ( in partnership with the American Society of Nephrology, advises avoiding NSAIDs in patients with hypertension, heart failure, or diabetic or other chronic kidney disease. 46 NSAIDs can increase blood pressure, cause fluid retention, and worsen renal function in these patients. 46 Among patients with hypertension, those who take NSAIDs for three months or longer are about 32% more likely to have chronic kidney disease than nonusers. 47 Consider NSAID alternatives such as acetaminophen, tramadol, or short-term use of an opioid. 46 If an NSAID must be used, monitor renal function and avoid ketorolac (a high-potency NSAID) and NSAIDs with half-lives over 12 hours, such as oxaprozin (Daypro), nabumetone, naproxen, meloxicam, or piroxicam An occasional dose of OTC ibuprofen or naproxen, or daily low-dose aspirin, should be safe for most patients. 51,52 If an NSAID must be used in a high-risk patient, including those taking an ACEI, ARB, or diuretic, consider checking

12 (Clinical Resource #340702: Page 9 of 13) Clinical Question Nephrotoxicity, continued Pertinent Information serum creatinine and potassium within the first three weeks. 53 Prescription NSAID labeling generally recommends 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 injectable NSAIDs pose lower systemic risks than oral NSAIDs? Little topical diclofenac is absorbed systemically, probably <5% of the amount absorbed after oral administration. 54 It appears to have a systemic safety profile comparable to placebo in studies of up to 12 weeks duration. 44,54 Topical NSAIDs, including topical diclofenac, posed a lower risk of GI side effects compared to oral NSAIDs in studies of up to 12 weeks in length. 54 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.

13 (Clinical Resource #340702: Page 10 of 13) Levels of Evidence In accordance with our goal of providing Evidence- Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish. Level Definition Study Quality A B C Good-quality patient-oriented evidence.* Inconsistent or limited-quality patient-oriented evidence.* 1. High-quality RCT 2. SR/Meta-analysis of RCTs with consistent findings 3. All-or-none study 1. Lower-quality RCT 2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings 3. Cohort study 4. Case control study Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. *Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life). RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69: Project Leader in preparation of this clinical resource (340702): Melanie Cupp, Pharm.D., BCPS References 1. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation 2008;118: Masso Gonzalez EL, Patrignani P, Tacconelli S, Garcia Rodriguez LA. Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum 2010;62: Hernandez-Diaz S, Rodriguez LA. Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies. J Clin Epidemiol 2002;55: Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104: Garcia Rodriguez LA, Barreales Tolosa L. Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population. Gastroenterology 2007;132: Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996;312: MacDonald TM, Morant SV, Robinson GC, et al. Association of upper gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs with continued exposure: cohort study. BMJ 1997;315: Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med 2016;375: MacDonald TM, Hawkey CJ, Ford I, et al. Randomized trial of switching from prescribed nonselective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT). Eur Heart J 2017;38: Clinical Pharmacology powered by ClinicalKey. Tampa, FL: Elsevier (Accessed May 25, 2018). 11. Coxib and traditional NSAID Trialists (CNT) Collaboration, Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382: Chen YF, Jobanputra P, Barton P, et al. Cyclooxygenase-2 selective non-steroidal antiinflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess 2008;12: Laporte JR, Ibáñez L, Vidal X, et al. Upper gastrointestinal bleeding associated with the use of NSAIDs. Newer versus older agents. Drug Safety 2004;27: Cryer B, Li C, Simon LS, et al. GI-REASONS: a novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial. Am J Gastroenterol 2013;108: Chan FK, Graham DY. Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complications-review and recommendations based on risk assessment. Aliment Pharmacol Ther 2004;19: Strand V. Are COX-2 inhibitors preferable to nonselective non-steroidal anti-inflammatory drugs in patients with risk of cardiovascular events taking lowdose aspirin? Lancet 2007;370: Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib

14 (Clinical Resource #340702: Page 11 of 13) Long-term Arthritis Safety Study. JAMA 2000;284: Roth S, Bennett R, Caldron P, et al. Reduced risk of NSAID gastropathy (GI mucosal toxicity) with nonacetylated salicylate (salsalate): an endoscopic study. Semin Arthritis Rheum 1990;19(4 Supp 2): Lanza F, Rack MF, Doucette M, et al. An endoscopic comparison of the gastroduodenal injury seen with salsalate and naproxen. J Rheumatol 1989;16: Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 2007;115: Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123: Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. 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Human pharmacology of naproxen sodium. J Pharmacol Exp Ther 2007;322: Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352: Ruschitzka F, Borer JS, Krum H, et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION- ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. Eur Heart J 2017;38: O Riordan M. Widely used diclofenac associated with increased risk of cardiovascular events. February 13, (Accessed June 15, 2018). 36. Fosbol EL, Gislason GH, Jacobsen S, et al. Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther 2009;85: Gislason GH, Jacobsen S, Rasmussen JN, et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation 2006;113: Andersohn F, Suissa S, Garbe E. Use of first- and second-generation cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs and risk of acute myocardial infarction. Circulation 2006;113: Schjerning Olsen AM, Fosbol EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal antiinflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation 2011;123: Olsen AM, Fosbol EL, Lindhardsen J, et al. Longterm cardiovascular risk of nonsteroidal antiinflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation 2012;126: Product information for Durlaza. New Haven Pharmaceuticals, Inc. 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15 (Clinical Resource #340702: Page 12 of 13) 44. Roth SH, Fuller P. Pooled safety analysis of diclofenac sodium topical solution 1.5% (w/w) in the treatment of osteoarthritis in patients aged 75 years or older. Clin Interv Aging 2012;7: Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver Injury in the general population of Iceland. Gastroenterology 2013;144: Choosing Wisely. American Society of Nephrology. Avoid nonsteroidal anti-inflammatory drugs (NSAIDS) in individuals with hypertension or heart failure or CKD of call causes, including diabetes. April 4, clinician-lists/american-society-nephrology-nsaids-inindividuals-with-hypertension-heart-failure-orchronic-kidney-disease/. (Accessed May 27, 2018). 47. Hsu CC, Wang H, Hsu YH, et al. Use of nonsteroidal anti-inflammatory drugs and risk of chronic kidney disease in subjects with hypertension: nationwide longitudinal cohort study. Hypertension 2015;66: Lapi F, Azoulay L, Yin H, et al. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ 2013;346:e Clinical Resource, Common Questions About Ketorolac. Pharmacist s Letter/Prescriber s Letter. June Ingrasciotta Y, Sultana J, Giorgianni F, et al. Association of individual non-steroidal antiinflammatory drugs and chronic kidney disease: a population-based case control study. PLoS One 2015;10:e Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med 2009;169: Bouvy ML, Heerdink ER, Hoes AW, Leufkens HG. Effects of NSAIDs on the incidence of hospitalisations for renal dysfunction in users of ACE inhibitors. Drug Saf 2003;26: Fournier JP, Lapeyre-Mestre M, Sommet A, et al. Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study. PLoS One 2012;7:e doi: 1371/journal.pone Epub 2012 Mar Derry S, Conaghan P, Da Silva JA, et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 2016;(4):CD Altman RD. Safety advantages of topical versus oral nonsteroidal antiinflammatory drugs. J Rheumatol 2011;38: Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 2012;64: Argoff CE, Gloth FM. Topical nonsteroidal antiinflammatory drugs for management of osteoarthritis in long-term care patients. Ther Clin Risk Manag 2011;7: Reed GW, Abdallah MS, Shao M, et al. Effect of aspirin coadministration on the safety of celecoxib, naproxen, or ibuprofen. J Am Coll Cardiol 2018;71: Anzellotti P, Capone ML, Jeyam A, et al. Low-dose naproxen interferes with the antiplatelet effects of aspirin in healthy subjects: recommendations to minimize the functional consequences. Arthritis Rheum 2011;63: FDA. Concomitant use of ibuprofen and aspirin: potential for attenuation of the antiplatelet effect of aspirin. September 8, tmarketdrugsafetyinformationforpatientsandprovider s/ucm pdf. (Accessed May 28, 2018). 61. Gurbel PA, Bliden KP, Zhu J, et al. Thromboxane inhibition during concurrent therapy with low-dose aspirin and over-the-counter naproxen sodium. J Thromb Thrombolysis 2018;45: Hudson M, Baron M, Rahme E, Pilote L. Ibuprofen may abrogate the benefits of aspirin when used for secondary prevention of myocardial infarction. J Rheumatol 2005;32: Fischer LM, Schlienger RG, Matter CM, et al. Current use of nonsteroidal anti-inflammatory drugs and the risk of acute myocardial infarction. Pharmacotherapy 2005;25: Cite this document as follows: Clinical Resource, Managing NSAID Risks. Pharmacist s Letter/Prescriber s Letter. July 2018.

16 (Clinical Resource #340702: Page 13 of 13) Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2018 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com