Monthly Clinical Update

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MONTHLY CLINICAL UPDATE

UNEXPECTED ASPIRIN POSITIVES

Q: My patient is not prescribed aspirin and is showing up positive on a KardiAssure™ report. Are there any sources outside of aspirin that could be causing this positive result?

A: Aspirin rapidly metabolizes to the active metabolite, salicylic acid, in the body; therefore, salicylic acid is the urinary marker used to determine aspirin adherence. Salicylic acid and/or its derivatives are in a variety of foods, medications, and health products. It is important to assess a patient’s diet, over-the-counter (OTC) product use, and prescription medications when interpreting positive results for aspirin on a KardiAssure™ report.

Aspirin plays an important role in prevention of cardiovascular events. Good adherence to aspirin therapy has been associated with a 40% and 55% reduction in risk of cardiovascular events and all-cause mortality, respectively.1 Upon ingestion, aspirin is rapidly converted to the active metabolite salicylic acid;2 therefore, salicylic acid is the marker tested in the KardiAssure urinalysis to determine aspirin adherence. Multiple prescription and OTC medications contain salicylates that metabolize to salicylic acid and will lead to a positive result on an Aegis KardiAssure test (see Table 1).3,4 Salicylic acid is also commonly used topically due to its exfoliative and keratolytic effects.2 It can be found in various health and beauty products such as acne treatments, dandruff products, shampoos, wart removers, face washes, makeup, and skin exfoliants.2,5

A surprising source of salicylic acid is commonly ingested fruits and vegetables where salicylic acid serves as a natural defense against environmental stress and pathogens. Examples of foods that may lead to salicylic acid excretion when ingested are found in Table 2.6-7 Studies have shown that vegetarians excrete more salicylic acid than non-vegetarians who consume less fruits and vegetables.8-10 In a study comparing salicylic acid excretion between non-vegetarians and vegetarians not taking salicylate drugs and patients taking daily aspirin (75-150 mg), no significant difference was observed in urinary salicylic acid concentrations between vegetarians and patients taking aspirin. Of note, aspirin was not reported to be directly administered in the study and there is no documentation of measures taken to determine adherence to aspirin therapy.9 Methyl salicylate, or oil of wintergreen, is widely available in topical OTC products like Bengay® as well as in hard candies like LifeSavers® Wint O Green® Sugar Free mints, some smokeless tobacco products, licorice, and some honeys. Ingestion or use of large quantities of methyl salicylate products has the potential to cause a positive result for aspirin on a KardiAssure report; however, the amount of methyl salicylate needed to cause a positive result is not well defined.11-12 More research is needed to determine dietary effects on urinalysis for aspirin adherence.

In a review of KardiAssure urinalysis results tested at Aegis from 145 patients treated for hypertension, 47 out of 76 (62%) patients prescribed aspirin were negative for salicylic acid, suggesting nonadherence. These results imply that exposures to salicylic acid outside of aspirin may not significantly interfere with adherence determinations in patients taking aspirin, although more research and evidence is needed. It is important to assess a patient’s diet, OTC product use, and prescription medications when interpreting positive results for aspirin on a KardiAssure report.

JULY 2018 | Copyright © 2018 Aegis Sciences Corporation All Rights Reserved Table 1 PRESCRIPTION AND OTC SOURCES OF SALICYLIC ACID (SKINCARE PRODUCTS NOT INCLUDED)3-4 BRAND NAME(S) GENERIC NAME INDICATION(S) Aggrenox aspirin/extended-release dipyridamole Stroke prevention, headache Alka-Seltzer products aspirin/sodium bicarbonate Antacid, pain Amigesic* / Salflex* salsalate Rheumatic disorders Ascriptin / Aspergum / Aspirtab Aspirin (could be regular, low dose, "baby", enteric Acute coronary syndrome, / Bayer / Easprin / Ecotrin / coated, buffered, gum, or in powder form) coronary artery disease, pain, Ecpirin / Entercote / etc. fever, stroke/transient ischemic attack (TIA) Aspercreme Pain Relieving trolamine salicylate Pain cream / Myoflex Cream / Arthricream Bengay Pain Relieving Cream / menthol/methyl salicylate Pain Salonpas Pain Patch / Menthol C / Their-Gesic Doan’s Pain Reliever magnesium salicylate Pain Durlaza extended-release aspirin Acute coronary syndrome, coronary artery disease, pain, fever, stroke/ transient ischemic attack (TIA) Excedrin Migraine / Goody’s / acetaminophen/aspirin/caffeine Pain, headache other names Fiorinal / Lanorinal aspirin/butalbital/caffeine Headache Fiorinal with Codeine aspirin/butalbital/caffeine/codeine phosphate Headache Methocarbamol and aspirin aspirin/methocarbamol Pain, muscular pain Norgesic* aspirin/orphenadrine/caffeine Muscular pain PainAid acetaminophen/aspirin/salicylamide Pain, fever Paser aminosalicylic acid Tuberculosis Pepto Bismol / other names bismuth subsalicylate Diarrhea, dyspepsia Percodan* aspirin/oxycodone hydrochloride Pain Phosphasal methenamine/sodium phosphate/monobasic/ Urinary tract symptoms monohydrate/phenyl salicylate/methylene blue/ hyoscyamine sulfate Prosed EC hyoscyamine/methenamine/methylene blue/phenyl Urinary tract symptoms salicylate Soma Compound aspirin/carisoprodol Musculoskeletal conditions Soma Compound with Codeine aspirin/carisoprodol/codeine Musculoskeletal conditions Synalgos-DC aspirin/caffeine/dihydrocodeine bitartrate Pain Tricosal choline salicylate/magnesium salicylate Pain Trilisate choline magnesium trisalicylate Pain Urised belladonna alkaloids/methenamine/methylene blue/ Urinary tract symptoms phenyl salicylate Yosprala aspirin/omeprazole Secondary prevention of cardiovascular and cerebrovascular events * Brand name has been discontinued; generic product available

JULY 2018 | Copyright © 2018 Aegis Sciences Corporation All Rights Reserved Table 2 DIETARY SOURCES OF SALICYLIC ACID6 FRUITS VEGETABLES SPICES DRINKS Apples Broccoli Cardamom Garlic Fruit Juices Apricots Cucumbers Chat masala Ginger Instant Coffee Bananas Green peppers Chili powder Honey Tea Blackberries Cinnamon Mint Wines Blueberries Cloves Nutmeg Cherries Coriander Oregano Grapes Cumin Paprika Grapefruit Curry powder Pepper Oranges Fennel Tamarind Peaches Fenugreek Tumeric Raspberries Garam masala Thyme Raisins Strawberries

Adapted from: Wood A, Baxter G, Thies F, Kyle J, Duthie G. A systematic review of salicylates in foods: Estimated daily intake of a Scottish population. Mol Nutr Food Res. 2011;55:S7-14.

Please call our clinical scientists at 1-877-552-3232 if you require additional information.

NOTICE: The information above is intended as a resource for health care providers. Providers should use their independent medical judgment based on the clinical needs of the patient when making determinations of who to test, what medications to test, testing frequency, and the type of testing to conduct.

REFERENCES:

1. Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J. 2013;34:2940-8. 2. Baselt RC. Disposition of Toxic Drugs and Chemicals in Man. 11th ed. Seal Beach, CA: Biomedical Publications; 2017. 3. U.S. National Library of Medicine. Daily Med. Available at: https://dailymed.nlm.nih.gov/dailymed/index.cfm. Accessed June 11, 2018. 4. U.S. Department of Health and Human Services. Drugs@FDA: FDA approved Drug Products. Available at: https://www. accessdata.fda.gov/scripts/cder/daf/. Accessed June 11, 2018. 5. Salicylic Acid. EWG’s Skin Deep® Cosmetics Database. Available at: https://www.ewg.org/skindeep/. Accessed June 11, 2018. 6. Wood A, Baxter G, Thies F, Kyle J, Duthie G. A systematic review of salicylates in foods: Estimated daily intake of a Scottish population. Mol Nutr Food Res. 2011;55:S7-14. 7. Duthie GG, Wood AD. Natural salicylates: foods, functions and disease prevention. Food Funct. 2011;2:515-20. 8. Baxter GJ, Lawrence JR, Graham AB, Wiles D, Paterson JR. Identification and determination of salicylic acid and salicyluric acid in urine of people not taking salicylate drugs. Ann Clin Biochem. 2002 Jan;39(Pt 1):50-5. 9. Lawrence JR, Peter R, Baxter GJ, Robson J, Graham AB, Paterson JR. Urinary excretion of salicyluric and salicylic acids by non- vegetarians, vegetarians, and patients taking low dose aspirin. J Clin Pathol. 2003 Sep;56(9):651-3. 10. Janssen PL, Hollman PC, Reichman E, Venema DP, van Staveren WA, Katan MB. Urinary salicylate excretion in subjects eating a variety of diets shows that amounts of bioavailable salicylates in foods are low. Am J Clin Nutr. 1996 Nov;64(5):743-7. 11. Swain AR, Dutton SP, Truswell AS. Salicylates in foods. J Am Diet Assoc. 1985 Aug;85(8):950-60. 12. Chen C, Isabelle LM, Pickworth WB, Pankow JF. Levels of mint and wintergreen flavorants: smokeless tobacco products vs. confectionery products. Food Chem Toxicol. 2010 Feb;48(2):755-63.