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Over-the-Counter Pain Reliever and Aspirin Use Within a Sample of Long-term Cyclooxygenase 2 Users

Over-the-Counter Pain Reliever and Aspirin Use Within a Sample of Long-term Cyclooxygenase 2 Users The Celecoxib Long-term Arthritis Safety Study (CLASS) evaluated the adverse gastrointestinal (GI) effects caused by the use of the selective cyclooxygenase 2 (COX-2) drug celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis and rheumatoid arthritis.1 The study found no significant difference in the GI ulcer complication rate (ie, bleeding, perforation, or obstruction in the GI tract) between celecoxib and nonselective NSAIDs. The authors attributed this finding to a higher-than-anticipated aspirin comedication rate of 21% among study participants, a rate almost double that of previous clinical trial experience. Since usage patterns in clinical trials and routine clinical practice often differ, the purpose of the present study was to estimate aspirin comedication rates among long-term COX-2 users. To provide a thorough description of over-the-counter (OTC) NSAID and pain reliever use, we also examine comedication with 2 other OTC NSAIDs (ie, ibuprofen and naproxen sodium) and another commonly used OTC pain reliever, acetaminophen. Methods A telephone survey was conducted among long-term COX-2 users, defined as members 18 years of age or older with at least a 90-day supply of COX-2 therapy (ie, celecoxib and rofecoxib) obtained through commercially available mail-order pharmacy services (Express Scripts Inc, Maryland Heights, Mo) in the months of August, September, or October 2001. The study sample consisted of members who were receiving health benefits through an employer located in the Northeast. This employer had a membership of approximately 95 000, with an approximate retiree–active employee ratio of 6:1. The average age of the enrollee population was 59 years. The telephone survey was administered by nurses who were trained in survey administration. The survey asked members about their use of COX-2s and OTC agents over the past 30 days. Information gathered included the number of days that members took each agent, the dose or strength of each agent, and, for those taking aspirin, the reason for use. Survey administration began December 3, 2001, and ended January 19, 2002. Calls were made until approximately 350 surveys were completed. Results Of the 525 sampling pool members we attempted to contact, 32 (6%) had disconnected or wrong telephone numbers, 106 (20%) were not available when calls were attempted, 31 (6%) were not taking COX-2s on a long-term basis, 2 (<1%) were no longer receiving health benefits through the employer, and 1 had died. Of those members who were contacted, 98% agreed to participate. The responses of 14 respondents were excluded owing to incomplete surveys, resulting in a final sample size of 325. Response bias between those with completed surveys (n = 325) and those whom we were unable to reach (n = 106) was evaluated using the chronic disease score.2 The chronic disease score is a measure of chronic disease status measured using pharmacy claims data and has been shown to predict total medical and outpatient costs. Using the outpatient-cost chronic disease score, no differences were found between those who completed the survey and those we attempted to contact but did not reach (mean [SD], 1566 [708.1] vs 1586 [619.3], respectively; t = −0.279; P = .78). The mean (SD) age of the respondents was 71 (9.4) years, and 67% were female. These numbers closely approximate the average age and sex distribution of all COX-2 users for this employer group (average age, 69 years; female, 64%). The mean (SD) number of days respondents took a COX-2 in the past 30 days was 28.2 (5.83), with 95% taking the same amount every day and 89% taking it every day in the past 30 days. More than 76% of respondents used at least 1 OTC NSAID or acetaminophen on 1 day or more in the past 30 days, with 48% using aspirin, 43% using acetaminophen, 7% using ibuprofen, and 3% using naproxen. Approximately 23% had used 2 or more OTC agents in the past 30 days, with 20% using both aspirin and acetaminophen in addition to their COX-2. Based on the number of days an OTC agent was taken, 53% of the respondents used at least 1 OTC product on 15 days or more over the past 30 days, with 45%, 12%, 2%, and fewer than 1% taking aspirin, acetaminophen, ibuprofen, and naproxen, respectively. Analysis of OTC use by age revealed that 50% of those aged 56 years and older but just 25% of those aged 37 to 55 years were taking aspirin (P = .03, Table 1). The rate of comedication with nonaspirin NSAIDs among those aged 56 years and older was lower than among those aged 37 to 55 years, but this findings represented a nonsignificant trend (P = .12). View LargeDownload Percentage of Long-term Cyclooxygenase 2 Users Taking Aspirin, Acetaminophen, or Nonaspirin Nonsteroidal Anti-inflammatory Drugs (NSAIDs) by Age Group Of the respondents who were taking aspirin (n = 156), 86% took it daily, 99% were using it for cardioprotection (93% for cardioprotection only and 6% for both cardioprotection and pain), and 79% took an enteric-coated or buffered form. Of those who were taking aspirin for cardioprotection only, 50% were taking doses of 325 mg or more, 43% were taking doses of 81 mg, and 7% were taking doses of 162 to 165 mg. Of those who were taking acetaminophen, 20% were taking it every day, and among those who were taking acetaminophen every day, 25% were taking 2 g/d or more. Comment Two patterns of OTC NSAID and acetaminophen use emerged among our sample of long-term COX-2 users: (1) a high rate of comedication with aspirin for cardioprotection, and (2) a sizeable percentage of comedication with OTC pain relievers, primarily acetaminophen, and less so with other nonaspirin NSAIDs (ie, ibuprofen and naproxen). These patterns of behavior have implications for patient GI safety and may suggest the need for better pain management. Limitations of these data should be noted. First, the data represent the experience of a predominantly retiree population in the northeastern United States. The rates of OTC use may not reflect those found in younger populations or in other parts of the country. However, the rates of OTC use were still substantial even among respondents aged 37 to 55 years. Additional research is needed to document comedication rates among enrollees who are younger or reside in different geographic regions. Approximately 50% of the long-term COX-2 users were taking aspirin for its cardioprotective effects. This rate is higher than that reported in the CLASS study (21%) and higher than population estimates among men and women aged 65 years and older (1-week prevalence, 39% and 23%, respectively).3 Concern over increased risk of adverse GI effects may be tempered by the fact that a majority of aspirin users were taking an enteric-coated or buffered form. However, evidence for the protective effects of enteric-coated or buffered aspirin is mixed,4-10 leading the US Preventive Services Task Force to conclude that "enteric-coated or buffered preparations do not clearly reduce adverse gastrointestinal effects of aspirin."11 Fifty percent of the aspirin users were taking daily doses of 325 mg or more, a dose considered higher than necessary for the primary prevention of cardiovascular disease and stroke (ie, 75-160 mg/d),12 and the highest dose recommended for secondary prevention (ie, 75-325 mg/d).13 Aspirin use has been shown to significantly increase the risk of bleeding in the GI tract,14 even at low doses (ie, 75-325 mg/d),15 and guidelines state that patients who require aspirin therapy for cardioprotection should use the lowest dose possible.16 The findings from the CLASS study suggest that concomitant aspirin use negates the GI benefit of COX-2s, calling into question one of the fundamental rationales for prescribing this expensive therapy class: the minimization of serious bleeding in the GI tract. However, the CLASS study did not report actual aspirin dosage, only that patients taking doses of 325 mg or less for cardioprotection were allowed in the study. Given the high rate of concomitant use observed in this sample, further research is needed to determine whether the use of COX-2s results in a lower risk of adverse GI effects than nonselective NSAIDs in patients who are on a low-dose regimen of aspirin (ie, 75 mg/d). Acetaminophen, ibuprofen, and naproxen are among the most commonly used drugs in the United States3 and are readily available OTC. Approximately 50% of the respondents in our survey were taking nonaspirin NSAIDs or acetaminophen along with their COX-2 (13% for ≥15 days in the past 30 days). A vast majority of this use was acetaminophen. The reason for concomitant use of these agents was not assessed (eg, lack of efficacy of COX-2 therapy or treatment of other pain-related conditions). Because acetaminophen is considered first-line therapy for the relief of mild-to-moderate pain associated with osteoarthritis,17 its use along with COX-2 therapy may be completely appropriate. However, patients taking their COX-2 along with other OTC nonaspirin NSAIDs may be placing themselves at increased risk for adverse GI events.18 Also, approximately 2% of the respondents in our study were taking acetaminophen at doses higher than 2 g/d, a dosage that has been associated with a 4-fold increase in the relative risk of complications in the upper GI tract.19 Physicians may not be aware of the extent of self-medication and should inquire more rigorously about the efficacy of COX-2 therapy and the concomitant use of other drugs. The reality is that patients who are on a long-term regimen of nonaspirin NSAIDs are often those who are most at risk for adverse GI and cardiovascular events. After making the decision to use NSAID therapy to treat pain, determining which NSAID to use is important. Factors to consider are the interference NSAIDs have with the antiplatelet effects of aspirin,20 differences in the cardioprotective benefits of NSAIDs,21-24 differences in the adverse GI event rates among NSAIDs,19,25 and the cost-effectiveness of adding gastroprotective agents (eg, proton pump inhibitors and misoprostol).17 Equally important is the choice of antiplatelet therapy for patients on COX-2 therapy. The US Preventive Services Task Force recommends that the added cardiovascular benefits of aspirin be weighed against its adverse effects,26,27 and the American Heart Association recommends that the use of aspirin be avoided in patients at increased risk for bleeding in the GI tract.12 Determining which combination of therapies is the most cost-effective approach in minimizing the risk of adverse GI events, while also providing optimal cardiovascular protection, is a complex issue, but one that must be addressed in an effort to provide high-quality, cost-effective health care. Corresponding author and reprints: Emily R. Cox, PhD, Express Scripts, Inc, 13900 Riverport Dr, Maryland Heights, MO 63043 (e-mail: ecox@express-scripts.com). We acknowledge Brenda Motheral, PhD, for critical review of the manuscript for this article, Doug Mager, for programming assistance, and Bonnie Goffo, RN, and Cathi Conlee, RN, for assistance in survey administration. During the conduct of this study, Dr Frisse was the chief medical officer and Ms Fairman was manager of outcomes research at Express Scripts, Inc, Maryland Heights, Mo. Ms Fairman now serves as a research consultant to Express Scripts. The authors have no relevant financial interest in this article. References 1. Silverstein FEFaich GGoldstein JL et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;2841247- 1255PubMedGoogle ScholarCrossref 2. Clark DOVon Korff MSaunders KBaluch WMSimon GE A chronic disease score with empirically derived weights. Med Care. 1995;33783- 795PubMedGoogle ScholarCrossref 3. Kaufman DWKelly JPRosenberg LAnderson TEMitchell AA Recent patterns of medication use in the ambulatory adult population of the United States. JAMA. 2002;287337- 344PubMedGoogle ScholarCrossref 4. Cole ATHudson NLiew LCWMurray FEHawkey CJHeptinstall S Protection of human gastric mucosa against aspirin—enteric coating or dose reduction? Aliment Pharmacol Ther. 1999;13187- 193PubMedGoogle ScholarCrossref 5. Hawthorne ABMahida YRCole ATHawkey CJ Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis. Br J Clin Pharmacol. 1991;3277- 83PubMedGoogle ScholarCrossref 6. Dammann HGBurkhardt FWolf N Enteric coating of aspirin significantly decreases gastroduodenal mucosal lesions. Aliment Pharmacol Ther. 1999;131109- 1114PubMedGoogle ScholarCrossref 7. Savon JJAllen MLDiMarion AJ JrHermann GAKrum RP Gastrointestinal blood loss with low dose (325 mg) plain and enteric-coated aspirin administration. Am J Gastroenterol. 1995;90581- 585PubMedGoogle Scholar 8. de Abajo FJRodriguez LAG Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations. BMC Clin Pharmacol. 2001;11PubMedGoogle ScholarCrossref 9. Kelly JPKaufman DWJurgelon JMSheehan JKoff RSShapiro S Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet. 1996;3481413- 1416PubMedGoogle ScholarCrossref 10. Sorensen HTMellemkjaer LBlot WJ et al. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol. 2000;952218- 2224PubMedGoogle ScholarCrossref 11. US Preventive Services Task Force, Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136157- 160PubMedGoogle ScholarCrossref 12. Pearson TABlair SNDaniels SR et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other artherosclerotic vascular diseases. Circulation. 2002;106388- 391PubMedGoogle ScholarCrossref 13. Smith SCBlair SNBonow RO et al. AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease: 2001 update: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation. 2001;1041577- 1579PubMedGoogle ScholarCrossref 14. Roderick PJWilkes HCMeade TW The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials. Br J Clin Pharmacol. 1993;35219- 226PubMedGoogle ScholarCrossref 15. Stalnikowicz-Darvasi R Gastrointestinal bleeding during low-dose aspirin administration for prevention of arterial occlusive events: a critical analysis. J Clin Gastroenterol. 1995;2113- 16PubMedGoogle ScholarCrossref 16. Awtry EHLoscalzo J Aspirin. Circulation. 2000;1011206- 1218PubMedGoogle ScholarCrossref 17. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines, Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;431905- 1915PubMedGoogle ScholarCrossref 18. Garcia Rodriguez LAJick H Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343769- 772PubMedGoogle ScholarCrossref 19. Garcia Rodriguez LAHernandez-Diaz S Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 2001;12570- 576PubMedGoogle ScholarCrossref 20. Catella-Lawson FReilly MPKapoor SC et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;3451809- 1817PubMedGoogle ScholarCrossref 21. Solomon DHGlynn RJLevin RAvorn J Nonsteroidal anti-inflammatory drug use and acute amyocardial infarction. Arch Intern Med. 2002;1621099- 1104PubMedGoogle ScholarCrossref 22. Rahme EPilote LLeLorier J Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med. 2002;1621111- 1115PubMedGoogle ScholarCrossref 23. Watson DJRhodes TCai BGuess HA Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med. 2002;1621105- 1110PubMedGoogle ScholarCrossref 24. Mukherjee DNissen SETopol EJ Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286954- 959PubMedGoogle ScholarCrossref 25. Henry DLim Lynette L-YGarcia 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;3121563- 1566PubMedGoogle ScholarCrossref 26. Lauer MS Aspirin for primary prevention of coronary events. N Engl J Med. 2002;3461468- 1474PubMedGoogle ScholarCrossref 27. Hayden MPignone MPhillips CMulrow C Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002;136161- 172PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Over-the-Counter Pain Reliever and Aspirin Use Within a Sample of Long-term Cyclooxygenase 2 Users

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Publisher
American Medical Association
Copyright
Copyright © 2004 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.164.11.1243
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Abstract

The Celecoxib Long-term Arthritis Safety Study (CLASS) evaluated the adverse gastrointestinal (GI) effects caused by the use of the selective cyclooxygenase 2 (COX-2) drug celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis and rheumatoid arthritis.1 The study found no significant difference in the GI ulcer complication rate (ie, bleeding, perforation, or obstruction in the GI tract) between celecoxib and nonselective NSAIDs. The authors attributed this finding to a higher-than-anticipated aspirin comedication rate of 21% among study participants, a rate almost double that of previous clinical trial experience. Since usage patterns in clinical trials and routine clinical practice often differ, the purpose of the present study was to estimate aspirin comedication rates among long-term COX-2 users. To provide a thorough description of over-the-counter (OTC) NSAID and pain reliever use, we also examine comedication with 2 other OTC NSAIDs (ie, ibuprofen and naproxen sodium) and another commonly used OTC pain reliever, acetaminophen. Methods A telephone survey was conducted among long-term COX-2 users, defined as members 18 years of age or older with at least a 90-day supply of COX-2 therapy (ie, celecoxib and rofecoxib) obtained through commercially available mail-order pharmacy services (Express Scripts Inc, Maryland Heights, Mo) in the months of August, September, or October 2001. The study sample consisted of members who were receiving health benefits through an employer located in the Northeast. This employer had a membership of approximately 95 000, with an approximate retiree–active employee ratio of 6:1. The average age of the enrollee population was 59 years. The telephone survey was administered by nurses who were trained in survey administration. The survey asked members about their use of COX-2s and OTC agents over the past 30 days. Information gathered included the number of days that members took each agent, the dose or strength of each agent, and, for those taking aspirin, the reason for use. Survey administration began December 3, 2001, and ended January 19, 2002. Calls were made until approximately 350 surveys were completed. Results Of the 525 sampling pool members we attempted to contact, 32 (6%) had disconnected or wrong telephone numbers, 106 (20%) were not available when calls were attempted, 31 (6%) were not taking COX-2s on a long-term basis, 2 (<1%) were no longer receiving health benefits through the employer, and 1 had died. Of those members who were contacted, 98% agreed to participate. The responses of 14 respondents were excluded owing to incomplete surveys, resulting in a final sample size of 325. Response bias between those with completed surveys (n = 325) and those whom we were unable to reach (n = 106) was evaluated using the chronic disease score.2 The chronic disease score is a measure of chronic disease status measured using pharmacy claims data and has been shown to predict total medical and outpatient costs. Using the outpatient-cost chronic disease score, no differences were found between those who completed the survey and those we attempted to contact but did not reach (mean [SD], 1566 [708.1] vs 1586 [619.3], respectively; t = −0.279; P = .78). The mean (SD) age of the respondents was 71 (9.4) years, and 67% were female. These numbers closely approximate the average age and sex distribution of all COX-2 users for this employer group (average age, 69 years; female, 64%). The mean (SD) number of days respondents took a COX-2 in the past 30 days was 28.2 (5.83), with 95% taking the same amount every day and 89% taking it every day in the past 30 days. More than 76% of respondents used at least 1 OTC NSAID or acetaminophen on 1 day or more in the past 30 days, with 48% using aspirin, 43% using acetaminophen, 7% using ibuprofen, and 3% using naproxen. Approximately 23% had used 2 or more OTC agents in the past 30 days, with 20% using both aspirin and acetaminophen in addition to their COX-2. Based on the number of days an OTC agent was taken, 53% of the respondents used at least 1 OTC product on 15 days or more over the past 30 days, with 45%, 12%, 2%, and fewer than 1% taking aspirin, acetaminophen, ibuprofen, and naproxen, respectively. Analysis of OTC use by age revealed that 50% of those aged 56 years and older but just 25% of those aged 37 to 55 years were taking aspirin (P = .03, Table 1). The rate of comedication with nonaspirin NSAIDs among those aged 56 years and older was lower than among those aged 37 to 55 years, but this findings represented a nonsignificant trend (P = .12). View LargeDownload Percentage of Long-term Cyclooxygenase 2 Users Taking Aspirin, Acetaminophen, or Nonaspirin Nonsteroidal Anti-inflammatory Drugs (NSAIDs) by Age Group Of the respondents who were taking aspirin (n = 156), 86% took it daily, 99% were using it for cardioprotection (93% for cardioprotection only and 6% for both cardioprotection and pain), and 79% took an enteric-coated or buffered form. Of those who were taking aspirin for cardioprotection only, 50% were taking doses of 325 mg or more, 43% were taking doses of 81 mg, and 7% were taking doses of 162 to 165 mg. Of those who were taking acetaminophen, 20% were taking it every day, and among those who were taking acetaminophen every day, 25% were taking 2 g/d or more. Comment Two patterns of OTC NSAID and acetaminophen use emerged among our sample of long-term COX-2 users: (1) a high rate of comedication with aspirin for cardioprotection, and (2) a sizeable percentage of comedication with OTC pain relievers, primarily acetaminophen, and less so with other nonaspirin NSAIDs (ie, ibuprofen and naproxen). These patterns of behavior have implications for patient GI safety and may suggest the need for better pain management. Limitations of these data should be noted. First, the data represent the experience of a predominantly retiree population in the northeastern United States. The rates of OTC use may not reflect those found in younger populations or in other parts of the country. However, the rates of OTC use were still substantial even among respondents aged 37 to 55 years. Additional research is needed to document comedication rates among enrollees who are younger or reside in different geographic regions. Approximately 50% of the long-term COX-2 users were taking aspirin for its cardioprotective effects. This rate is higher than that reported in the CLASS study (21%) and higher than population estimates among men and women aged 65 years and older (1-week prevalence, 39% and 23%, respectively).3 Concern over increased risk of adverse GI effects may be tempered by the fact that a majority of aspirin users were taking an enteric-coated or buffered form. However, evidence for the protective effects of enteric-coated or buffered aspirin is mixed,4-10 leading the US Preventive Services Task Force to conclude that "enteric-coated or buffered preparations do not clearly reduce adverse gastrointestinal effects of aspirin."11 Fifty percent of the aspirin users were taking daily doses of 325 mg or more, a dose considered higher than necessary for the primary prevention of cardiovascular disease and stroke (ie, 75-160 mg/d),12 and the highest dose recommended for secondary prevention (ie, 75-325 mg/d).13 Aspirin use has been shown to significantly increase the risk of bleeding in the GI tract,14 even at low doses (ie, 75-325 mg/d),15 and guidelines state that patients who require aspirin therapy for cardioprotection should use the lowest dose possible.16 The findings from the CLASS study suggest that concomitant aspirin use negates the GI benefit of COX-2s, calling into question one of the fundamental rationales for prescribing this expensive therapy class: the minimization of serious bleeding in the GI tract. However, the CLASS study did not report actual aspirin dosage, only that patients taking doses of 325 mg or less for cardioprotection were allowed in the study. Given the high rate of concomitant use observed in this sample, further research is needed to determine whether the use of COX-2s results in a lower risk of adverse GI effects than nonselective NSAIDs in patients who are on a low-dose regimen of aspirin (ie, 75 mg/d). Acetaminophen, ibuprofen, and naproxen are among the most commonly used drugs in the United States3 and are readily available OTC. Approximately 50% of the respondents in our survey were taking nonaspirin NSAIDs or acetaminophen along with their COX-2 (13% for ≥15 days in the past 30 days). A vast majority of this use was acetaminophen. The reason for concomitant use of these agents was not assessed (eg, lack of efficacy of COX-2 therapy or treatment of other pain-related conditions). Because acetaminophen is considered first-line therapy for the relief of mild-to-moderate pain associated with osteoarthritis,17 its use along with COX-2 therapy may be completely appropriate. However, patients taking their COX-2 along with other OTC nonaspirin NSAIDs may be placing themselves at increased risk for adverse GI events.18 Also, approximately 2% of the respondents in our study were taking acetaminophen at doses higher than 2 g/d, a dosage that has been associated with a 4-fold increase in the relative risk of complications in the upper GI tract.19 Physicians may not be aware of the extent of self-medication and should inquire more rigorously about the efficacy of COX-2 therapy and the concomitant use of other drugs. The reality is that patients who are on a long-term regimen of nonaspirin NSAIDs are often those who are most at risk for adverse GI and cardiovascular events. After making the decision to use NSAID therapy to treat pain, determining which NSAID to use is important. Factors to consider are the interference NSAIDs have with the antiplatelet effects of aspirin,20 differences in the cardioprotective benefits of NSAIDs,21-24 differences in the adverse GI event rates among NSAIDs,19,25 and the cost-effectiveness of adding gastroprotective agents (eg, proton pump inhibitors and misoprostol).17 Equally important is the choice of antiplatelet therapy for patients on COX-2 therapy. The US Preventive Services Task Force recommends that the added cardiovascular benefits of aspirin be weighed against its adverse effects,26,27 and the American Heart Association recommends that the use of aspirin be avoided in patients at increased risk for bleeding in the GI tract.12 Determining which combination of therapies is the most cost-effective approach in minimizing the risk of adverse GI events, while also providing optimal cardiovascular protection, is a complex issue, but one that must be addressed in an effort to provide high-quality, cost-effective health care. Corresponding author and reprints: Emily R. Cox, PhD, Express Scripts, Inc, 13900 Riverport Dr, Maryland Heights, MO 63043 (e-mail: ecox@express-scripts.com). We acknowledge Brenda Motheral, PhD, for critical review of the manuscript for this article, Doug Mager, for programming assistance, and Bonnie Goffo, RN, and Cathi Conlee, RN, for assistance in survey administration. During the conduct of this study, Dr Frisse was the chief medical officer and Ms Fairman was manager of outcomes research at Express Scripts, Inc, Maryland Heights, Mo. Ms Fairman now serves as a research consultant to Express Scripts. The authors have no relevant financial interest in this article. References 1. Silverstein FEFaich GGoldstein JL et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;2841247- 1255PubMedGoogle ScholarCrossref 2. Clark DOVon Korff MSaunders KBaluch WMSimon GE A chronic disease score with empirically derived weights. Med Care. 1995;33783- 795PubMedGoogle ScholarCrossref 3. Kaufman DWKelly JPRosenberg LAnderson TEMitchell AA Recent patterns of medication use in the ambulatory adult population of the United States. JAMA. 2002;287337- 344PubMedGoogle ScholarCrossref 4. Cole ATHudson NLiew LCWMurray FEHawkey CJHeptinstall S Protection of human gastric mucosa against aspirin—enteric coating or dose reduction? Aliment Pharmacol Ther. 1999;13187- 193PubMedGoogle ScholarCrossref 5. Hawthorne ABMahida YRCole ATHawkey CJ Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis. Br J Clin Pharmacol. 1991;3277- 83PubMedGoogle ScholarCrossref 6. Dammann HGBurkhardt FWolf N Enteric coating of aspirin significantly decreases gastroduodenal mucosal lesions. Aliment Pharmacol Ther. 1999;131109- 1114PubMedGoogle ScholarCrossref 7. Savon JJAllen MLDiMarion AJ JrHermann GAKrum RP Gastrointestinal blood loss with low dose (325 mg) plain and enteric-coated aspirin administration. Am J Gastroenterol. 1995;90581- 585PubMedGoogle Scholar 8. de Abajo FJRodriguez LAG Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations. BMC Clin Pharmacol. 2001;11PubMedGoogle ScholarCrossref 9. Kelly JPKaufman DWJurgelon JMSheehan JKoff RSShapiro S Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet. 1996;3481413- 1416PubMedGoogle ScholarCrossref 10. Sorensen HTMellemkjaer LBlot WJ et al. Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol. 2000;952218- 2224PubMedGoogle ScholarCrossref 11. US Preventive Services Task Force, Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136157- 160PubMedGoogle ScholarCrossref 12. Pearson TABlair SNDaniels SR et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other artherosclerotic vascular diseases. Circulation. 2002;106388- 391PubMedGoogle ScholarCrossref 13. Smith SCBlair SNBonow RO et al. AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease: 2001 update: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation. 2001;1041577- 1579PubMedGoogle ScholarCrossref 14. Roderick PJWilkes HCMeade TW The gastrointestinal toxicity of aspirin: an overview of randomised controlled trials. Br J Clin Pharmacol. 1993;35219- 226PubMedGoogle ScholarCrossref 15. Stalnikowicz-Darvasi R Gastrointestinal bleeding during low-dose aspirin administration for prevention of arterial occlusive events: a critical analysis. J Clin Gastroenterol. 1995;2113- 16PubMedGoogle ScholarCrossref 16. Awtry EHLoscalzo J Aspirin. Circulation. 2000;1011206- 1218PubMedGoogle ScholarCrossref 17. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines, Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;431905- 1915PubMedGoogle ScholarCrossref 18. Garcia Rodriguez LAJick H Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343769- 772PubMedGoogle ScholarCrossref 19. Garcia Rodriguez LAHernandez-Diaz S Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 2001;12570- 576PubMedGoogle ScholarCrossref 20. Catella-Lawson FReilly MPKapoor SC et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;3451809- 1817PubMedGoogle ScholarCrossref 21. Solomon DHGlynn RJLevin RAvorn J Nonsteroidal anti-inflammatory drug use and acute amyocardial infarction. Arch Intern Med. 2002;1621099- 1104PubMedGoogle ScholarCrossref 22. Rahme EPilote LLeLorier J Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med. 2002;1621111- 1115PubMedGoogle ScholarCrossref 23. Watson DJRhodes TCai BGuess HA Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med. 2002;1621105- 1110PubMedGoogle ScholarCrossref 24. Mukherjee DNissen SETopol EJ Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286954- 959PubMedGoogle ScholarCrossref 25. Henry DLim Lynette L-YGarcia 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;3121563- 1566PubMedGoogle ScholarCrossref 26. Lauer MS Aspirin for primary prevention of coronary events. N Engl J Med. 2002;3461468- 1474PubMedGoogle ScholarCrossref 27. Hayden MPignone MPhillips CMulrow C Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2002;136161- 172PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Jun 14, 2004

Keywords: aspirin,cyclooxygenase-2,drugs, non-prescription,pain

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