This report was reviewed for medical and scientific accuracy by Paula S. Krauser, MD, MA, Clinical Associate Professor, Department of Family Medicine, University of Medicine & Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Expert Commentary and Analysis by A. Mark Fendrick, MD, Division of General Internal Medicine, Department of Internal Medicine, School of Medicine; Department of Health Management and Policy, School of Public Health; University of Michigan, Ann Arbor, Michigan

Introduction

The results of a recently published study suggest that the concomitant administration of ibuprofen with aspirin may antagonize the cardioprotective effects of aspirin in patients with established cardiovascular disease.¹ Moreover, compared to patients using single-agent aspirin, patients taking aspirin plus ibuprofen had an increased risk of all-cause mortality and cardiovascular mortality. These findings support previously published data from Catella-Lawson et al that demonstrated that the concomitant use of ibuprofen, but not acetaminophen, diclofenac, or rofecoxib, antagonized the irreversible platelet inhibition induced by aspirin.²

Aspirin is widely utilized to reduce the risk of recurrent myocardial infarction and stroke in high-risk patients.^3,4 High-risk patients would include, but are not limited to, those with occlusive arterial disease, stable angina, intermittent claudication, and diabetes. However, because of comorbid diseases such as osteoarthritis, many high-risk patients with cardiovascular risk factors or established cardiovascular disease require additional pharmacologic therapies to address chronic pain and/or inflammation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are available over-the-counter for a variety of uses and are widely prescribed for symptomatic relief for patients with arthritis.⁵ In fact, more than 30 million people worldwide take NSAIDs on a daily basis.⁶ As the population of the United States ages, it will become increasingly likely that many patients will be taking aspirin for its cardioprotective benefit and concomitant NSAIDs for their analgesic and/or anti-inflammatory properties.

In light of these recently published studies, clinicians must caution high-risk patients taking prophylactic aspirin for cardioprotection not to take ibuprofen. Fortunately, a multitude of alternative options to ibuprofen are available. Such options would include other NSAIDs and the cyclooxygenase (COX)-2 specific inhibitors. However, NSAIDs have been well documented for causing life-threatening toxicities in the form of gastric ulcers, gastrointestinal bleeding, and their complications (eg, perforation, pyloric obstruction).^7-11 The COX-2 specific inhibitors were developed as theoretically offering a lower risk of gastrointestinal complications than NSAIDs because these agents spare the action of COX-1, the enzyme responsible for producing gastroprotective prostaglandins. However, recent revelations concerning trial design have called into question the validity of the claim of lower risk of gastrointestinal complications with COX-2 specific inhibitors.^12,13 Moreover, there is much controversy surrounding the use of COX-2 specific inhibitors and their possible association with adverse cardiovascular events.¹⁴ In addition to their ability to diminish the antihypertensive effect of angiotensin-converting enzyme (ACE) inhibitors, COX-2 specific inhibitors are capable of inducing elevations in blood pressure.^15,16 Emerging evidence suggests than even small incremental increases in blood pressure (1 to 5 mm Hg) may result in significant additional ischemic heart disease and stroke events annually.¹⁷ For high-risk cardiovascular patients taking prophylactic aspirin for cardioprotection, the administration of NSAIDs and/or COX-2 specific inhibitors may exacerbate existing comorbidities.

Conversely, acetaminophen is a viable alternative to ibuprofen in patients using aspirin for cardioprotection. In addition to not modifying the antiplatelet action of aspirin,² acetaminophen may be routinely used in patients with congestive heart failure, hypertension, anticoagulant therapy, and a history of gastrointestinal complications. Due to its lack of antiplatelet interference and superior gastrointestinal safety profile, acetaminophen should be given appropriate consideration in high-risk cardiovascular patients on cardioprotective aspirin therapy.

Ibuprofen and Aspirin: Reduced Cardioprotective Effect

Following the study by Catella-Lawson et al demonstrating the inhibitory effect of ibuprofen on aspirin,² MacDonald and Wei conducted a retrospective analysis of 7107 patients who were taking low-dose aspirin (<325 mg/day) upon hospital discharge for first admission for cardiovascular disease and had survived for at least one month post-hospitalization. The investigators postulated that patients with known cardiovascular disease (myocardial infarction, angina, stroke or transient ischemic attack, and peripheral vascular disease) who took low-dose aspirin and ibuprofen might have increased risk of cardiovascular mortality. Patients were divided into four groups based on their discharge prescriptions for (1) aspirin alone; (2) aspirin plus ibuprofen; (3) aspirin plus diclofenac; or (4) aspirin plus any other NSAIDs. The outcomes of the study were all-cause mortality or cardiovascular mortality.

Of the 7107 patients (age range 27 to 100 years), 6285 (88.4%) received aspirin alone, 187 (2.6%) received aspirin plus ibuprofen, 206 (2.9%) received aspirin plus diclofenac, and 429 (6.0%) received aspirin and other NSAIDs. The mean doses of ibuprofen and diclofenac were 1210 mg/day and 117 mg/day, respectively. A total of 3593 (50.5%) patients had myocardial infarction, 1165 (16.4%) had angina, 1689 (23.8%) had stroke or transient ischemic attack, and 660 (9.3%) had peripheral vascular disease. The distribution of cardiovascular diseases was similar between the four treatment groups. A total of 2266 (32%) patients died during a median of 3.3 years of follow-up.

A Cox regression analysis showed that patients taking both aspirin and ibuprofen had a significantly higher risk of all-cause mortality than those taking aspirin alone (P = .0011) (Table 1). However, the risk did not differ from patients who took aspirin alone in either the aspirin plus diclofenac group (P = .3571) or the aspirin plus other NSAIDs group (P = .4322).

The results for cardiovascular mortality paralleled all-cause mortality between treatment groups (Table 2).

Summarizing their findings, investigators reported both a statistically and clinically significant increased risk of mortality in users of aspirin plus ibuprofen compared with users of aspirin alone. No such increased risk was noted in users of aspirin plus diclofenac or aspirin plus other NSAIDs.

Although not conclusive, the results of this study lend support to the hypothesis that treatment with a combination of ibuprofen and aspirin given for secondary cardiovascular protection may be deleterious, possibly through the antagonism of the cardioprotective effects of aspirin in patients with established cardiovascular disease.

Mechanism of Action: Basis for Interaction

Aspirin, NSAIDs and COX-2 specific inhibitors all inhibit prostaglandin H₂ synthase (the COX enzyme; COX-1 and COX-2 isomers), which is the rate-limiting enzyme responsible for catalyzing the first two steps in the synthesis of prostaglandin from arachidonic acid. When arachidonic acid inserts itself into a hydrophobic channel of the COX enzyme, it is catalyzed into prostaglandin. In platelets, catalysis of arachidonic acid leads to the formation of thromboxane A₂, an important factor in platelet aggregation.

Aspirin conveys its beneficial antiplatelet effects by irreversibly acetylating a serine residue at position 529 near the top of the hydrophobic channel of COX-1, thus blocking the active site for the life of the platelet [COX-2 is not expressed in platelets]. NSAIDs such as ibuprofen also block the active site by forming a hydrogen bond with an arginine residue located half-way down the hydrophobic channel. However, its effect is reversible; ibuprofen can be displaced by arachidonic acid, leading to subsequent production of thromboxane. The potential for a competitive interaction between aspirin and ibuprofen as a result of these structural relations has been previously established.¹⁸ COX-2 specific inhibitors do not interact with COX-1 at clinical doses and thus have no effect on platelet aggregation.

Conclusion

Given the accepted benefit of cardioprotective aspirin therapy, the studies by MacDonald and Wei and Catella-Lawson et al underscore the importance of preserving the antiplatelet effects of aspirin. Careful consideration must be given for those high-risk cardiovascular patients who require chronic analgesic therapy. Clinicians may individualize therapy after assessing the patient's risk for gastrointestinal adverse effects, need for analgesic efficacy, concomitant pharmacologic therapy to treat existing comorbidities, and lastly, the cost of therapy to the patient. Given the evidence that indicates acetaminophen does not adversely affect the cardioprotective effects of aspirin, acetaminophen offers a safe and effective treatment option for high-risk cardiovascular patients needing analgesic therapy.

Expert Commentary and Analysis

A. Mark Fendrick, MD, Division of General Internal Medicine, Department of Internal Medicine, School of Medicine; Department of Health Management and Policy, School of Public Health; University of Michigan, Ann Arbor, Michigan

Combining Aspirin and NSAIDs: When Two "Rights" Make a Wrong

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used by millions of Americans, many on a daily basis, for their well-established analgesic and anti-inflammatory properties. Increasing numbers of NSAID users also take an aspirin a day. Many individuals take an aspirin to reduce the likelihood of cardiovascular events, others to prevent or reduce the progression of colorectal cancer, and some take aspirin for less well-documented indications such as the prevention of dementia.

Although many of the health benefits of aspirin cannot be disputed, aspirin is not free of adverse events. The most worrisome side effects attributable to aspirin include gastrointestinal and central nervous system bleeding. However, it is apparent from most population-based studies that the risk of gastrointestinal bleeding increases with aspirin dose. Available data suggest that an aspirin dose of 81 mg daily is all that is necessary to produce the clinical benefits. Thus, low doses of aspirin should be recommended in most patients taking aspirin for cardioprotection. It should be pointed out, however, that in patients at high risk of gastrointestinal bleeding (eg, prior gastrointestinal bleeding), low-dose aspirin used alone is associated with a very high rate of re-bleeding. Thus, risk-reducing interventions (eg, gastroprotective therapy) are indicated for those high-risk individuals for whom aspirin must be continued for cardioprotection.

The confirmation that the combination of any NSAID (including COX- 2 selective inhibitors) and aspirin is a significant risk factor for gastrointestinal complications requires a careful assessment of available treatment options. Large population-based studies reveal that the risk of gastrointestinal complications for those individuals who take concomitant aspirin and a traditional NSAID is roughly double the complication risk of those people who take low-dose aspirin alone (5.6 vs 2.6, compared to non-aspirin users). Controlled studies (CLASS and VIGOR) demonstrated that COX-2 selective inhibitors reduce gastrointestinal complications by approximately one-half when compared to traditional NSAIDs. However, a pre-specified analysis of CLASS enrollees (n >1000) who took aspirin and a traditional or a selective NSAID, revealed an approximately 50% risk-reduction attributable to COX-2 selective inhibitors in the absence of aspirin was substantially diminished when aspirin was taken concomitantly. The rate of gastrointestinal complications was 4 times higher in those patients who took aspirin concomitantly with their COX-2 selective inhibitor when compared to those who took a COX-2 selective inhibitor without aspirin. This finding raises the question "does an aspirin a day take the gastrointestinal benefit of COX-2 selective inhibitors away?"

The increasing amount of evidence supporting the use of daily low-dose aspirin, combined with the rising incidence of arthritis and other chronic inflammatory conditions, will lead to large numbers of multiple NSAID users. This substantial and under-appreciated risk factor necessitates increasing educational efforts to clinicians and vulnerable patient populations. The substantial risk of hemorrhage for concomitant aspirin/NSAID users, coupled with emerging evidence that certain NSAIDs (eg, ibuprofen) likely block the cardioprotective effect of aspirin, requires clinicians to revisit the selection of a safe and effective treatment regimen for individuals requiring concomitant aspirin and analgesic therapy. First, management strategies should focus on ensuring that patients at-risk for cardiovascular events receive the potentially life-saving benefits of aspirin. Second, if adequate levels of analgesia can be achieved without the addition of a non-aspirin NSAID, this second NSAID should be stopped for two reasons: 1) a substantial increase in multiple NSAID risk of gastrointestinal hemorrhage when compared to aspirin alone; and 2) for concern over NSAID competition on the platelet binding site and elimination of aspirin's effect. If possible, the non-aspirin NSAID (traditional and COX-2 selective inhibitor) can be substituted with acetaminophen, tramadol, a non-acetylated salicylate or narcotics (in certain circumstances). In many instances, proven non-pharmacological interventions such as exercise and physical therapy should be implemented to reduce pain burden. If multiple NSAIDs cannot be avoided, gastroprotective therapy (eg, misoprostol, proton pump inhibitor) should be added for those at-risk individuals irrespective of whether a NSAID or COX-2 selective inhibitor is used.

In sum, demographic trends assure that the numbers of individuals with an indication for daily low-dose aspirin therapy and analgesic therapy will continue to rise. While the benefits of highly accessible NSAID therapy are well marketed to the public and clinicians, two potential adverse events—inhibition of the cardioprotective effects of aspirin and increases in the risk of gastrointestinal bleeding—warrant that we carefully consider the risk-benefit tradeoff of multiple NSAID use. Alternative therapies are available, that when substituted for the non-aspirin NSAID can produce similar levels of analgesia and reduce NSAID-related adverse events.

Additional Reading Suggested by A. Mark Fendrick, MD

U.S. Preventative Services Task Force. Recommendations and rationale: aspirin for the primary prevention of cardiovascular events. Ann Intern Med. 2002;136:157-160.

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 Long-term Arthritis Safety study. JAMA. 2000;284;1247-1255.

Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520-1528.

Fendrick AM, Garabedian-Ruffalo SM. A clinician's guide to the selection of NSAID therapy. P&T.; 2002;27:579-582.

Fendrick AM, Bandekar RR, Chernew ME, Scheiman JM. Role of initial NSAID choice and patient risk factors in the prevention of NSAID gastropathy: a decision analysis. Arthritis Rheum. 2002;47:36-43.

References

1. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003;361:573-574.
2. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809-1817.
3. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ. 2002;324:71-86.
4. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2001;119(Suppl):39S-63S.
5. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999;26(Suppl 56):18-24.
6. Singh G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther. 2000;7:115-121.
7. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet. 1994;343:769-772.
8. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual nonsteroidal anti-inflammatory drugs. Lancet. 1994;343:1075-1078.
9. Lanza LL, Walker AM, Bortnichak EA, Dreyer NA. Peptic ulcer and gastrointestinal hemorrhage associated with nonsteroidal anti-inflammatory drug use in patients younger than 65 years. A large health maintenance organization cohort study. Arch Intern Med. 1995;155:1371-1377.
10. Peura DA, Lanza FL, Gostout CJ, Foutch PG. The American College of Gastroenterology Bleeding Registry: preliminary findings. Am J Gastroenterol. 1997;92:924-928.
11. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med. 1999;340:1888-1899.
12. Berg Hrachovec J, Mora M. Reporting of 6-month vs. 12-month data in a clinical trial of celecoxib. JAMA. 2001;286:2398.
13. Wright JM, Perry TL, Bassett KL, Chambers KG. Reporting of 6-month vs. 12-month data in a clinical trial of celecoxib. JAMA. 2001;286:2398-2399.
14. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-959.
15. Vioxx prescribing information [package insert]. Merck & Co., Inc. Available at http://www.vioxx.com. Accessed April 18, 2003.
16. Celebrex prescribing information [package insert]. Pharmacia Corp. Available at http://www.celebrex.com. Accessed April 18, 2003.
17. Singh G, Miller JD, Huse DM, Pettit D, D'Agostino RB, Russell MW. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol. 2003;30:714-719.
18. Rao GHR, Johnson GG, Reddy KR, White JG. Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. Arteriosclerosis. 1983;3:383-388.

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Disclosure

A. Mark Fendrick, MD
Consultant-AstraZeneca, Merck, Procter & Gamble, TAP; Speakers Bureau-AstraZeneca, McNeil, TAP

Paula S. Krauser, MD, MA
Has no significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Pain Management Express Report™ does not include discussion of treatment and indications outside of current approved professional labeling. This Pain Management Express Report™ was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education