This report was reviewed for medical and scientific accuracy by Ronald S. Freudenberger, MD, Director of Heart Failure and Transplant Cardiology, Associate Professor of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

The cardioprotective effects of aspirin have been clearly demonstrated in numerous clinical trials.^1-3 However, the results of several clinical trials have raised speculation over whether the beneficial cardioprotective effects of aspirin are diminished when aspirin is used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs). The most recent publication was a subgroup analysis of a 5-year randomized, double-blind, placebo-controlled trial originally designed to examine the effect of regular use, intermediate use, or no use of NSAIDs and their impact on the cardioprotective effects of aspirin.⁴ The study concluded that regular, but not intermittent use of NSAIDs, inhibited the cardioprotective benefits of aspirin.

The results of this study confirm the findings of MacDonald and Wei⁵ who also determined the inhibitory effects of NSAIDs on aspirin and concluded that patients with known cardiovascular disease treated with aspirin plus ibuprofen versus patients treated with aspirin alone had an increased risk of all-cause mortality and cardiovascular mortality. Similarly, Catella-Lawson et al⁶ found that the concomitant use of ibuprofen, but not rofecoxib, acetaminophen, or diclofenac antagonized the irreversible platelet inhibition induced by aspirin thus potentially reducing the cardioprotective effects of aspirin.

The results of these trials raise understandable concern over the use of NSAIDs in patients taking aspirin for cardioprotection. NSAIDs are readily available over-the-counter and are widely used both over-the-counter and by prescription on a regular basis for patients with arthritis.⁷ It is estimated that more than 30 million people worldwide take NSAIDs on a daily basis.⁸ As the population of the United States (U.S.) ages, it becomes increasing likely that more people will be utilizing aspirin for its cardioprotective effects, as well as NSAIDs for their analgesic and/or anti-inflammatory properties.

Acetaminophen can be used as a viable alternative to NSAIDs in patients using aspirin for cardioprotection. In addition to not modifying the antiplatelet action of aspirin,⁶ 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 patients on cardioprotective aspirin therapy requiring analgesic treatment.

Inhibition of Cardioprotective Benefits of Aspirin by NSAIDs

A recently published clinical trial demonstrated that regular use of NSAIDs inhibited the cardioprotective benefits of aspirin.⁴ This subgroup analysis is from a 5-year randomized, double-blind, placebo-controlled trial in 22,071 apparently healthy U.S. male physicians (The Physicians Health Study⁹). Patients randomized to 325 mg of aspirin every other day or placebo were examined for their utilization of NSAIDs and were stratified into 3 groups: no use, intermittent use (1-59 days per year), and regular use (≥60 days per year). The objective of the study was to determine whether NSAIDs inhibit the clinical benefit of aspirin on first myocardial infarction. During a mean follow-up of 5-years, 378 myocardial infarctions were confirmed, 139 of which occurred in the aspirin group and 239 in the placebo group (relative risk 0.56, 95% Confidence Interval (CI), 0.45-0.70). When further assessed, intermediate use of NSAIDs was not associated with increased risk of first myocardial infarction in either the aspirin or the placebo group. Combined use of aspirin and regular use of NSAIDs was significantly associated with an increased risk of first myocardial infarction (Table 1.)

Although specific NSAIDs were not defined in this observational study and there were few myocardial infarctions in the exposed groups, this data provides further evidence to indicate that NSAIDs may inhibit the cardioprotective effects of aspirin.

Clinical trials by Catella-Lawson et al⁶ and MacDonald and Wei⁵ confirm the results of this study. Catella-Lawson et al investigated potential interactions between aspirin and commonly prescribed arthritis therapies. Combinations of aspirin with ibuprofen, rofecoxib, acetaminophen, or diclofenac were administered and serum thromboxane B₂ levels and platelet aggregation were measured. At the conclusion of the study, investigators found that the concomitant use of ibuprofen, but not rofecoxib, acetaminophen, or diclofenac antagonized the irreversible platelet inhibition induced by aspirin thus potentially reducing the cardioprotective effects of aspirin.⁶

MacDonald and Wei conducted a retrospective analysis of 7,107 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 primary endpoints of the study were all-cause mortality or cardiovascular mortality.

Of the 7,107 patients (age range 27 to 100 years), 6,285 (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 1,210 mg/day and 117 mg/day, respectively. A total of 3,593 (50.5%) patients had myocardial infarction, 1,165 (16.4%) had angina, 1,689 (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 2,266 (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 2). 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 3).

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 these studies lend support to the hypothesis that treatment with a combination of ibuprofen and aspirin, in patients taking aspirin for cardioprotection, may be deleterious.

The Basis for Interaction

Aspirin, NSAIDs and cyclooxygenase (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.¹⁰ COX-2 specific inhibitors do not interact with COX-1 at clinical doses and thus have no effect on platelet aggregation.

Issues Surrounding the use of NSAIDs with Aspirin: Therapeutic Alternatives

The emerging evidence that ibuprofen may antagonize the cardioprotective effect of aspirin, coupled with the welldocumented ability of NSAIDs to cause life-threatening toxicities in the form of gastric ulcers, gastrointestinal bleeding, and their complications (eg, perforation, pyloric obstruction)^11-15 which may be further enhanced with concomitant aspirin administration, requires clinicians to revisit the selection of a safe and effective treatment regimen for individuals requiring concomitant aspirin and analgesic therapy. The concern for gastrointestinal complications with combination aspirin therapy also holds true for the COX-2 specific inhibitors.¹⁶ In treating these patients, 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 with acetaminophen, tramadol or a non-acetylated salicylate, concern over NSAID competition with aspirin on the platelet binding site (thus negating aspirin's beneficial effect) and the potential increased risk of gastrointestinal complications associated with NSAID/aspirin combination therapy is removed. In many instances, proven non-pharmacologic interventions such as exercise and physical therapy should be implemented to reduce pain burden.

In addition to gastrointestinal concerns, there are other issues to consider when selecting analgesic therapy for the patient taking cardioprotective aspirin. There is much controversy surrounding the use of COX-2 specific inhibitors and their possible association with adverse cardiovascular events.17 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.18,19 For high-risk cardiovascular patients taking prophylactic aspirin for cardioprotection, the administration of NSAIDs and/or COX-2 specific inhibitors may exacerbate existing comorbidities.

Conclusion

Demographic trends assure that the numbers of individuals with an indication for daily aspirin therapy and analgesic therapy will continue to rise. With the continued emergence of evidence showing NSAIDs inhibitory effect on cardioprotection when used concurrently with aspirin, clinicians must give careful consideration to those high-risk cardiovascular patients taking aspirin who require chronic analgesic therapy. Assessment of 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.

References

1. 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.
2. 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.
3. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:161-172.
4. Kurth T, Glynn RJ, Walker AM, et al. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal anti-inflammatory drugs. Circulation. 2003;108:1191-1195.
5. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003;361:573-574.
6. Catella-Lawson F, Muredach RP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809-1817.
7. Singh G, Triadafilopouls G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999;26(Suppl 56):18-24.
8. 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.
9. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:129-135.
10. Rao GHR, Johnson GG, Reddy KR, White JG. Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin. Arteriosclerosis. 1983;3:383-388.
11. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet. 1994;343:769-772.
12. 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.
13. 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.
14. Peura DA, Lanza FL, Gostout CJ, Foutch PG. The American College of Gastroenterology Bleeding Registry: preliminary findings. Am J Gastroenterol. 1997;92:924-928.
15. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs. N Engl J Med. 1999;340:1888-1899.
16. 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. JAMA. 2000;284:1247.
17. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-959.
18. Vioxx prescribing information [package insert]. Merck & Co., Inc. Available at http://www.vioxx.com. Accessed August 28, 2003.
19. Celebrex prescribing information [package insert]. Pharmacia Corp. Available at http://www.celebrex.com. Accessed August 28, 2003.

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Disclosure
Ronald S. Freudenberger, MD
Shareholder-GlaxoSmithKline; Speakers Bureau-AstraZeneca, GlaxoSmithKline

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 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