This report was reviewed for medical and scientific accuracy by John B. Kostis, MD, John G. Detwiler Professor of Cardiology and Professor of Medicine and Pharmacology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

Muredach Reilly, MD, Instructor, Cardiovascular Medicine and Experimental Therapeutics, University of Pennsylvania Medical Center, Philadelphia, PA. Co-Author "Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin". N Eng J Med 2001;345(25)1809-1817.

Prescribing for Pain: The Platelet Problem

The potential for a pharmacodynamic interaction between reversible nonselective cyclooxygenase (COX) inhibitors (nonsteroidal anti-inflammatory drugs-NSAIDs) used for pain relief, and aspirin, an irreversible COX inhibitor used for platelet inhibition, has been recognized for some time.^1,2 In a series of small, controlled studies performed in normal volunteers, we showed that concomitant administration of ibuprofen (at clinically relevant doses), but not rofecoxib, acetaminophen, or diclofenac antagonizes the irreversible platelet inhibition induced by aspirin.³

What are the clinical implications of these studies? Treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. However, this is likely to be important only for those patients taking ibuprofen on a regular basis. The antagonist effect may hold for other nonselective COX inhibitors [e.g., indomethacin] that bind to the same site on the COX enzyme as aspirin¹ but does not appear to be the case for diclofenac. Therefore, in patients with chronic arthritic symptoms who also require aspirin for cardioprotection, ibuprofen and possibly other NSAIDs [e.g., indomethacin] should be avoided when possible.

What are the alternatives for these patients? Diclofenac appears to be a reasonable alternative to ibuprofen but whether this is true for any other NSAID is not yet known. As expected, rofecoxib-a COX-2 inhibitor,⁴ did not influence the antiplatelet effects of aspirin, as COX-2 is not expressed in platelets. Thus, it is unlikely that other COX-2 selective inhibitors antagonize aspirin. Acetaminophen, at 1000 mg, is a weak, reversible, nonselective COX inhibitor that failed to modify the antiplatelet action of aspirin. However, it remains to be determined if higher doses of acetaminophen, frequently prescribed in osteoarthritis,⁵ might attain COX inhibition comparable to ibuprofen and have similar effects on aspirin action. Higher doses of aspirin can be used for both antiplatelet and anti-inflammatory effects but this approach will only prove effective in a limited number of patients. Finally, an alternative approach is to use an anti-inflammatory agent of choice in combination with an effective antiplatelet agent that does not act via COX, such as clopidogrel.⁶

Large clinical trials, with cardiovascular endpoints, of anti-inflammatory agent/aspirin combinations may never be performed because of large sample size requirements and the difficulty in selecting appropriate target populations and anti-inflammatory approaches that are relevant to clinical practice. In the absence of such data, the choice of strategies in patients who require long-term antiplatelet and anti-inflammatory therapies should be considered on a case-by-case basis, taking into account potential drug interactions, the overall risk of cardiovascular events, GI side effects and indeed the preference of patients with respect to efficacy and tolerability.⁷

Introduction

Aspirin is widely utilized to reduce the risk of recurrent myocardial infarction (MI) and stroke in high-risk patients.^8,9 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 (OA), many high-risk patients with cardiovascular risk factors require additional pharmacologic therapies to address chronic pain and inflammation associated with OA. Currently, in addition to nonpharmacologic modalities, aspirin, acetaminophen, NSAIDs, and COX-2 inhibitors constitute oral OA pharmacotherapy. Because the mechanism of action of all these drugs is based on the inhibition of the COX enzymes [acetaminophen is a weak, reversible COX inhibitor whose mechanism of action has yet to be completely elucidated], it has been postulated that there may be a pharmacodynamic drug interaction between the use of aspirin as an antiplatelet and concomitant administration of acetaminophen, NSAIDs and COX-2 selective inhibitors. In order to address this question, Catella-Lawson et al³ investigated potential interactions between aspirin and these commonly prescribed arthritis therapies. The results demonstrated an interaction between ibuprofen and aspirin with no evidence of an interaction between aspirin and acetaminophen, diclofenac (NSAID), or rofecoxib. These findings take on clinical relevance in light of current American College of Rheumatology (ACR) guidelines on the pharmacologic treatment of mild-to-moderate OA pain that recommend acetaminophen as first-line pharmacologic therapy.⁵ Treatment with acetaminophen, diclofenac and rofecoxib in patients with increased cardiovascular risk does not limit the cardioprotective effects of aspirin.

Analgesics, NSAIDs, and Cyclooxygenase

Aspirin, NSAIDs, and COX-2 selective inhibitors all act to inhibit prostaglandin H₂ synthetase, more commonly known as cyclooxygenase (COX). COX, which exists as two isomers, COX-1 and COX-2, is the rate-limiting enzyme responsible for catalyzing the first two steps in the synthesis of prostaglandin (PG) from arachidonic acid (AA). X-ray crystallographs show that COX-1 and COX-2 are very similar enzymes having a hydrophobic channel that leads to the core of the enzyme. When AA inserts itself into the channel, it is catalyzed into PG. In platelets, catalysis of AA 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. Ibuprofen also blocks the active site by forming a hydrogen bond with an arginine residue located halfway down the hydrophobic channel. However, its effect is reversible; AA, leading to subsequent production of thromboxane, can displace ibuprofen. COX-2 selective inhibitors, such as rofecoxib and celecoxib, do not interact with COX-1 at clinical doses and thus have no effect on platelet aggregation and do not alter the effect of aspirin.

NEJM Study

Catella-Lawson et al conducted a 2-part controlled clinical study to identify potential interactions between aspirin and commonly prescribed arthritis therapies. More specifically: (1) whether an antiplatelet interaction exists between aspirin and ibuprofen, acetaminophen, or rofecoxib, (2) whether that interaction is dependent upon the sequence of administration, and (3) whether a clinically relevant dosing regimen of NSAIDs (i.e. multiple doses of ibuprofen or diclofenac) would have an effect on the antiplatelet efficacy of a single morning dose of aspirin.

To examine (1) and (2), the investigators conducted a randomized, crossover study of combinations of single daily doses of two treatments for 6 days, with a washout period of at least 14 days. One group received aspirin (81 mg) two hours before ibuprofen (400 mg) for six days and, after the washout period, the same medications in the reverse order. Another group received aspirin two hours before acetaminophen (1000 mg) for six days and then the same medications in the reverse order. A third group received aspirin two hours before rofecoxib (25 mg) and then the same medications in the reverse order.

Blood samples were taken at multiple time points on day 1 and 6 of each treatment to determine serum thromboxane B₂ (TxB₂) and platelet aggregation [assessment of COX-1 activity], as well as ex vivo liposaccharide-induced PGE₂ formation [assessment of COX-2 activity]. Urine was collected throughout day 1 and day 6 to assess production of 2,3-dinor-6-keto PGF₁, an index of PGI₂ synthesis [assessment of COX-2 activity]. The primary endpoint of this study was that administering ibuprofen before aspirin would antagonize the irreversible effects of aspirin as assessed by TxB₂. The secondary endpoint was platelet aggregation 24 hours after the administration of the first study drug on day 6 of concomitant therapy.

Parallel Study Reflects Real World Situation

To examine (3), a parallel-group, randomized, open-label, 6-day study was conducted in which one group was given enteric-coated aspirin (81 mg) at 8 AM and ibuprofen (400 mg) at 10 AM, 3 PM, and 8 PM and another group was given enteric-coated aspirin at 8 AM and delayed-release diclofenac (75 mg) at 10 AM and 6 PM. Again, the inhibition of platelet COX-1 activity was assessed by measurement of serum TxB₂ and platelet aggregation. The primary hypothesis of this study was that ibuprofen or diclofenac would antagonize the irreversible effects of enteric-coated aspirin 24 hours after the administration of the first study drug on day 6 of the combination therapy.

Adverse Antiplatelet Interaction Between Ibuprofen and Aspirin

The primary hypothesis of the first study was indeed confirmed. Investigators found that in the single-dose ibuprofen group, subjects who took aspirin first had at least 98% inhibition of serum TxB₂ up to 24 hours after dosing on day 6. When the same subjects took ibuprofen before aspirin, serum TxB₂ was more than 97% inhibited two hours after the administration of ibuprofen on day 6, but it later recovered, as would be expected after the administration of a reversible COX-1 inhibitor such as ibuprofen. Specifically, 24 hours after the administration of the first study drug on day 6, the mean degree of inhibition of serum TxB₂ was 99% when the subjects had taken aspirin before ibuprofen and 53% when the subjects had taken ibuprofen before aspirin (p < 0.001). It was noted that platelet aggregation was irreversibly inhibited when subjects took aspirin before ibuprofen but reversibly inhibited when subjects took ibuprofen before aspirin.

Concerning the group who took single-dose acetaminophen, the inhibition of serum TxB₂ in subjects who took aspirin before acetaminophen was similar to that in subjects who took aspirin before ibuprofen, with at least 96% inhibition up to 24 hours post-dose on day 6. However, the pretreatment with acetaminophen did not alter the antiplatelet effect of aspirin. The inhibition of serum TxB₂ was similar on day 6 regardless of whether subjects had taken aspirin or acetaminophen first.

Acetaminophen did not inhibit platelet aggregation, but neither did it interfere with the ability of aspirin to do the same, whether it was given before or after aspirin. Similarly, rofecoxib had no effect on aspirin-induced inhibition of serum TxB₂ or platelet aggregation, whether it was given before or after aspirin. Aspirin did not inhibit COX-2 activity; neither did it interfere with the ability of ibuprofen, acetaminophen, or rofecoxib to do the same.

In the parallel-group study with multiple dosing regimens, multiple daily doses of ibuprofen administered after a single daily dose of enteric-coated aspirin interfered with the ability of aspirin to inhibit serum TxB₂ and platelet aggregation, a result the investigators described as "consistent with the reversible inhibition of COX-1 activity and antagonism of aspirin's irreversible effect by the multiple-dose NSAID [ibuprofen] regimen."

Interestingly, multiple doses of delayed-release diclofenac given after aspirin did not interfere with aspirin's ability to inhibit COX-1. Similarly, a 75 mg single dose of delayed-release diclofenac given two hours before aspirin for six days did not antagonize the irreversible antiplatelet effect of aspirin.

Clinical Implications

As the NEJM study reveals, the choice of analgesic medication is important to preserve the antiplatelet effects of aspirin in high-risk patients who must take aspirin for cardioprotective effects. The question for clinicians becomes one of clinical utility: how to approach treatment in this group?

Dr. Garret Fitzgerald, Robinette Professor of Cardiovascular Medicine, University of Pennsylvania School of Medicine, the study's principal investigator, noted that there is little concern for individuals taking occasional doses of ibuprofen. The adverse interaction can be avoided by taking aspirin earlier in the day, but even if the medications are taken in reverse order, the negation of antiplatelet effect is lost only for the duration of action of the ibuprofen dose-approximately one day.

For people who must take chronic pain medication, the matter is more complicated. Dr. Fitzgerald recommends an individualized approach for each patient that considers factors such as risk for gastrointestinal (GI) adverse effects, need for analgesic efficacy, and cost of therapy. For example, the study supports diclofenac as a viable and cost-effective alternative to ibuprofen in OA patients, however, for patients at risk for NSAID-induced GI adverse effects, a selective COX-2 inhibitor such as rofecoxib may be preferred. However, the GI safety advantages of the COX-2 inhibitors are significantly diminished with concomitant aspirin¹⁰ while potentially increasing the risk of GI bleeding as compared to the use of COX-2 inhibitors alone.^11,12

An additional consideration for clinicians is the potential effect of these therapies on the kidneys. As proposed by Fored et al,¹³ regular use of either acetaminophen or aspirin in the absence of the other was associated with an increase by a factor of 2.5 in the risk of chronic renal failure from any cause. However, the Scientific Advisory Committee of the National Kidney Foundation recommends acetaminophen as the drug of choice for analgesia in patients with impaired renal function.¹⁴

Role of Acetaminophen

The ACR guidelines recommend acetaminophen in doses up to 4000 mg/day as the first pharmacologic treatment for patients with mild-to-moderate OA. Although some patients may fail to obtain adequate relief even with full doses of acetaminophen, acetaminophen merits a trial as initial therapy, based on its overall cost, efficacy, and toxicity profile.

The study by Catella-Lawson et al supplements existing safety data on acetaminophen with the additional reassurance that acetaminophen will not adversely interact with prophylactic aspirin.

In an accompanying editorial,⁷ Dr. Leslie J. Crofford, University of Michigan, Ann Arbor, Michigan, emphasized that the findings of Catella-Lawson et al need to be confirmed in clinical studies. Dr. Crofford noted "the platelet-aggregation studies ... were performed ex vivo and tested platelet function in isolation... other factors may well contribute to the overall vascular effects of these drugs."

Both Drs. Fitzgerald and Crofford agree on one point: the selection of an anti-inflammatory or analgesic agent in patients taking low-dose aspirin should be considered on an case-by-case basis, taking into account the risk of cardiovascular events, GI side effects, and progressive renal failure. Furthermore, Dr. Crofford advises, "the choice of therapeutic agent should otherwise be based on the preference of the patient with respect to efficacy and tolerability, but the cost of the drugs should be taken into account as well. Future studies should focus on the many important and unanswered questions regarding the effects of the different analgesic and anti-inflammatory drugs, used alone or in combination with aspirin, in patients with cardiovascular and renal disease."

Conclusion

For patients taking low-dose aspirin for cardioprotection and who have conditions such as arthritis that require chronic pain management, this recent clinical study on platelet interference and other factors suggests considerations in selection of analgesic therapy. As Dr. Fitzgerald points out, an individualized approach needs to take into account the various risk factors, including GI adverse effects, drug interactions, amount of analgesia needed, and cost of therapy.

While diclofenac did not interfere with the antiplatelet effects of aspirin, unlike ibuprofen, there are still concerns for patients at risk for NSAID-induced GI adverse effects. The selective COX-2 inhibitor, rofecoxib, may be preferred based on lack of interference with antiplatelet effect, but the GI safety advantages of the COX-2s may be diminished with used with concomitant aspirin.

Due to its lack of antiplatelet interference and superior GI safety profile, acetaminophen should be given appropriate consideration when managing chronic pain in patients on low-dose aspirin therapy.

References

1. Livio M, Del Maschio A, Cerletti C, de Gaetano G. Indomethacin Prevents the Long-Lasting Inhibitory Effect of Aspirin on Human Platelet Cyclooxygenase Activity. Prostaglandins 1982;23:787-796.

2. Rao GHR, Johnson GG, Reddy KR, White JG. Ibuprofen Protects Platelet Cyclooxygenase from Irreversible Inhibition by Aspirin. Arteriosclerosis 1983;3:383-388.

3. Catella-Lawson F, Reilly MP, Kapoor SC et al. Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin. N Eng J Med 2001;345(25):1809-1817.

4. Luong C, Miller A, Barnett J, Chow J, Ramesha C, Browner MF. Flexibility of the NSAID Binding Site in the Structure of Human Cyclooxygenase-2. Nat Struct Biol 1996;3(11):927-933.

5. Recommendations for the Medical Management of Osteoarthritis of the Hip and Knee. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905-1915.

6. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of Clopidrogel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation. N Engl J Med 2001;345(7):494-502.

7. Crofford LJ. Rational Use of Analgesic and Anti-Inflammatory Drugs. N Engl J Med 2001;345(25):1844-1846.

8. Antiplatelet Trialists' Group. Prevention of Death, Myocardial Infarction and Stroke by Antiplatelet Therapy in High Risk Patients. BMJ (in press).

9. 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.

10. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal Toxicity with Celecoxib vs. Nonsteroidal Anti-Inflammatory Drugs for Osteoarthritis-The CLASS Study: A Randomized Controlled Trial. JAMA 2000 Sep 13;;284(10):1247-1255.

11. Celebrex Package Insert. Pharmacia Corp. Available at: http://www.pharmacia.com/products/pharm.asp#C. Accessed January 7, 2002.

12. Vioxx Package Insert. Merck & Co. Inc. Available at: http://www.merck.com/product/usa. Accessed January 7, 2002.

13. Fored CM, Ejerblad E, Lindblad P, et al. Acetaminophen, Aspirin, and Chronic Renal Failure. N Eng J Med 2001;345(25):1801-1808.

14. Henrich WL, Agodoa LE, Barrett B, et al. Analgesics and the Kidney: Summary and Recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. Am J Kidney Dis 1996;27:162-165.

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Disclosure

John B. Kostis, MD
Has no significant relationships to disclose.

Muredach Reilly, MD
Research Grants: Merck

David C. Howard
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.

Medical Writer
David C. Howard, BS Pharmacy, Director of Research, Millennium Medical Communications, Inc., Hampton, NH

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 Cardiology Express Report was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2002 Millennium Medical Communications, Inc. and UMDNJ - Center for Continuing and Outreach Education