Education
Éducation

 

Acetylsalicylic-acid-containing drugs and nonsteroidal anti-inflammatory drugs available in Canada

Malcolm Brigden, MD, CM; Reginald E. Smith, PharmD

CMAJ 1997;156:1025-8

[ résumé ]

Dr. Brigden is Regional Medical Oncologist, Penticton Regional Hospital, Penticton, BC, and Dr. Smith is with the Pharmacy Department, Division of Cardiology and Cardiovascular Surgery, Royal Jubilee Hospital, Victoria, BC.

This article has been peer reviewed.

Reprint requests to: Dr. Malcolm Brigden, Regional Medical Oncologist, Penticton Regional Hospital, 550 Carmi Ave., Penticton BC V2A 3G6; fax 250 492-9036

© 1997 Canadian Medical Association (text and abstract/résumé)

Abstract

A large number of drugs containing acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are available by prescription and over the counter in Canada. The possibility of serious side effects and drug interactions is therefore high. The authors have compiled a comprehensive list of products containing these drugs from information supplied by pharmaceutical databases, independent marketing researchers and Health Canada's Drug Directorate. Physicians should ensure that additional ASA-containing drugs or NSAIDs are not inadvertently taken by patients, especially those receiving oral anticoagulant therapy or those with a qualitative platelet defect. Patients at risk should be cautioned to check with their physician before taking any new medication, even over-the-counter products.

Résumé

De nombreux médicaments contenant de l'acide acétylsalicylique (ASA) et des anti-inflammatoires non stéroïdiens (AINS) sont disponibles sur ordonnance et en vente libre au Canada. Le risque d'effets secondaires graves et d'interactions entre médicaments est donc élevé. Les auteurs ont dressé une liste détaillée des produits qui contiennent ces médicaments à partir de renseignements provenant de bases de données pharmaceutiques, de chercheurs indépendants en marketing et de la Direction des médicaments de Santé Canada. Les médecins devraient s'assurer que leurs patients ne prennent pas par inadvertance d'autres médicaments contenant de l'ASA ou des AINS, surtout dans le cas des personnes qui prennent des anti-coagulants par voie orale ou qui ont un défaut plaquettaire qualitatif. Il faudrait prévenir les patients à risque de consulter leur médecin avant de prendre de nouveaux médicaments, même en vente libre.

Drugs containing acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available and frequently prescribed. The possibility of serious side effects and drug interactions is therefore high. Physicians need to ensure that additional ASA-containing drugs or NSAIDs are not inadvertently taken, especially by patients receiving oral anticoagulant therapy or those with a qualitative platelet defect such as that associated with von Willebrand's disease, uremia, dysproteinemia or a myeloproliferative disorder.

Although a variety of population-based surveys of ASA awareness and utilization have been performed, most antedated the widespread publicity surrounding primary and secondary prevention trials.[1­3] One recent survey of a Canadian community found that 8% of 666 respondents took ASA routinely.[4] Among those over the age of 50 (who would be more likely to receive concomitant oral anticoagulant therapy) the figures rose to 19% of men and 14% of women. In addition, there is evidence that NSAIDs are used more frequently than physicians suspect.[5­7] Furthermore, regular NSAID users are as likely to use ASA as non-NSAID users, despite the dubious additional analgesic benefit.[8] We hope that the provision of up-to-date information on the availability of ASA-containing drugs and NSAIDs will help inform physicians as to the magnitude of this problem.

No single database of ASA-containing drugs and NSAIDs is readily available in Canada. Therefore, we created a comprehensive list by examining information from pharmaceutical databases, independent marketing researchers and Health Canada's Drug Directorate. The lists of products were extensively cross-checked against information in Health Canada's database. The ASA-containing product list was generated by searching the Health Canada database for any registered human drug product with ASA as an ingredient. The NSAID list was generated by searching the same database for human drugs that had American Hospital Formulary Service therapeutic classification 28:08.04 (nonsteroidal anti-inflammatory agent).

We were able to identify over 130 ASA-containing medications (Table 1) and 27 NSAIDs (Table 2) from the Health Canada database. Although many of the ASA-containing drugs identify ASA in the product name, many do not.

Drug mechanisms and interactions

When patients receive oral anticoagulant therapy the addition of a qualitative platelet defect may increase the risk of hemorrhage. Several investigators have evaluated the clinical efficacy of combining anticoagulants with antiplatelet drugs, especially ASA.[9­15] Although results from these trials are difficult to compare because of differing target INRs (international normalized ratios) and ASA dosages, every trial demonstrated an increased incidence of hemorrhage, even with ASA dosages as low as 100 mg/d. Fortunately, major hemorrhage has occurred mainly with high-dose ASA therapy; low-dose ASA therapy has been associated more often with an increased risk of minor hemorrhage and only a slightly increased risk of major hemorrhage.[10­15]

ASA inactivates cyclooxygenase, therefore decreasing the production of prostaglandins.[16­18] Although the lowest possible dose of ASA that will induce a qualitative platelet defect is not precisely known, a single oral dose of 5 to 100 mg has been shown to produce dose-dependent inhibition of platelet cyclooxygenase activity, with 100 mg almost completely suppressing the biosynthesis of thromboxane A2 in healthy subjects.[18] This inhibitory effect is rapid and occurs before the drug appears in the systemic circulation, probably because of the acetylation of platelet prostaglandin synthase in the portal circulation. Thus, the antiplatelet effect of ASA is not necessarily related to its systemic bioavailability.[18]

Because platelets lack a nucleus and cannot synthesize new proteins, the qualitative defect induced by ASA lasts the platelet's life span (approximately 8 to 10 days). After the last dose of ASA has been administered, there is little or no recovery of platelet cyclooxygenase activity for 2 to 3 days.

Whereas ASA acetylates the platelet membrane for the duration of the platelet's life span, NSAIDs are reversible inhibitors of platelet cyclooxygenase activity and hence prostaglandin synthesis.[19­22] Several studies have shown that, as with ASA use, the administration of NSAIDs can increase postoperative blood loss.[23­26] However, careful studies attempting to correlate the degree of NSAID-induced inhibition of prostaglandin synthesis, anti-inflammatory efficacy and the associated degree of qualitative platelet defect induced by individual agents are reportedly not available.[26,27]

NSAIDs may interact with warfarin through a number of mechanisms.[27,28] Some NSAIDs may be less likely to interact with coumarin anticoagulants; however, the available information is conflicting.[27­30] It is beyond the scope of this paper to quantify the degree of risk for each drug.

Conclusion

The large number of ASA-containing drugs and NSAIDs available in Canada make it necessary for physicians to ensure that patients requiring oral anticoagulant therapy do not acquire a superimposed qualitative platelet defect. A list of ASA-containing drugs and NSAIDs should be reviewed with all patients beginning oral anticoagulant therapy and with those who have a qualitative platelet defect such as that associated with von Willebrand's disease, uremia, dysproteinemia or a myeloproliferative disorder. The patients should be cautioned to check with their physicians always before taking any new medication, including over-the-counter preparations.

We thank Dr. Jeffrey Mahon and Ayfer Karaoku of Health Canada, Gail Judd and Linda Hooper of the Drug Information Service of the Pharmacy Department, University Hospital, London, Ont., and staff at the Northwest Drug Company Ltd. and International Medication Systems for their help in providing the background information for our article.

References

  1. Rubin RJ, Brown DJ, Taylor JW. Public awareness of aspirin and sources of aspirin information in a rural Iowa community. J Community Health 1983;8:229-39.
  2. Rubin RJ, Brown DJ, Taylor JW. Public awareness of aspirin and sources of aspirin information in a rural Iowa community. J Community Health 1983;8:229-39.
  3. National Center for Health Statistics. Use habits among adults of cigarettes, coffee, aspirin, and sleeping pills 1976 (Vital and Health Statistics series 10 no 131) DHEW publ no [PHS] 80-1559). Washington: US Governmentt Printing Office; 1979:1-48.
  4. Mahon J, Steel K, Feagan BG, et al. Use of acetylsalicylic acid by physicians and in the community. CMAJ 1991;145:1107-16.
  5. Strom BL. Adverse reactions to over-the-counter analgesics taken for therapeutic purposes. JAMA 1994;272:1866-7.
  6. Wilcox CM, Shalek KA, Cotsonis G. Striking prevalence of over-the-counter non-steroidal anti-inflammatory drug use in patients with upper gastrointestinal hemorrhage. Arch Inter Med 1994;154:42-6.
  7. Gabriel ES, Fehring RA. Trends in the utilization of non-steroidal anti-inflammatory drugs in the United States, 1986­1990. J Clin Epidemiol 1992;45(9):1041-4.
  8. Chrischilles EA, Lemke JH, Wallace RB. Prevalence and characteristics of multiple analgesic drug use in an elderly study group. J Am Geriatr Soc 1990;38:979-84.
  9. Cheesbro JH, Fuster V, Elveback LR, et al. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol 1983;51:1537-41.
  10. Dale J, Myhe E, Loew D. Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. Am Heart J 1980;99:746-51.
  11. Turpie AGG, Gent M, Laupacis A, et al. Reduction in mortality by adding aspirin (100 mg) to oral anticoagulants in patients with heart valve replacement [abstract]. J Am Coll Cardiol 1992;19:103.
  12. Meade TW, Roderick PJ, Brennan PJ, et al. Extracranial bleeding and other symptoms due to low-dose aspirin and low-intensity oral anticoagulation. Thromb Haemost 1992;68:1-6.
  13. Cohen M, Adams PC, Parry G, et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Circulation 1994;89:81-8.
  14. Goodman SG, Langer A. Duries SS, et al. Safety and anticoagulation effect of a low-dose combination of warfarin and aspirin in clinically stable coronary artery disease. Coumadin Aspirin Reinfarction (CARS) Pilot. Am J Cardiol 1994;74:656-7.
  15. Hurlen M, Brikssen J, Smith P, et al. Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: a study in 3166 outpatients. J Intern Med 1994;236:299-304.
  16. Roth GJ, Calverley DC. Aspirin, platelets, and thrombosis: theory and practice. Blood 1994;83:885-98.
  17. Kearon C, Hirsh J. Optimal dose for starting and maintaining low-dose aspirin. Arch Intern Med 1993;153:700-2.
  18. Patrono C. Aspirin as an antiplatelet drug. Drug Therapy 1994;330:1287-94.
  19. Brooks PM, Day RO. Non-steroidal anti-inflammatory drugs -- differences and similarities. N Engl J Med 1991;324:1716-25.
  20. Ali M, McDonald JWD. Reversible and irreversible inhibition of platelet cyclooxygenase and serotonin release by nonsteroidal and antiinflammatory drugs. Thromb Res 1978;13:1057-65.
  21. Amadio P, Cummings DM, Amadio P. Non-steroidal anti-inflammatory drugs. Tailoring therapy to achieve results and avoid toxicity. Postgrad Med 1993;93:73-97.
  22. Simon LS, Mills. JA. Non-steroidal anti-inflammatory drugs. N Engl J Med 1980;302:1237-43.
  23. Kallis P. Tooze JA, Talbot S, et al. Pre-operative aspirin decreases platelet aggregation and increases post-operative blood loss -- a prospective, randomized, placebo controlled, double-blind clinical trial in 100 patients with chronic stable angina. Eur J Cardiothorac Surg 1994;8:404-9.
  24. Eauno P, Petersen KD, Husted SE. Increased blood loss after preoperative NSAID. Retrospective study of 186 hip arthroplasties. Acta Orthop Scand 1993;64:522-4.
  25. Robinson CM, Christie J, Malcolm-Smith N. Non-steroidal anti-inflammatory drugs, perioperative blood loss, and transfusion requirements in elective hip arthroplasty. J Arthroplasty 1993;8:607-10.
  26. Kenny GNC. Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-inflammatory drugs. Drugs 1992;44:31-7.
  27. Jacobus RBJ, Brouwers de Sinel P. Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet 1994;27:462-85.
  28. Wells PS, Holbrook AM, Crowther NR, et al. Interactions of warfarin with drugs and food. Ann Intern Med 1994;121:676-83.
  29. O'Callaghan JW, Thompson RN, Russell AS. Combining NSAIDs with anticoagulants: yes and no. CMAJ 1984;131:857-9.
  30. Hilleman DE, Mohiuddin SM, Lucas BD Jr. Nonsteroidal antiinflammatory drug use in patients receiving warfarin: emphasis on nabumetone [review]. Am J Med 1993;95(2A):30S-34S.

Comments Send a letter to the editor responding to this article
Envoyez une lettre à la rédaction au sujet de cet article

| CMAJ April 1, 1997 (vol 156, no 7) / JAMC le 1er avril 1997 (vol 156, no 7) |