Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed medications worldwide (and this does not take into account the over-the counter market)1. They are the foundation therapy for musculoskeletal conditions. The search for the ultimate NSAID continues due to the high demand and the dissatisfaction with those currently available. In parallel with their popularity, NSAIDs also happen to be one of the most common drug groups associated with serious adverse effects. These side effects are well established and – to some extent – predictable. However, their potential and actual harmfulness came into focus after recent publications2,3 raised concerns about the cardiovascular (CV) safety profile of these agents.

Initially, the most widely known negative effect of traditional (t-) NSAIDs has been identified as gastrointestinal irritation. The estimated risk ranges from one bleeding ulcer per 1,000 patients (60 years and older)4 to as high as 10.3 per cent of patients5. A meta-analysis concluded that the one-year prevalence of serious gastrointestinal (GI) events among NSAID users was one per 1,000; among the elderly it was 3.2 per 1,0006. These conclusions measure bleeding ulcer as the endpoint, thereby ignoring the many patients who discontinue NSAID use when DR YASSER EL-MIEDANY experiencing GI upset. This effect was attributed to blocking prostaglandin G/H synthesase (commonly known as COX) enzymes, both Cox-1 and Cox-2 enzymes. Unlike COX-1, which appeared to be expressed constitutively in most tissues, COX-2 was subject to rapid induction by inflammatory cytokines and mitogens and seemed to account largely, if not exclusively, for prostaglandin formation in inflammation and cancer. The attraction of having compounds able to inhibit COX-2 enzyme only – and possibly not inducing the most common complication of tNSAIDs – led to the development of COX-2 enzyme inhibitors. However, questions about CV risk with these COX-2 selective drugs were raised by the finding of a fivefold difference in incidence of acute myocardial infarction between patients treated with rofecoxib 50mg/day and naproxen 1000mg/day in a large randomised trial7 and by a meta-analysis of the clinical trials of celecoxib and rofecoxib8 . Amid a flurry of concern over specific COX-2 inhibitors, many doctors have been switching patients to t-NSAIDs, but the latest observational9,10 as well as prospective11 studies, suggest even the old mainstays of pain relief may be problematic. This has led to a dilemma among treating physicians regarding how to use NSAIDs and the best options for the patients.

Biological basis for CV effects

Arachidonic acid is metabolised by COX enzymes, lipozygenases and epozygenases to form an array of biologically active products. These are, in turn, acted on by isomerases and synthesase to form the prostaglandin I2 (prostacyclin) and thromboxane A2 (TxA2)12-14. Prostacyclin (progstaglandin I2 (PGI2)) is a vasodilator that inhibits platelet function. However, inhibition of PGI2, synthesis does not lead to spontaneous thrombosis15. In endothelial cells PGI2 synthesis is mediated by COX-2, which in turn is hemodynamically induced or activated by oestrogen16. PGI2 modulates platelet vascular interactions and specifically limits the response to TxA2. Specific COX-2 inhibitors inhibit PGI2 but not TxA217. Furthermore, specific COX-2 inhibitors reduce PGI2 dependent atheroprotective process, such as platelet aggregation inhibition and vasodilatation, and decrease the proliferation and contraction of smooth muscle cells. COX-2 inhibitors promote interactions between neutrophils and platelets and the vessel wall, thus contributing to atherogenesis16,18. In premenopausal women chronic treatment of patients with specific inhibitors of COX-2 could undermine oestrogen protection from CV disease16,17.

Unlike specific COX-2 inhibitors, NSAIDs reversibly inhibit the production of TxA2. The resulting decrease in platelet aggregation does not generally persist beyond the overall dosing interval19. Moreover, the correlation between NSAID-induced inhibition of TxA2 production and platelet functions is not linear. The imbalance between PGI2 and TxA2, said to be the reason for the atherogenic potential of specific COX-2 inhibitors, is also likely to exist in large segments of the dosing intervals during NSAIDs treatment20. A possible exception is naproxen (500mg twice daily), which at least under study conditions, can attain stable and sufficiently high plasma concentration to compensate for the PGI2/TxA2 imbalance21. With most NSAIDs therefore, an increase in the thrombogenic risk must be expected.

On the other hand, aspirin acetylates a single serine residue in the COX-1 and the COX-2 channel and thereby permanently inactivates the enzyme22. The resulting long-lasting inhibition of TxA2 synthesis in anuclear platelets is the basis for the antithrobmotic cardioprotective effect of low doses of aspirin21. Daily aspirin doses of 75–325mg are regarded as suitable for inhibiting platelet aggregation as a means of cardioprophylaxis in patients at risk, including those with: acute MI; a history of MI; a history of stroke; transient ischemic attacks; unstable angina; vascular surgery; angioplasty; atrial fibrillation; heart defects; or peripheral vascular disease23. When doses higher than 100mg/day are used, aspirin also inhibits COX-2 dependent PGI2 synthesis23,24. The expected simultaneous suppression of TxA2 and PGI2 may reduce the cardioprotective effect of low dose treatment. It remains difficult to interpret the results of a recent placebo-controlled study where the use of aspirin at doses of 81mg and 325mg were investigated over a three-year period for the prevention of colorectal adenoma. In the 749 subjects treated with aspirin, seven myocardial infarctions and seven strokes occurred compared with only one myocardial infarction among the 372 patients in the placebo group25. When the published data is analysed to the criteria of the Antiplatelet Trialists’ Collaboration (APTC), the difference is significant (P=0.006, 95 per cent CI1.3 –78)26.

The concomitant administration of ibuprofen but not rofecoxib or diclofenac, antagonises the irreversible platelet inhibition induced by aspirin. Other anti-inflammatory drugs with the potential to offset the cardioprotective effect of low dose aspirin include flubiprofen, indomethacin and, to some extent, naproxen25. Lastly, the need to assess the CV risk of a NSAID should not be confined to the active treatment phase. The risk of a primary myocardial infarction appears to be increased for several weeks after the withdrawal of NSAID treatment, especially if the treatment was long term and another systemic inflammatory disease present at the same time. The cause is assumed to be a vascular rebound effect27. The activation of platelet functions and TxA2 synthesis following the absence of COX-1 inhibition, as well as the flaring up of inflammatory processes in the coronary vessel wall with subsequent plaque instability, are possible reasons for the increase in the incidence of acute myocardial infarction.

Lower GI tract

Earlier studies revealed that serious lower GI tract (GIT) events occurred at a rate of 0.9 per cent per year in patients with rheumatoid arthritis taking t-NSAID naproxen, accounting for nearly 40 per cent of the serious GI events that developed in these patients25. Serious lower GI events were 54 per cent lower with the use of the specific COX-2 inhibitor rofecoxib28. A clinically meaningful decrease in haemoglobin or packed cell volume level was seen significantly more among patients taking ibuprofen (5.4 per cent) than in those taking placebo, aspirin or acetyl salicylic acid plus rofecoxib (0.8 per cent – 1.6 per cent)28. In capsule endoscopic studies, celecoxib leads to significant reduction in lower bowel lesions compared with the combination of naproxen with proton pump inhibitor29.

Patients with inflammatory bowel disease (IBD) such as ulcerative colitis or Crohn’s disease, is another group who need careful consideration. Previous reports have demonstrated both risks of fl are-ups and relative safety, and treatment guidelines warn against the potential for disease exacerbation when t-NSAIDs are commenced30,31. The safety of COX-2 inhibitors has been studied in patients with IBD. Etoricoxib as well as celecoxib has shown good safety profile in comparison to placebo in patients with ulcerative colitis and Crohn’s disease32,33.

Assessment and guidelines

Given the varied combinations of patient characteristics the clinician is likely to confront in the clinic, it makes sense to probe whether the patient has any of the risk factors related to NSAID therapy. Such stratification would enable the clinician to choose a management approach that offers the optimal combination of anti-inflammatory efficacy, patient safety and cost effectiveness. Assessment of the risk factors can be carried out via direct questioning during the clinic visit, though this would be time consuming. The other way is through questionnaires, given to patients to be completed while they are in the waiting area. An example of these questionnaires, is the Non-steroidal Anti-inflammatory Risk Assessment Questionnaire (NARAQ) (Fig 1, page 55)34. It is composed of 13 questions that assess for the six main risk factors: CV disease, upper GIT or lower GIT kidney infection, asthma and concomitant medications. An earlier study revealed that the NARAQ is a valid instrument that can be self-administered for assessment of risk factors among patients who are due to start NSAID therapy.

The questionnaire was found to be simple, quick and accurate – and can be used in standard clinical practice. This patient index provided a quick guide to individualised decision making for this group of patients who are in need to NSAIDs. Table 1 shows a suggested guideline for preferred treatment options32.

Table 1. Suggested guidelines for preferred treatment options (*level of evidence)

Risk

Taking aspirin

Not taking aspirin

Low GI risk

t-NSAID + PPI (*2b, 2a)

t-NSAID (*2b, 2a)

High GI risk

Cox-2 + PPI (*etoricoxib 1b, celecoxib 2)

Upper GI: cox-2 or tNSAID + PPI (*2b, 2a) Lower GI: cox-2 inhibitor (*2b, 2a)

AERD

Contraindicated

Cox-2 inhibitor (*2a)

Cardiovascular disease

Anti-inflammatory drug therapy should be avoided. Aspirin does not protect against cox-2 CVS side effect (*5)

*The level of evidence are based on the scoring system of the Oxford Centre for Evidence-Based Medicine35: 1a: systematic reviews (with homogeneity) of RCTs; 1b: individual RCTs (with narrow confidence intervals); 1c: all or none RCTs; 2a: systematic reviews (with homogeneity) of cohort studies, 2b: individual cohort study or low quality RCTs; 2c: outcome research ecological studies; 3a: systematic review (with homogeneity) of case control studies; 3b: individual case-control study; 4: case series (and poor quality control and case-control studies); 5: expert opinion based on physiology, bench research or first principles.

Recommendations

Despite the inconsistency of their conclusions on CV safety, earlier studies have, nevertheless, had an influence on pending approval procedures, treatment recommendations and practical treatment decisions. In addition to GI safety issues, recommendations should take CV aspects into account. To summarise the recommendations for prescribing NSAIDs:

  • therapeutic tactics should be changed to individualised decision making, keeping in mind the individual risk factors and therapeutic indications that should be regularly reviewed;
  • courses of anti-inflammatory drug therapy should be given in the lowest dose and the shortest duration possible. There is no real evidence of increased risk with short-term use ( selective COX-2 inhibitors remain a sensible choice for patients with low CV risk who have experienced severe GI events or are suffering from IBD;
  • based on the data available, both t-NSAIDs and specific COX-2 inhibitors should not, as far as possible, be used in patients with CV disorders or increased cardiovascular risks25;
  • pharmacodynamic studies have raised the possibility that t-NSAIDs (ibuprofen, flubiprofen, indomethacin and, to some extent, naproxen) interact with and undermine the cardioprotective effect of aspirin36. A recent study suggested combing naproxen and clopidogrel (instead of aspirin) to avoid potential interaction with low dose aspirin, as a therapeutic option for treatment of patients with high cardiovascular and low GI risk37; for patients with high CV and GI risks, the authors suggested a combination of naproxen/ibuprofen in addition to clopidogrel and proton pump inhibitor;
  • abrupt withdrawal of NSAIDs should be avoided because of possible vascular rebound effects in patients with systemic inflammatory disorders.

Conclusion

In any NSAID treatment, the individual indications and risk factors must be regularly reviewed. Unnecessary courses of treatment should be avoided and treatment should be kept with the range of lowest dose for the shortest duration possible. Specific COX-2 inhibitors remain a sensible choice for patients with low cardiovascular risk who have sustained severe GI events, especially if they had past history of t-NSAID intolerance. In patients with CV risk factor, alternatives with minimal side effects and adequate efficacy are advised.

Figure 1 Figure 1 : Non-Steroidal Anti-Inflammatory Risk Assessment Questionnaire

References 

  1. Saag KG, Cowdery JS. Nonsteroidal antiinfl ammatory drugs. Spine 1994; 19: 1530-4
  2. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med N Engl J Med 2005;352: 1092-102.
  3. FDA. Statement on the halting of a clinical trial of the cox-2 inhibitor Celebrex 2004. Available at: http://www.fda.gov/bba/topics/news/2004/ NEW01133.html, accessed 10th October 05
  4. Langman MJS, Weil J, Wainwright P, et al. Risk of bleeding peptic ulcer associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994;343: 1075-8
  5. Melo-Gomes JA, Roth SH, Zeeh J, et al. Double-blind comparison of efficacy and gastroduodenal safety of diclofenac/ misoprostol, piroxicam, and naproxen in the treatment of osteoarthritis. Ann Rheum Dis 1993; 52: 881-5
  6. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-infl ammatory drugs. Ann Int Med 1991; 115: 787-96.
  7. Bomardier C, Laine L, Reicin A. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid Arthritis. N Engl J Med N Engl J Med 2000;343: 1520-28
  8. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective Cox-2 inhibitors. JAMA 2001; 286: 954-59
  9. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclooxygenase-2 inhibitors or conventional nonsteroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005; 330 (7504): 1366-1343.
  10. Graham D, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cox-2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005;365: 475-81
  11. Chan AT, Manson JE, Albert CM. Nonsteroidal anti-inflammatory drugs, acetaminophen and the risk of cardiovascular events. Circulation 2006; DOI: 10: 1161/CIRCULATIONAHA.105.5 95793
  12. Smyth E, Burke A, FitzGerald GA. Lipid-derived autacoids. In Goodman and Gilman’s. The Pharmacological basis of therapeutics. McGraw-Hill. New York, USA. 2005; 653-70
  13. Funk CD. Leukotriene modifiers as potential therapeutics for cardiovascular disease. Nat Rev Drug Discov 2005; 4: 664-72
  14. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular and molecular biology. Annu Rev Biochem 2002; 69: 145-82
  15. FitzGerald GA. Cardiovascular pharmacology of nonselective NSAID and coxibs: Clinical considerations. Am J Cardiol Am J Cardiol 2002;89: 26- 32D
  16. Egan KM, Lawson JA, Fries S, Koller B, Rader DJ, Smyth EM. Cox-2 derived prostacyclin confers atheroprotection on female mice. Science 2004; 306: 1954-7
  17. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296: 539-41
  18. FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med N Engl J Med 2004;351: 1709-11
  19. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclo-oxygenase inhibitors and the antiplatelet effect of aspirin. N Engl J Med N Engl J Med 2001;345: 1809-17
  20. 20. Wolfe MM. Rofecoxib, Merck and the FDA. N Engl J Med Engl J Med 2004;351: 2877
  21. Capone MI, Tacconelli S, Sciulli MG, et al. clinical pharmacology of platelet monocyte and vascular cyclo-oxygenase inhibition by naproxen and low dose aspirin in healthy subjects. Circulation 2004; 109: 1468-71
  22. Farkouh ME, Kirshner H, Harrington RA, Ruland S, Verheugt FW, Schnitzer TJ. Comparison of lumiracoxib with naproxen and ibuprofen in the therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004;364: 665-74
  23. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy-I: Prevention of death, myocardial infarction and stoke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81-106
  24. Patrono C, Coller B, Dalen JE, et al. Platelet active drugs: the relationships among dose, effectiveness and side effects. Chest 2001; 119 (suppl): 39-63S
  25. Bolten WW. Problem of the atherothrombotic potential of non-steroidal anti-infl ammatory drugs. Ann Rheum Dis 2006; 65: 7-13
  26. Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal ademonas. N Engl J Med N Engl J Med 2003;348: 891-9
  27. Fisher LM, Schlienger RG, Matter CM, et al. Discontinuation of nonsteroidal antiinfl ammatory drug therapy and risk of acute myocardial infarction. Arch Intern Med Arch Intern Med 2004; 164: 2472-6
  28. Laine L, Connors LG, Reicin A, et al. Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. Gastroenterology 2003; 124: 288-92
  29. Goldstein JL, Eisen GM, Lewis B, et al. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeperazole and placebo. Clin Gatroenterol Hepatol Gatroenterol Hepatol 2005;3: 133-41
  30. Kaufmann JH, Taubin HL. Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-6
  31. Rampton DS, Sladen GE. Relapse of ulcerative proctocolitis during treatment with nonsteroidal anti-inflammatory drugs. Postgrad Med J 1981; 57(667): 297-9
  32. El Miedany YM, Youssef SS, Ahmed I, El Gaafary M. The gastrointestinal safety and effect on disease activity of Etoricoxib, a selective Cox-2 inhibitor in inflammatory bowel disease. Am J Gastroenterol Am J Gastroenterol 2006;101: 311- 317
  33. Sanborn WJ, Stenson WF, Brynskov J. Safety of celecoxib in patients with ulcerative colitis in remission: a randomized double-blind , placebo-controlled study [Abstract]. Am J Gastoenterol 2004; 99(Suppl): S257
  34. El Miedany YM, Palmer D, El Gaafary M. Validity of a non-steroidal anti-infl ammatory risk assessment questionnaire (NARAQ) for standard clinical practice. Rheumatology (Oxford) 2006; 45(suppl 1): i59
  35. http://www.cebm.net/levels_of_evidence.asp
  36. Catella-Lawson F. Cyclo-oxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001;345: 1809-17 37. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of Cox-2 inhibition: therapeutic challenges and opportunities. J Clin Invest J Clin Invest 2006;116: 4-15