Madhok, R.

McKellar, G.

Singh, G.

Wu, O.

English

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Non-steroidal anti-inflammatory drugs—changes in prescribing may be warranted

R.  Madhok

O. Wu

G. McKellar

G. Singh

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Non-steroidal anti-inflammatory drugs--changes in prescribing may be warranted

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      Madhok, R. and Wu, O. and McKellar, G. and Singh, G. (2006) Non-steroidal anti-inflammatory drugs—changes in prescribing may be warranted. Rheumatology 45(12):pp. 1458-1460.        http://eprints.gla.ac.uk/4201/  Deposited on: 30 May 2008   Glasgow ePrints Service http://eprints.gla.ac.uk Non-steroidal anti-inflammatory drugs—changes inprescribing may be warrantedNon-steroidal anti-inflammatory drugs (NSAIDs) are amongone of the most frequently prescribed classes of drugs. Both theirbenefits and harms arise due to inhibition of cycloxygenase(COX) of which there are two isoenzymes, COX 1 and 2.Both COX isoenzymes have a hydrophobic tunnel, through whichthe substrate accesses the active site. The tunnel is larger inthe COX 2 isoenzyme with a side pocket, a property exploited inthe development of specific COX 2 inhibitors [1]. The premiseof the initial, COX 2 hypothesis was that the gastrointes-tinal side effects arose due to inhibition of COX 1 whereastheir anti-inflammatory or analgesic properties were COX 2mediated. Although now appreciated to be rather naı¨ve, thesuperiority of the selective COX 2 inhibitors in preventing gastro-duodenal mucosal ulceration over the non-selective NSAIDs isstriking [2, 3].There has been continuing scientific and media attention onreports that selective COX 2 inhibitors increase the risk ofcardiovascular events. In an early study of major gastrointestinalevents, an unexpected 5-fold increase in the risk of acutemyocardial infarction (AMI) with rofecoxib was observed whencompared with naproxen [4]. At the time, many suggested andaggressively pursued the hypothesis that the increased frequencyof events was a spurious observation not due to any prothrombo-tic effects of rofecoxib, but the cardioprotective properties ofnaproxen. However, subsequent placebo-controlled studies ofboth rofecoxib, and celecoxib in chemoprevention also reportedan approximate 2-fold increase in cardiovascular events withboth drugs [5, 6].More recently, attention has turned to the effects of the non-selective NSAIDs. As aspirin confers its cardiovascular benefitsby inhibiting COX 1 [7], received wisdom has never consideredthe possibility that the non-selective NSAIDs could increase therisk of cardiovascular events. However, in February 2005,the Food and Drugs Administration (FDA) decided to advisethat the risk of cardiovascular events for both selective COX 2and non-selective NSAIDs is similar and has taken the step tocategorize this as a class effect [8]. In the US, all COX 2 selectiveand non-selective NSAIDs now carry a black-boxed warningon the package insert advising patients of the potential increasedcardiovascular risk [9]. The European Agency for the Evaluationof Medicine Products (EMEA) [10] and the Medicines andHealthcare Products Regulatory Agency (MRHA) [11] have,however, been much more reassuring with regard to non-selectiveNSAIDs and advised that ‘the data are insufficient to warrantchanges in current prescribing’.The association between increased AMI risk and non-selectiveNSAIDs has been evaluated predominantly in observationalstudies [12–28]. These were primarily based on data from largepopulation and hospital databases that recorded the prevalenceof NSAID use combined with confirmed AMI diagnosis. Whilemost studies also accounted for the presence of other risk factors,confounders and use of aspirin, few recorded the indicationand duration of NSAID use [15, 16, 18]. Overall, a generaldirection of effect has been reported from the observationalstudies—with the exception of one study [21], which reportedno effect between non-selective NSAID use and AMI, allstudies showed a similar trend of increased risk of AMIcompared with remote and non-use, ranging from relative riskof 1.00 (95% CI: 0.73–1.37) [21] to 1.47 (95% CI: 1.00–2.16) [22].Although the size of the overall relative risk appears small,however, due to the large number of patients prescribed NSAIDs,the absolute risk may be considerable. In addition, these studieshave presented data that suggested a differential risk betweenindividual NSAID such as diclofenac, naproxen and ibuprofen,but there is insufficient evidence to conclude whether this trulyrepresents a class effect.The main concern in the context of these studies is whetherthe small effect observed is a real one or due to unknown orunmeasured confounding factors, a limitation that is inherentto all observational studies. However, such studies may be theonly feasible method to determine the potential harms of drugsif the effects are small.It has been advocated that the only method to resolve theissue would be to undertake a large randomized-control trial ofnon-selective NSAIDs vs placebo [29]. However, it is unlikely thatsuch trial would ever be funded, and it would be unethicalto randomize patients to an intervention that may be potentiallyharmful.Kearney et al. [30] have undertaken a meta-analysis of dataof vascular events from randomized-controlled trials of selectiveCOX 2 inhibitors. They found that in all studies selective COX 2inhibitors increased the risk of vascular events, mainly AMIby 42% (rate ratio 1.42; 95% CI: 1.13–1.78). Trials that compareda COX 2 inhibitor with a traditional NSAID (n¼ 91 trials)showed no significant difference in the risk of vascular events(rate ratio 1.16; 95% CI: 0.97–1.38). There were no significantdifferences whether all non-selective NSAIDs were consideredtogether, in combination, or alone when compared with COX 2inhibitors. However, a comparison of non-selective NSAIDswith placebo showed differences between NSAIDs—naproxenwas associated with the lowest risk (0.92; 95% CI: 0.67–1.21), butthere were insufficient data to show a cardioprotective effect;whereas the rate ratios for ibuprofen and diclofenac were 1.51(95% CI: 0.96–2.37) and 1.63 (95% CI: 1.12–2.37), respectively.This study thus confirms the findings of the epidemiologicalstudies, but the number of cardiovascular events were small,a limitation acknowledged by the investigators. Furthermore,none of the comparative studies of COX 2 inhibitors withnon-selective studies were conducted in patients with highcardiovascular risk or specifically powered to evaluate cardio-vascular events.The MEDAL programme and PRECISION studies arepharmaceutical industry sponsored trials designed to addressthese concerns. The MEDAL programme consists of three studies(EDGE, EDGE II and MEDAL), and is a non-inferioritycomparison of cardiovascular events between etoricoxib anddiclofenac [31]. The EDGE studies where originally designed tocompare the gastrointestinal tolerability of etoricoxib comparedwith diclofenac in osteoarthritis and rheumatoid arthritis, whereasthe MEDAL study is specifically designed to compare cardio-vascular events in 17 804 osteoarthritis and 5700 rheumatoidarthritis patients treated with either etoricoxib or diclofenac.All three studies will continue until the total number of confirmedthrombotic reaches 635 with at least 430 in the MEDAL study.The PRECISION study is a multi-centre comparative study For Evaluation Only.Copyright (c) by Foxit Software Company, 2004 - 2007Edited by Foxit PDF Editorof celecoxib, diclofenac or ibuprofen coordinated by the ClevelandClinic which is to report in 4 yrs time [32].Common to both non-selective NSAIDs and COX 2 inhibitorsis the adverse event of hypertension [33, 34]. Most NSAIDsraise blood pressure by approximately 3–5mmHg [34]. Even sucha modest rise will result in a significantly increased frequency ofcardiovascular events; a 3mmHg rise in systolic blood pressureincreases the frequency of congestive cardiac failure by 10–20%,increases the risk of stroke up to 20% and angina by 12% [35].It has also been predicted that a 3mmHg in blood pressure inrheumatoid arthritis patients in the US will result in an additional21 390 ischaemic heart disease and stroke events [36]; whenextrapolated to the UK rheumatoid arthritis population, this isequivalent to 2058 potentially avoidable fatal events.The current evidence strongly suggests that the risk forcardiovascular events to be similar for both non-selectiveNSAIDs and COX 2 inhibitors. The potential size of the problemis substantial. Physicians should reconsider their prescription ofnon-selective NSAIDs in line with those advocated by the FDA.Any other advice on current prescribing is unwarranted.R. MADHOK, O. WU1, G. MCKELLAR and G. SINGH2Centre for Rheumatic Diseases, Glasgow Royal Infirmary, CastleSt,1Division of Developmental Medicine, University of Glasgow,Glasgow, UK and 2Division of Gasterenterology and Hepatology,Department of Medicine, Stanford University School of Medicine,California, USAAccepted 12 September 2006Correspondence to: Rajan Madhok, Centre for RheumaticDiseases, Glasgow Royal Infirmary, Castle St, Glasgow, UK.E-mail: gcl103@clinmed.gla.ac.ukReferences1. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis forselective inhibition of cyclooxygenase-2 by anti-inflammatory agents.Nature 1996;384:644–8.2. Seibert K, Masferrer J, Zhang Y et al. Mediation of inflammation bycyclooxygenase-2. Agents Actions (Suppl) 1995;46:41–50.3. Garner S, Fidan D, Frankish R et al. Celecoxib for rheumatoidarthritis. Cochrane Database Syst Rev 2002;4:CD003831.4. Bombardier C, Laine L, Reicin A et al. VIGOR Study Group.Comparison of upper gastrointestinal toxicity of rofecoxib andnaproxen in patients with rheumatoid arthritis – VIGOR StudyGroup. N Engl J Med 2000;343:1520–8.5. Bresalier RS, Sandler RS, Quan H et al. AdenomatousPolyp Prevention on Vioxx (APPROVe) Trial Investigators.Cardiovascular events associated with rofecoxib in a colorectaladenoma chemoprevention trial. N Engl J Med 2005;352:1092–102.6. Solomon SD, McMurray JJ, Pfeffer MA et al. Adenoma Preventionwith Celecoxib (APC) Study Investigators. Cardiovascular riskassociated with celecoxib in a clinical trial for colorectal adenomaprevention. N Engl J Med 2005;352:1071–80.7. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. Drugtherapy: low dose aspirin for prevention of atherothrombosis.N Engl J Med 2005;353:2373–83.8. TMT Review of cardiovascular safety of Celebrex. January 2005.Accessed 23 August 2006. Page 8 of http://www.fda.gov/ohrms/dockets/dockets/04n0559/04N-0559_emc-00002-01.pdf9. Decision Memo: Analysis and recommendations for Agencyaction: Cox 2 selective and non-selective NSAIDs. Accessed23 August 2006. http://www.fda.gov/cder/drug/infopage/cox2/NSAIDdecisionmemo.pdf10. EMEA press release on non-selective NSAIDS, 2nd August 2005.Accessed 23 August 2006. http://www.emea.eu.int/pdfs/human/press/pr/24732305en.pdf11. MHRA release: ‘‘Cardiovascular safety of NSAIDs – review of theevidence’’. Accessed 23 August 2006. http://www.mhra.gov.uk/home/idcplg?IdcService¼GET_FILE&dID¼1428&noSaveAs¼0&Rendition¼WEB12. Kimmel SE, Berlin JA, Reilly M et al. Patients exposed to rofecoxiband celecoxib have different odds of nonfatal myocardial infarction.Ann Intern Med 2005;142:157–64.13. Kimmel SE, Berlin JA, Reilly M et al. The effects of non-selectivenon-aspirin non-steroidal anti-inflammatory medications on the riskof nonfatal myocardial infarction and their interaction with aspirin.J Am Coll Cardiol 2004;43:985–90.14. Jick SS. The risk of gastrointestinal bleed, myocardial infarction, andnewly diagnosed hypertension in users of meloxicam, diclofenac,naproxen and piroxicam. Pharmacotherapy 2000;20:741–4.15. Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thrombo-embolic cardiovascular events with naproxen among patients withrheumatoid arthritis. Arch Intern Med 2002;162:1105–10.16. Garcia Rodriguez LA, Varas C, Patrono C. Differential effects ofaspirin and non-aspirin nonsteroidal antiinflammatory drugs in theprimary prevention of myocardial infarction in postmenopausalwomen. Epidemiology 2000;11:382–7.17. Fischer L, Schlienger RG, Matter CM, Jick H, Meir CR. Current useof non-steroidal anti-inflammatory drugs and the risk of myocardialinfarction. Pharmacotherapy 2005;25:503–10.18. Garcia Rodriguez LA, Varas-Lorenzo C, Maguire A, Gonzalez-Perez A. Non steroidal anti-inflammatory drugs and the risk ofmyocardial infarction in the general population. Circulation2004;109:3000–6.19. Graham DJ, Campen D, Hui R et al. Risk of acute myocardialinfarction and sudden cardiac death in patients treated withcyclo-oxygenase 2 selective and non-selective non-steroidalanti-inflammatory drugs: nested case-control study. Lancet2005;65:475–81.20. Johnsen SP, Larsson H, Tarone RE et al. Risk of hospitalization formyocardial infarction among users of rofecoxib, celecoxib, and otherNSAIDs: a population-based case-control study. Arch Intern Med2005;165:978–84.21. Levesque LE, Brophy JM, Zhang B. The risk for myocardialinfarction with cyclooxygenase-2 inhibitors: a population study ofelderly adults. Ann Intern Med 2005;142:481–9.22. Mamdani M, Rochon P, Juurlink DN et al. Effect of selectivecyclooxygenase 2 inhibitors and naproxen on short-term risk ofacute myocardial infarction in the elderly. Arch Intern Med2003;163:481–6.23. Ray W, Stein MC, Daugherty JR, Hall K, Arbogast PG, Griffin MR.Cox-2 selective non steroidal anti-inflammatory drugs and risk ofcoronary heart disease. Lancet 2002;360:1071–3.24. Ray W, Stein MC, Hall K, Daugherty JR, Griffin MR. Non steroidalanti-inflammatory drugs and risk of serious coronary heart disease;an observational cohort. Lancet 2002;359:118–23.25. Rhame E, Pilote L, LeLorier J. Association between naproxen useand protection against acute myocardial infarction. Arch Intern Med2002;162:1111–5.26. Schlienger RG, Jick H, Meier CR. Use of non steroidal anti-inflammatory drugs and the risk of first acute myocardial infarction.Br J Clin Pharmacol 2002;54:327–32.27. Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch InternMed 2002;162:1099–104.28. Hippisley-Cox J, Coupland C. Risk of myocardial infarction inpatients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. Br Med J 2005;330:1366.29. Juni P, Reichenbach S, Egger M. COX-2 inhibitors, traditionalNSAIDs, and the heart. Br Med J 2005;330:1342–3.30. Kearney PM, Baignent C, Godwin J, Halls H, Emerson JR.Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk ofFor Evaluation Only.Copyright (c) by Foxit Software Company, 2004 - 2007Edited by Foxit PDF Editoratherothrombosis? Meta-analysis of randomised trials. Br Med J2006;332:1302–8.31. Cannon CP, Curtis SP, Bolognese JA, Laine L – for the MEDALSteering Committee. Clinical trial design and patient demographicsof the Multinational Etoricoxib and Diclofenac Arthritis Long-term(MEDAL) Study Program: cardiovascular outcomes with etoricoxibversus diclofenac in patients with osteoarthritis and rheumatoidarthritis. Am Heart J 2006;152:237–45.32. Cleveland Clinic website, PRECISION study. Accessed 23 August2006. http://www.clevelandclinic.org/heartcenter/pub/news/archive/2005/painrelief12_13.asp33. Aisen PS, Schafer K, Grundman M et al. NSAIDs and hypertension.Arch Int Med 2003;163:1115.34. Johnson AG, Nguyen TV, Day RO. Do non-steroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. AnnIntern Med 1994;121:289–300.35. ALLHAT Collaborative Research Group. Major cardiovascularevents in hypertensive patients randomized to doxazosin vs chlortha-lidone. JAMA 2000;283:1967–75.36. Singh G, Miller JD, Huse DM et al. Consequences of increasedsystolic blood pressure in patients with osteoarthritis and rheumatoidarthritis. J Rheumatol 2003;30:714–9.For Evaluation Only.Copyright (c) by Foxit Software Company, 2004 - 2007Edited by Foxit PDF Editor

Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.

Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.

ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone.

Analysis and recommendations for Agency action: Cox 2 selective and non-selective NSAIDs.

Association between naproxen use and protection against acute myocardial infarction.

Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev

Clinic website, PRECISION study.

Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol 2003;30:714–9. For Evaluation Only. Copyright (c) by Foxit Software Company,

COX-2 inhibitors, traditional NSAIDs, and the heart.

Cox-2 selective non steroidal anti-inflammatory drugs and risk of coronary heart disease.

Current use of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction.

Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women.

Do non-steroidal antiinflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med

Do selective cyclo-oxygenase-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs increase the risk of For Evaluation Only. Copyright (c) by Foxit Software Company,

Drug therapy: low dose aspirin for prevention of atherothrombosis.

Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly.

Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis.

Mediation of inflammation by cyclooxygenase-2. Agents Actions (Suppl)

MHRA release: ‘‘Cardiovascular safety of NSAIDs – review of the evidence’’.

Non steroidal anti-inflammatory drugs and risk of serious coronary heart disease; an observational cohort.

Non steroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. Circulation

Nonsteroidal antiinflammatory drug use and acute myocardial infarction.

NSAIDs and hypertension.

Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction.

Reicin A et al. VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis

Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study.

Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study.

Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional nonsteroidal anti-inflammatory drugs: population based nested casecontrol analysis.

Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents.

The effects of non-selective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin.

The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults.

The risk of gastrointestinal bleed, myocardial infarction, and newly diagnosed hypertension in users of meloxicam, diclofenac, naproxen and piroxicam.

TMT Review of cardiovascular safety of Celebrex.

Use of non steroidal antiinflammatory drugs and the risk of first acute myocardial infarction.

http://eprints.gla.ac.uk/4201/1/Wu4201.pdf

Non-steroidal anti-inflammatory drugs—changes in prescribing may be warranted

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