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  • 1. Appropriate use of NSAIDs: Considering cardiovascular risk in the elderly<br />Publish date: Mar 1, 2007By:  Martin J. Stillman, MD, JD, FCLM, M. Thomas Stillman, MD, FACP<br />Geriatrics. 2007 Mar;62(3):16-21.<br />Abstract<br />In the first of this two-part article, we reviewed essential gastrointestinal (GI) data necessary for choosing selective COX-2 inhibitors (coxibs) versus nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other NSAID-related GI issues. Although GI considerations are critical to appropriate NSAID selection, the worldwide withdrawal of rofecoxib because of adverse cardiovascular (CV) events has changed the focus of appropriate NSAID selection. In part 2, we discuss relevant CV adverse effects related to NSAID use. Based upon data reviewed, we believe there are differences between coxibs and that all NSAIDs, including nonselective agents, have some degree of CV risk. Their use should be based upon patients' risks and benefits. Our clinical use pathway or algorithm will continue to frame the ongoing discussion and guide clinicians along what has become a difficult decision in daily practice.<br />Stillman MJ, Stillman MT. Appropriate use of NSAIDs. Considering cardiovascular risk in the elderly. GERIATRICS 2007; 62(Mar):16-21.<br />Key words: nonsteroidal anti-inflammatory drugs (NSAIDs) • COX-2 inhibitors (coxibs) • hypertension • cardiovascular toxicity adverse effects • aspirin • clinical use pathway<br />Drugs discussed: rofecoxib • lumiracoxib • ibuprofen • celecoxib aspirin • naproxen • meloxicam • diclofenac • acetaminophen valdecoxib<br />Nonsteroidal anti-inflammatory drugs (NSAIDs), both cyclooxygenase-2 (COX-2) selective and nonselective, play a valuable role in treating certain types of pain and inflammation. Deciding when to use more costly pharmacologic therapies is often difficult, and making the appropriate choice to use selective COX-2 inhibitors (coxibs) is no exception. Since all types of NSAIDs are essentially equally efficacious to each other, selection of one over another generally depends on cost, side effect profiles, and ease of patient compliance.<br />As we discussed in part 1 of this two-part article,* we believe that data support the improved safety of coxibs over nonselective NSAIDs regarding fewer GI adverse events. However, this improved safety has more clinical meaning and impact in the patient at higher risk for GI complications. The degree of GI benefit may be reduced in certain clinical situations, possibly in patients taking low-dose aspirin for cardioprotection.<br />Figure 1 NSAID clinical use pathway for managing pain<br />The clinical use pathway presented in part 1, as well as in this paper (figure), helps guide physicians in deciding who should receive an NSAID and considers factors affecting the choice between specific agents in the NSAID class. In part 2, we navigate decision making in light of the cardiovascular (CV) effects of NSAIDs, and review study findings while comparing risk across the NSAID group.<br />Does the evidence support an association of coxibs with CV events?<br />This question has moved to the forefront of discussions involving coxibs since rofecoxib was globally withdrawn from the market because of its increased association with CV events. Since the short answer to this question is "yes," physicians should consider whether this CV side effect is unique to rofecoxib or if it is a class effect shared by all coxibs. Our belief is that there are differences among the coxibs, and that not all coxibs have the same CV risk.<br />As support for this opinion, it is important to note that several differences in the side effect profiles of coxibs are well established. Specifically, rofecoxib has been shown to have a higher incidence of edema and destabilization of treated hypertension than celecoxib. In patients with concomitant osteoarthritis (OA) and stable treated hypertension, rofecoxib, 25 mg/d, was associated with a significant increase in systolic blood pressure and peripheral edema, compared with celecoxib, 200 mg/d.1 Similar results were noted in patients with OA and type II diabetes mellitus who had stable hypertension after treatment with an angiotensin-converting enzyme (ACE) inhibitor.2<br />A retrospective study examined the incidence of new-onset hypertension following the initiation of coxib therapy in 17,844 patients aged 65 or older.3 Rofecoxib users had an overall increased relative risk of 1.6 compared with patients taking celecoxib. This relative risk of new-onset hypertension increased to 2.1 in patients with a history of chronic renal disease, liver disease, or congestive heart failure (CHF).<br />In a 1-year cardiovascular outcome trial, patients taking lumiracoxib had a significantly smaller mean change from baseline of systolic blood pressure than those taking ibuprofen or naproxen.4<br />The association between NSAIDs and CHF has also been examined. Although prospective randomized controlled studies are lacking, retrospective analyses have been completed. In a study of elderly patients, it was estimated that non-selective NSAIDs were responsible for close to 20% of first hospital admissions with CHF.5 In a large retrospective cohort analysis, general rates of admission for CHF were examined. In this study, patients on rofecoxib and nonselective NSAIDs had an increased risk of admission for CHF compared with non-NSAID users. This difference was not seen with users of celecoxib.6<br />These differences in edema, hypertension, and CHF outcomes suggest that side effect profiles may vary among coxibs. Theoretically, endothelial COX-2 produces a prostacyclin-induced vasodilatory effect, as well as an inhibitory effect on platelet thrombosis.7 It has been proposed that the use of a coxib therefore causes unopposed COX-1-directed platelet formation of thromboxane and thus a prothrombotic effect in certain at-risk patients. This effect was considered on reviewing cardiovascular data seen in the Vioxx Gastrointestinal Outcome Research (VIGOR) trial.8 In this trial, patients taking rofecoxib, 50 mg/d, had a 5 times greater incidence of nonfatal myocardial infarction (MI) than patients taking naproxen, 500 mg/bid.<br />Three possible explanations have been proposed for this finding.7 First, since the VIGOR trial was powered to look at GI outcome and not CV outcome, this study of 8,000 patients was underpowered to evaluate the incidence of CV events, and the increased CV events in the rofecoxib arm may have occurred entirely on the basis of chance.<br />Second, because naproxen blocks platelet formation of thromboxane via COX-1 inhibition, patients who were taking naproxen had a cardioprotective effect (similar to aspirin) not present in the rofecoxib group. Based on subsequent retrospective observational studies, mixed results have been reported on the cardioprotective effect of naproxen.9,10 Although there may have been some naproxen-related protection in the VIGOR data, it is unlikely to be the entire explanation, since naproxen would have then been associated with a 75% reduction in non-fatal MI in the VIGOR trial. This finding would far exceed that of any primary prevention trial using the established choice of aspirin, which has been shown to reduce the risk of a first MI by about one-third.11<br />The third possibility is that there was an increase in nonfatal MI in the VIGOR trial because of an increased CV risk associated with rofecoxib. Since the VIGOR trial, the concern about coxibs and CV risk has prompted many investigations. These have primarily been case-controlled retro-spective analyses looking for such associations. Although studies have supported that rofecoxib and celecoxib have differences in their effects on CV events,12 there is growing evidence that patients taking any NSAID, selective or nonselective, have a higher incidence of CV events compared with nonusers.<br />In an FDA-contracted, retrospective case-controlled study in collaboration with the Kaiser Permanente integrated managed care organization, investigators looked for an NSAID-associated risk of acute MI or sudden cardiac death (SCD) in 1.4 million patients taking selective and nonselective NSAIDs over a 3-year period.13 Analysis was carried out on a total of 8,143 patients who had serious coronary heart disease that resulted in an MI. Of these patients, 2,210 died of cardiac causes. The matched control group was made up of 31,496 patients who had not been taking any NSAID for at least 60 days before the cardiac event index date.<br />Study results revealed that rofecoxib use at a dose greater than 25 mg/d increased the risk of acute MI and SCD by 3.15. Rofecoxib use at all doses increased the risk compared with celecoxib. Of additional interest was the finding of a statistically significant increase in cardiac events in patients taking naproxen or other nonselective NSAIDs, including meloxicam. This finding provided additional evidence for a lack of a cardioprotective effect with nonselective NSAIDs (eg, naproxen) and, in fact, supported the concept that CV risk may be associated with all NSAIDS.<br />An additional retrospective study14 examined a cohort of 651,000 adults with physician-diagnosed arthritis and involved nearly 2.4 million patient-years of follow-up. In this retrospective analysis, 15,343 patients with acute MI had been taking selective or nonselective NSAIDs. Although the group taking celecoxib, 200 mg/d, had a lower incidence of MI than the group taking rofecoxib, 50 mg/d, almost all NSAIDs, including celecoxib, were associated with some degree of CV risk for acute MI. Additionally, increased dosing of the NSAIDs was associated with higher increased MI risk.<br />Although these studies focused on comparing the CV effects among coxibs and between coxibs and nonselective NSAIDs, other studies have more directly examined the CV effects of coxibs compared with placebo. This comparison emerged through the review of studies involving coxibs and prevention of colorectal polyps. Specifically, the studies were designed to examine the effect of coxibs versus placebo in preventing the recurrence of adenomatous colorectal polyps.<br />In the prospective, randomized placebo-controlled Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, 2,600 patients were to be observed for 3 years to evaluate the efficacy of rofecoxib, 25 mg/d, in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas.15 This trial was stopped early because of a twofold increase in relative risk for confirmed CV events (eg, MI, stroke), for patients taking rofecoxib compared with placebo.<br />Notably in this study, the rofecoxib group had a statistically significant higher percentage of hypertension and edema than the placebo group. This hypertension and edema difference began to occur at approximately 5 months into the study. When the study was terminated early because of these CV events, Merck and Co. announced a voluntary worldwide withdrawal of rofecoxib.<br />A similar prospective, randomized placebo-controlled clinical trial involving approximately 2,100 patients was designed to evaluate the efficacy of celecoxib, 200 mg/bid and 400 mg/bid, in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas.16The Data Safety Monitoring Board discontinued this study after 33 months because of a statistically significant dose-related increase in CV risk seen in the patients taking celecoxib compared with placebo. Specifically, the incidence of CV events was 2.3% and 3.4% for the 200 mg/bid and 400 mg/bid doses, respectively, compared with 1% for the placebo population.<br />In a nearly identical polyp prevention study comparing celecoxib, 400 mg/d, to placebo, there was no statistically significant difference in CV events between the two treatment groups.17<br />Further reports of these studies suggest that the drug-related CV risk may be of more concern in patients with preexisting CV risk. CV adverse events were four to five times higher in both the placebo and celecoxib arms if the patient had a prior history of CV events.18,19 Additionally, Gislason et al reported that coxibs in all dosages and nonselective NSAIDs in high dosages increase mortality in patients with previous MI.20<br />Finally, an extensive meta-analysis reviewed 23 observational studies regarding NSAIDs and CV risk.21 Analysis of the 17 case-controlled portion included more than 86,000 cases of CV events. This robust review further substantiated the increased risk of CV events associated with rofecoxib and also concluded that celecoxib, 200 mg/d, was not associated with an increased CV risk. As noted in other studies, the authors felt that data did not exclude an increased risk with celecoxib at higher dosages. The meta-analysis reviewed nonselective NSAIDs as well. Most had an associated CV risk similar to celecoxib, although the study found that diclofenac was associated with increased CV risk. While this study seems to substantiate the current relationship of CV events and NSAIDs, especially with increased dosing, to best assess the CV concern regarding all NSAIDs, additional prospective, double-blind, placebo-controlled studies are needed.<br />Is there an effect of NSAIDs, nonselective or selective, on aspirin's cardioprotective effect?<br />Many patients who take NSAIDs for pain control also take low-dose aspirin for cardioprotection. Concern has been raised regarding the possibility that the NSAID use limits the cardioprotective effect of aspirin.<br />In a pharmacologic prospective trial measuring thromboxane B2 formation,22 investigators concluded that ibuprofen administered 2 hours before aspirin may interfere with the cardioprotective effect of aspirin. This was explained by ibuprofen's initial competitive inhibition at the blocking site of serum thromboxane B2 formation and consequent interference of aspirin-induced platelet inhibition. This inhibition was not seen when aspirin was given 2 hours before ibuprofen. The same effect was not demonstrated by simultaneous use of aspirin and rofecoxib, diclofenac, or acetaminophen.<br />In an attempt to support or refute this antagonistic relationship, clinical studies have reviewed the incidence of CV events in patients taking aspirin and non-aspirin NSAIDs. Results have been mixed. In a study of more than 7,000 patients discharged with a low-dose aspirin regimen following a CV event,23 those taking ibuprofen concurrently had an increased risk of CV mortality of 1.93. Another study24 suggested that regular, but not intermittent, use of NSAIDs inhibited the clinical benefits of aspirin. Finally, in a large, nested, case-controlled analysis,25several different nonselective NSAIDs appeared to have no effect on the risk of acute CV events, irrespective of aspirin use. At this point, the question of whether there may be a mitigating effect on CV protection in patients taking con-current aspirin and NSAIDs remains unanswered.<br />What were the recommendations of the FDA review?<br />In February 2005, all available CV data were reviewed at a joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee convened by the FDA.26 This combined committee set out to discuss the overall risk-benefit considerations involving CV and GI safety concerns for coxibs and related agents. They reaffirmed that coxibs are important treatment options for arthritis patients in the United States, and voted that the overall risk-benefit profile of celecoxib, valdecoxib, and rofecoxib supported their being marketed in the United States.<br />Somewhat contrary to these recommendations, in April 2005, the FDA announced a series of changes to the entire class of NSAIDs.27 This series included a boxed warning for the potential risk of CV events and GI bleeding associated with all prescription NSAIDs, including celecoxib. In light of this increased CV risk, as well as the increased reporting rate of rare skin reactions with valdecoxib, the FDA requested that valdecoxib be withdrawn from the market.28 For all prescription NSAIDs, the FDA requested a contraindication for use in patients who have recently undergone coronary artery bypass surgery. Additionally, manufacturers of over-the-counter NSAIDs have been asked to include potential CV, GI, and skin reaction risks on their labels.<br />Summary<br />Recently, greater attention has been given to the CV side effect profile that led to the withdrawal of rofecoxib and, to some degree, the suspension of valdecoxib. We believe that data describing the differing incidence of edema, aggravated hypertension, and CHF, as well as variation in the incidence of other CV events, support that there are differences among the coxibs and that CV events are not entirely related to a class effect of the coxibs. Rather, retrospective studies have shown a varying degree of CV risk, especially with increased dosing, with both coxibs and nonselective NSAIDs. Therefore, all NSAIDs should be used in the lowest effective dosage and with caution in high-risk CV patients, particularly in our elderly patients. Further well-designed prospective studies are needed to better clarify both the characteristics that define "high risk" and the degree of CV differences among available NSAIDs.<br />While one school of thought has been to avoid the use of coxibs altogether, we believe this is clinically inappropriate. Many elderly patients need treatment of pain, and NSAIDs provide a significant degree of relief, especially when inflammation is present. As our first article discussed, GI risk can be a significant barrier to using nonselective NSAIDs, and the coxibs' general risk reduction of GI events by 50% compared with nonselective NSAIDs is clinically meaningful. This is especially so in the elderly, since age alone represents a GI risk factor in NSAID use. While a link between NSAIDs and CV events appears to exist, the risk of NSAID use cannot outweigh the benefit in every patient. For many elderly patients, improving quality of life by relieving pain at least warrants an informed consent discussion with their physician regarding NSAID use. The clinical use pathway reviewed in this paper can assist with this informed discussion. In addition, it lends itself to accomplishing certain goals in clinical practice: delivering medical treatment that accounts for appropriate evidence-based decisions and medical costs, while still providing thorough, thoughtful, and effective patient care.<br />Dr. Martin Stillman is an internist and attorney. He is a faculty member in the department of medicine, Hennepin County Medical Center, and assistant professor, University of Minnesota Medical School.<br />Dr. M. Thomas Stillman is a rheumatologist. He is director, undergraduate medical education, former director, division of rheumatology, department of medicine, Hennepin County Medical Center, and clinical professor, University of Minnesota Medical School.<br />Disclosures: Dr. Martin Stillman is a study design consultant and medical lecturer for Pfizer, Inc., and medical consultant for Novartis Pharmaceuticals Corp. Dr. M. Thomas Stillman is a medical consultant and lecturer for Pfizer, Inc., medical consultant for Merck & Co., and medical consultant for Novartis Pharmaceuticals Corp. No grant, research support, consulting/advising fees, or any financial remuneration was received for preparation of this manuscript.<br />Acknowledgments<br />The authors would like to thank Colleen Sauber for her assistance with final editing, Shannon Benson and Angie Knauss for their administrative assistance, and David Howzer for his ongoing support.<br />References<br />1. 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Consumption of NSAIDs and the development of congestive heart failure in elderly patients. An underrecognized public health problem. Arch Intern Med 2000; 160: 777-84.<br />6. Mamdani M, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004; 363:1751-56.<br />7. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345(6):433-42.<br />8. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343(21):1520-8, 2 p following 1528.<br />9. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal antiinflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 359(9301):118-23.<br />10. Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002; 162(10):1099-104.<br />11. Eidelman RS, Hebert PR, Weisman SM, Hennekens CH. An update on aspirin in the primary prevention of cardiovascular disease. Arch Intern Med 2003; 163(17):2006-10.<br />12. Ray WA, Stein CM, Daugherty JR, Hall K, Arbogast PG, Griffin MR. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002; 360(9339):1071-3.<br />13. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and nonselective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365 (9458):475-81.<br />14. Singh G, Mithal A, Triadafilopoulos G. Both selective COX-2 inhibitor and nonselective NSAIDs increase the risk of acute myocardial infarction in patients with arthritis: selectivity is with the patient, not the drug class. Ann Rheum Dis. 2005; 64(suppl III):85.<br />15. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352(11):1092-1102.<br />16. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 352(11):1071-80.<br />17. Food and Drug Administration. Advisory committee briefing document. January 12, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090±_03_pfizer-celebrex-bextra.pdf. Accessed February 21, 2007.<br />18. Bertagnoli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355(9):873-84.<br />19. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006; 355(9):885-95.<br />20. Gislason GH, Jacobsen S, Rasmussen JN, et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs after acute myocardial infarction. Circulation 2006; 113(25):2906-13.<br />21. McGettigan P, Henry, D. Cardiovascular risk and inhibition of cyclooxygenase. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296:1633-44.<br />22. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345(25):1809-17.<br />23. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003;361(9357):573-4.<br />24. Kurth T, Glynn RJ, Walker AM, Chan KA, Buring JE, Hennekens CH, Gaziano JM. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation 2003; 108(10): 1191-5.<br />25. Garcia Rodriguez LA, Varas C, Patrono C. Differential effects of aspirin and non- aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000; 11(4):382-7.<br />26. Food and Drug Administration. Minutes of the joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee, February 16-18, 2005. Available at: http://www.fda.gov/ohrms/dockets/ac/05/minutes/2005-4090m1_Final.htm. Accessed February 21, 2007.<br />27. Food and Drug Administration. COX-2 selective (includes Bextra, Celebrex, and Vioxx) and nonselective non-steroidal anti-inflammatory drugs (NSAIDs). April 7, 2005; updated July 18, 2005. Available at: http://www.fda.gov/cder/drug/infopage/cox2/default.htm. Accessed February 21, 2007.<br />28. Food and Drug Administration. Alert for healthcare professionals: vadecoxib (marketed as Bextra). April 7, 2005. Available at: http://www.fda.gov/cder/drug/infosheets/hcp/valdecoxibhcp.htm. Accessed February 21, 2007.<br />