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The NSAID and CVD Balancing Act

An Expert Interview With Daniel Solomon, MD
Linda Brookes, Daniel Solomon, MD

Aug 30, 2011

A Best Evidence Interview With Daniel Solomon, MD

About the Interviewee

Daniel Solomon, MD, MPH, is an Associate Professor of Medicine at Harvard Medical School and Chief of the Section of Clinical Sciences in Rheumatology at Brigham and Women's Hospital, where he is coappointed in the Division of Pharmacoepidemiology and Pharmacoeconomics. The focus of his research is health services research, quality of care, and pharmacoepidemiology as it pertains to rheumatic diseases and osteoporosis. Specific topics of interest include: indicators of quality prescribing, patterns of medication use for osteoporosis, quality improvement in osteoporosis care, and cardiovascular disease in patients with rheumatoid arthritis. Dr. Solomon is the Past Chair of the Quality of Care Committee of the American College of Rheumatology. He serves as an unpaid member of the Executive Committee on the PRECISION trial assessing the cardiovascular safety of celecoxib vs nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) and as an unpaid member of the Data and Safety Monitoring Board for trials testing a nerve growth factor inhibitor, tanezumab.

Background to the Interview on Cardiovascular Risks and NSAID Use

The cardiovascular safety of NSAIDs, commonly used by patients for the pain of osteoarthritis and rheumatoid arthritis, remains a subject of controversy. Following the withdrawal of the cyclo-oxygenase (COX) 2 inhibitor rofecoxib from the US market in 2004[1] because of an increased risk for cardiovascular events and the subsequent boxed warning applied to the label of the only COX-2 inhibitor currently available, celecoxib,[2,3] attention turned to possible side effects of the traditional, nonselective NSAIDs.[4] In 2005, the US Food and Drug Administration (FDA) concluded that an increased risk for serious adverse cardiovascular events might be a class effect for NSAIDs (excluding aspirin) and requested that a boxed warning be added to the package insets for all NSAIDs highlighting the potential increased risk for cardiovascular events (as well as the risk for serious and potentially life-threatening gastrointestinal bleeding).[5] However, whereas the cardiovascular adverse effects associated with rofecoxib were demonstrated in a randomized trial[6] and subsequently confirmed in other trials and by a cumulative meta-analysis,[7] few data from large randomized trials are available about the cardiovascular safety of most of the nonselective NSAIDs. Further meta-analyses of randomized trials and observational studies of NSAIDs including nonselective drugs indicated that all NSAIDs are associated with an increase in cardiovascular risk, but that this varies with different agents. Several studies published earlier this year demonstrated cardiovascular effects in patients at high risk for or with established coronary artery disease,[8-11] and a population-based case-control study indicated that use of nonaspirin NSAIDs is associated with an increased risk for atrial fibrillation or flutter.[12] Daniel Solomon, MD, MPH, spoke with Linda Brookes, MSc, for Medscape, about these studies and how the current understanding of the cardiovascular safety of NSAIDs should be taken into account when determining optimal analgesic strategies for their arthritis patients.

Cardiovascular Effects: Not All NSAIDS Are Alike

Medscape: Are all the issues about the cardiovascular safety of the COX-2 inhibitors clear now? Dr. Solomon: No, there are many fundamental issues that are not settled. The comparative cardiovascular safety of celecoxib vs nonselective NSAIDs is still not clear. While high dosages of celecoxib (ie, at least 200 mg twice daily)
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are associated with cardiovascular risk compared with placebo,[13-17] the risk of lower dosages compared with nonselective NSAIDs is not known. Medscape: What is known about the cardiovascular effects of traditional NSAIDs at present? Dr. Solomon: Traditional NSAIDs are not all similar in their risk. Naproxen appears to be safest from a cardiovascular standpoint,[11,18-22] but it may be associated with more gastrointestinal bleeding. Agents, such as diclofenac, with greater COX-2 inhibition appear to be most risky on the cardiovascular system. Medscape: How do the risks differ in patients with and without cardiovascular disease risk factors? Dr. Solomon: This has not been well studied, but it appears that patients with more cardiovascular disease risk factors are at a heightened risk with nonselective and selective NSAIDs.[17] This needs further study. Medscape: So in younger patients, say aged 50 years, with no other risk factors, presumably these drugs are safe? Dr. Solomon: The baseline risk for cardiovascular events is lower in younger people who do not have cardiovascular risk factors. So, even if the risk is raised by 20%-50%, the absolute rate of events is still very low. It is bad if you are one of those people who has an event but, obviously, the vast majority do not have events. While cardiovascular morbidity is a big deal, especially at the population level, the truth is that patients come in asking for pain relief and providers want to help. Medscape: There have been a number of meta-analyses published this year that looked at the cardiovascular safety of NSAIDs, including the network meta-analysis by Trelle and colleagues,[11] which concluded that all NSAIDs are associated with increased cardiovascular risk but that naproxen is safest in this respect. Dr. Solomon: A network meta-analysis, such as the one by Trelle and colleagues,[11] takes data from randomized clinical trials and attempts to use the "transitive property" to make indirect comparisons across studies. So, if naproxen has been shown in one study to be safer than ibuprofen and in another study ibuprofen was safer than diclofenac, then naproxen is concluded to be safer than diclofenac. However, as I said in a recent commentary,[22] I am not certain that this meta-analysis has given us new insight. It was conducted using very rigorous methodology, with large numbers of people from randomized controlled trials, and so it adds to the literature. However, most doctors and patients are more interested in comparisons between active agents than comparisons with placebo. Moreover, overall safety (not just cardiovascular) and the benefit-risk ratio for analgesics would really help guide prescribing. One can interpret the results of the Trelle study to say that all NSAIDs (selective and nonselective) are risky on the heart. However, as a rheumatologist, I treat patients who come in with joint pain. So the rheumatologist says, "Look, I have to give analgesics to people with arthritis and other chronic painful conditions; that is why they are coming in to see me. These drugs are useful for pain and a small risk is likely acceptable." All drugs have risks, so it's more about managing the risk through appropriate patient selection and good communication rather than complete risk avoidance.

Weighing the Risks and Benefits of NSAIDs When Managing Pain

Medscape: At the time of the FDA hearings into the COX-2 inhibitors, some patients were concerned about potentially losing rofecoxib, which they claimed was the only drug that gave them pain relief, and they said that they were willing to accept a small increase in cardiovascular risk for this.[23] Dr. Solomon: It comes down to a benefit-to-risk ratio, and that is very much about your perspective. Is it cardiocentric (ie, anything that might cause damage to the heart should not be used)? Or is your perspective that of a
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physician trying to treat patients' symptoms -- their pain and their lack of function -- and trying to trade off the potential benefits and risks of these analgesics? NSAIDs have been used for decades for this indication, and patients and randomized trials clearly speak to their benefits. When I discuss risks and benefits with patients in pain and explain that these drugs may increase their risk for a heart attack from 5 per 1000 per year to 6 or 7 per 1000 per year, they reply, "So, I should take it?" How do you weigh the benefits and how do you weigh the potential risks? No one would say that these drugs are not risky -- we know they are risky. All of them, including the nonselective drugs, have significant risk for gastrointestinal bleeding. They all have significant risk for renal insufficiency. They all have a minimal risk for liver toxicity. This is very long list of potential risks, as with all drugs. But they have known benefits. And again, if you are a physician seeing patients with pain, you are sitting there saying, "What am I going to give for this patient's pain?" When you are talking about cardiovascular risk, patients do not come in and say, "Is this drug risky for my heart?" They say, "Is it safe?" They are not asking about their heart, they are asking about overall safety. So we want to think about composite measures of safety. And patients are also asking about benefits: "Is it going to help me?" So the $64,000 question for a given patient is: which drugs have the best benefit-to-risk ratio? We do not really know, that is the bottom line, because most of the information, including the data from the study by Trelle and colleagues, does not tell us about people with different sets of risk factors. It only tells us about cardiovascular outcomes in the whole population. Medscape: There has been concern about cardiovascular side effects of drug classes used in other areas of medicine, but a lot of attention has been focused on analgesics used in rheumatology. Dr. Solomon: People focus on this because NSAIDs are such commonly used drugs, because there was a very high-profile issue with rofecoxib, and because cardiovascular risks in the elderly are a big deal. I completely agree with the perspective that even a 1% increase in risk multiplied in the millions of people who take NSAIDs is a public health issue. However, pain and disability are also public health issues.

A General Approach to Managing Chronic Pain

Medscape: In light of current knowledge, how would you advise physicians who need to prescribe pain medication for arthritis patients? Dr. Solomon: Nonpharmacologic methods are the first line for several forms of arthritis. They include physical therapy, injections, heat, or cold. Assistive devices are worth considering. I would consider bracing for knee osteoarthritis, when there are deformities amenable to shifting the load. A cane can also be considered at first line, but it meets with some patient resistance. You can get into acupuncture or meditation, and many other nonpharmacologic therapies, but most patients are not interested in such treatments. Low- to high-dose acetaminophen would be second line, and topical NSAIDs in combination with acetaminophen as third line. Oral NSAIDs at low to high doses with or without acetaminophen are next. Then, low potency opioids and adjunctive analgesics (tricyclic antidepressants, anticonvulsants, serotonin-norepinephrine reuptake inhibitors) as next line. These can be used in combination with acetaminophen and NSAIDs if necessary, but the total acetaminophen daily dosage must be considered. At some point the conversation has to be about joint replacement for someone with severe osteoarthritis.

PRECISION: A Randomized Trial Comparing the Safety of Celecoxib vs Ibuprofen or Naproxen

Medscape: The first randomized trial data about the cardiovascular adverse effects of NSAIDs will come from the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial[24,25]
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and you are on the Executive Committee. PRECISION will compare the cardiovascular safety of celecoxib with the 2 most commonly prescribed nonselective NSAIDs, ibuprofen and naproxen, in patients with osteoarthritis or rheumatoid arthritis and established or be at high risk of developing cardiovascular disease. The high-risk patients you are enrolling have to meet 3 inclusion criteria: age > 55 years, hypertension, dyslipidemia, family history of premature cardiovascular disease, current smoker, left ventricular hypertrophy, documented ankle brachial index < 0.9, and history of microalbuminuria. So this will be a very mixed population. Dr. Solomon: To some extent it is a real-world population of moderate to high cardiovascular risk patients because that is the group that we are most concerned about. We are on our way to enrolling 20,000 people; it is quite a task to keep such a large number in the trial and on a drug for several years. Medscape: In the paper describing rationale and the design of the trial,[25] you say that the absence of a true placebo arm makes determination of the risk associated with each of these agents impossible. Dr. Solomon: Yes, but you cannot have a placebo arm in any long-term trials of analgesics; it would be unethical. Furthermore, giving nothing is not an option for many patients in clinical practice. Medscape: Drug dosages in the trial are celecoxib 100-200 mg twice a day, naproxen 375-500 mg twice a day, and ibuprofen 600-800 mg 3 times a day, with esomeprazole in all patients. Doses of naproxen and ibuprofen may be further increased in patients with osteoarthritis. How safe would the higher doses of ibuprofen be? Haven't doses above 1800 mg daily been associated with an increased risk for cardiovascular disease[4,26,27] and with increased risk for death in hospitalized cardiovascular patients on aspirin,[28] which is permitted in this trial? Dr. Solomon: That ibuprofen dose is moderate to maximum; it is what you would give when you give prescription strength. We were trying to find an equally analgesic dose. It is not obvious what the right dose is. So, we tried to develop equally analgesic dosing and there was a lot of discussion and a lot of examination of the pharmacodynamic data. The choices we made were very reasonable but can be debated. Medscape: According to the latest update, the estimated completion date for the PRECISION trial is 2014.[24] Do you think that by that time there will be any new NSAIDs available, ones that are known to be without cardiovascular side effects? There are a number of NSAIDs in various stages of clinical development, including new classes of molecules. Dr. Solomon: There are always more on the horizon. I am not involved in drug development and am not aware of the details of such agents. Medscape: Several drugs have reached phase 3, but these new first-in-class drugs have not yet reached regulatory approval. Dr. Solomon: It is not for lack of trying. There has been a lot of work done on the COX-inhibiting nitric oxide donators (CINODs). The first in class was naproxcinod, but it failed to gain approval by the FDA.[29] Medscape: Another class of drugs in development for chronic pain is the nerve growth factor (NGF) inhibitors, including the monoclonal antibodies tanezumab and fulranumab. At this time, clinical development of all anti-NGFs is on hold, following reports of a need for total joint replacements in some patients in the tanezumab trials.[30,31] The FDA's Arthritis Advisory Committee is due to decide in September whether development of these drugs should continue.[32] It does seem difficult to bring a new class of drugs for chronic pain in arthritis to the clinic. Dr. Solomon: First, I should disclose that I am on the data and safety monitoring boards for several clinical trials of tanezumab. But yes, I think you are right -- it is tough. These drugs are tested in people who have many comorbidities, so it is not surprising that adverse outcomes develop. It is sometimes hard to determine whether these adverse outcomes are drug-related or related to an underlying condition. As well, in the NGF inhibitor trials, many
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subjects are very old and chronically disabled. These drugs are not being tested in healthy, young adults. One should not generalize from the CINODs to the NGF inhibitors; however, it is hard to do drug development in old sick people. Because this is a large population with an unmet need, I hope that companies continue to work in the area of chronic pain and osteoarthritis.
References

1. Merck &. Co., Inc. Merck announces voluntary worldwide withdrawal of VIOXX. News release. Whitehouse Station, NJ: Merck & Co., Inc.; September 30, 2004. Available at: http://www.merck.com/newsroom/vioxx/pdf/vioxx_press_release_final.pdf Accessed August 23, 2011. 2. CELEBREX (celecoxib) capsules. Prescribing information. New York, NY: G. D. Searle, Inc; January 2011. Available at: http://www.pfizer.com/files/products/uspi_celebrex.pdf Accessed August 23, 2011. 3. US Food and Drug Administration. FDA Announces Series of Changes to the Class of Marketed Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). FDA News release P05-16. April 7, 2005. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108427.htm Accessed August 23, 2011. 4. 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;296:16331644. 5. Information for Healthcare Professionals: Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) April 7, 2005. Available at: http://www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ ucm085282.htm Accessed August 23, 2011. 6. Bombardier C, Laine L, Reicin A, et al; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520-1528. 7. Juni P, Nartey L, Reichenbach S, et al. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004;364:2021-2029. 8. Rodriguez LAG, Gonzlez-Prez A, Bueno H, Hwa J. NSAID use selectively increases the risk of non-fatal myocardial infarction: a systemic review of randomized trials and observational studies. PLoS One. 2011;6:e16780. 9. Olsen AMS, Fosbl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011;123:2226-2235. 10. Bavry AA, Khaliq A, Gong Y, et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med. 2011;124:614-620. 11. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. 12. Schmidt M, Christiansen CF, Mehnert F, et al. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case control study. BMJ. 2011;343:d3450.
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13. Solomon SD, McMurray JJ, Pfeffer MA, et al; Adenoma Prevention with Celecoxib (APC) Study Investigators. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352:1071-1080. 14. TMT review: Cardiovascular safety of celecoxib. Protocol IXQ-97-02-001. New York, NY: Taylor MicroTechnology Inc.; 2005. Available at: http://www.fda.gov/OHRMS/DOCKETS/dockets/04n0559/04N0559_emc-000002-01.pdf Accessed August 23, 2011. 15. Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355:885-895. 16. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355:873-884. 17. Solomon SD, Wittes J, Finn PV, et al; Cross Trial Safety Assessment Group. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008;117:2104-2113. 18. Ray WA, Varas-Lorenzo C, Chung CP, et al. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes. 2009;2:155163. 19. Wang BH, Bertucci MC, Ma JY, et al. Celecoxib, but not rofecoxib or naproxen, attenuates cardiac hypertrophy and fibrosis induced in vitro by angiotensin and aldosterone. Clin Exp Pharmacol Physiol. 2010;37:912-918. 20. Fosbl EL, Folke F, Jacobsen S, et al. Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes. 2010;3:395-405. 21. Salpeter SR, Gregor P, Ormiston TM, et al. Meta-analysis: cardiovascular events associated with nonsteroidal anti-inflammatory drugs. Am J Med. 2006;119:552-559. 22. Young Kim SY, Solomon DH. Pharmacotherapy: comparative safety of nonsteroidal anti-inflammatory drugs. Nat Rev Cardiol. 2011;8:193-195. 23. When patients say: don't ban my drug. BusinessWeek. April 25, 2005. Available at: http://www.businessweek.com/magazine/content/05_17/b3930067_mz011.htm Accessed August 23, 2011. 24. Prospective Randomized Evaluation Of Celecoxib Integrated Safety Vs Ibuprofen Or Naproxen (PRECISION). NCT00346216. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00346216?term=COX2+inhibitor+AND+arthritis&recr=Open&rank=10 Accessed August 23, 2011. 25. Becker MC, Wang TH, Wisniewski L, et al. Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis. Am Heart J. 2009;157:606-612. 26. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional nonsteroidal antiinflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006;332:1302-1308. 27. Hernandez-Diaz S, Varas-Lorenzo C, Garcia Rodriguez LA. Nonsteroidal antiinflammatory drugs and the risk of acute myocardial infarction. Basic Clin Pharmacol Toxicol. 2006;98:266-274. 28. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet. 2003;361:573-574.
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29. NicOx S.A. FDA provides complete response letter to NicOx's application for naproxcinod. Press release. Sophia Antipolis, France: NicOx S.A.; July 22, 2010. Available at: http://www.nicox.com/files/pdf/PR2010072200EN.pdf Accessed August 23, 2011. 30. Pfizer Suspends Tanezumab Osteoarthritis Clinical Trial Program. Press release. New York, New York: Pfizer Inc.; June 23, 2010. Available at: http://www.pfizer.com/news/press_releases/ pfizer_press_release_archive.jsp#guid=tanezumab_clinical_hold_062310&source=RSS_2010&page=6 Accessed August 23, 2011. 31. Reuters Health Information. FDA Places Anti-NGF Pain Drugs on Clinical Hold. Medscape. December 28, 2010. Available at: http://www.medscape.com/viewarticle/734913 Accessed August 23, 2011. 32. US Food and Drug Administration (FDA). September 13, 2011: Arthritis Advisory Committee meeting announcement. Available at: http://www.fda.gov/AdvisoryCommittees/Calendar/ucm263496.htm Accessed August 23, 2011. Medscape Cardiology 2011 WebMD, LLC

Cite this article: The NSAID and CVD Balancing Act. Medscape. Aug 30, 2011.

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