The Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
A Science Advisory From the American Heart Association
- AHA Science Advisory
- anti-inflammatory agents, nonsteroidal
- cyclooxygenase inhibitors
- risk factors
Recent clinical trial data have raised questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. In September 2004, Merck announced a voluntary worldwide withdrawal of Vioxx (rofecoxib) because of an increased risk of heart attack and stroke. In early December 2004, the US Food and Drug Administration (FDA) announced a “black box” warning for Bextra (valdecoxib), stating that its use in patients undergoing coronary artery bypass grafting is contraindicated. A week later, the National Institutes of Health suspended the use of Celebrex (celecoxib) in the APC (Adenoma Prevention with Celecoxib) clinical trial because of increased cardiovascular events. The drug was not removed from the market, but the FDA advised physicians to consider alternate therapy or to use the smallest effective dose of Celebrex. Three days later, the National Institutes of Health announced that the ADAPT (Alzheimer’s Disease Anti-inflammatory Prevention Trial) showed an increase in the risk of cardiovascular events in patients given naproxen but not in those given celecoxib; the trial was halted. At the end of 2004, the FDA issued a Public Health Advisory summarizing the agency’s recent recommendations concerning the use of the nonsteroidal anti-inflammatory drug products (NSAIDs) Vioxx, Bextra, Celebrex, and naproxen.1 Quoting from the Public Health Advisory:
“Physicians prescribing Celebrex (celecoxib) or Bextra (valdecoxib) should consider this emerging information when weighing the benefits against risks for individual patients. Patients who are at a high risk of gastrointestinal (GI) bleeding, have a history of intolerance to non-selective NSAIDs, or are not doing well on non-selective NSAIDs may be appropriate candidates for COX-2 selective agents.
Individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account for each prescribing situation.
Consumers are advised that all over-the-counter (OTC) pain medications, including NSAIDs, should be used in strict accordance with the label directions. If use of an OTC NSAID is needed for longer than ten days, a physician should be consulted.”
We support these recommendations and here provide a brief scientific background for them. We also expand on the relevance of these recommendations to patients with or at risk for cardiovascular disease.
The primary property of this class of drugs is the inhibition of cyclooxygenase (COX). COX enzymes have 2 major classes. COX-1 is broadly considered to be expressed constitutively (constantly) in most tissues, whereas COX-2 is induced in inflammation. Both COX-1 and -2 enzymes use arachidonic acid to generate the same product, prostaglandin H2 (PGH2). A number of enzymes further modify this product to generate bioactive lipids (prostanoids), including prostacyclin, thromboxane A2, and prostaglandins D2, E2, and F2, which influence immune, cardiovascular, GI, renovascular, pulmonary, central nervous system, and reproductive function. The COX-2 inhibitors vary in their selectivity for the COX-2 versus the COX-1 enzyme (for medications currently or formerly on the market in the US, rofecoxib > valdecoxib > parecoxib > celecoxib). Other COX-2 inhibitors are under development and may be introduced onto the US market in the future. The differences in the biological effects of COX inhibitors are a consequence of the degree of selectivity for COX-2 versus COX-1 and tissue-specific variations in the distribution of COX and related enzymes that convert prostaglandin H2 into specific prostanoids. For example, several prostanoids, including prostaglandin E2 and prostacyclin, are both hyperalgesic (ie, elicit an increased sense of pain) and gastroprotective. Thus, nonselective COX inhibition with agents such as aspirin, ibuprofen, indomethacin, and naproxen, which inhibit both COX-1 and COX-2 enzymes, provides effective pain relief for inflammatory conditions but carries with it a risk for erosive gastritis and GI bleeding. Selective COX-2 inhibitors (valdecoxib, rofecoxib, celecoxib, and others yet in development) were developed to minimize GI toxicity because of the relative paucity of COX-2 expression in the GI tract and the relative abundance of COX-2 expression in inflamed and painful tissues.
In the cardiovascular system, the products of COX regulate complex interactions between platelets and the vessel wall. Prostacyclin is the dominant prostanoid produced by endothelial cells.2,3 In addition to producing local smooth muscle cell relaxation and vasodilation, prostacyclin can also interact with platelet IP receptors, thereby antagonizing aggregation. Platelets contain only COX-1, which converts arachidonic acid to the potent proaggregatory, vasoconstrictive eicosanoid thromboxane A2 (TXA2), the major COX product formed by platelets. Nonselective COX inhibition with aspirin is effective for arterial thrombosis because of its ability to reduce COX-1–dependent production of platelet TXA2; however, selective inhibition of COX-2 could produce a relative reduction in endothelial production of prostacyclin, but leave the platelet production of TXA2 intact. It has been speculated that this imbalance of hemostatic prostanoids may increase the risk for cardiovascular events.4,5 COX-2 inhibitors, like NSAIDs, also raise blood pressure slightly, and in one study the incidence of heart failure was significantly increased compared with placebo.6 Prostacyclin may also retard the pathogenesis of atherosclerosis,4 and inhibition of prostacyclin with a COX-2 inhibitor has been predicted to promote lesion formation4; however, results in different mouse models of atherosclerosis have been contradictory.7–13
In mid-February 2005, the FDA conducted an extensive review of all of the data concerning the cardiovascular risks of selective and nonselective COX inhibitors. It is anticipated that more information and guidance are forthcoming as a result of this meeting. In the meantime, practical guidance is needed by patients (and their physicians) who are making decisions about the use of these drugs for pain relief, especially if the patients are also at high risk for cardiovascular events. The importance of these issues for patients with or at risk for cardiovascular or cerebrovascular disease cannot be overstated because it is in these patients that the absolute risks are likely the greatest.
From the patient’s—and the physician’s—perspective, the decision turns on balancing the risks and benefits of medications for pain relief. Of course, risks and benefits are not unique to these medications, but their use highlights the issues to be considered. The following lists several issues that should be considered when treatment decisions are made concerning pain medications in patients with or at high risk for cardiovascular disease.
What Is the Risk/Benefit Ratio?
When a choice is being made about medication, both safety and efficacy should be considered. In general, the least risky medication should be tried first, with escalation considered only if this medication is ineffective. In practice, this usually means starting with acetaminophen or aspirin at the lowest efficacious dose, especially for short-term needs. The potential for abuse notwithstanding, a role remains for narcotic medications for short-term pain relief as well. It should be recognized that with the exception of aspirin, the “low-risk” medications mentioned above have not been subjected to randomized clinical trials to conclusively demonstrate their superior safety.
For patients who do not tolerate these simple interventions or who require long-term or high-dose therapy, the issues become more complex. Long-term or high-dose therapy with aspirin and other NSAIDs is associated with increased risk for GI bleeding. Occasionally, high-dose acetaminophen can result in hepatic toxicity, especially in patients who consume excess amounts of alcohol. When acetaminophen, aspirin, and perhaps even narcotic medications (for acute pain) are not effective, tolerated, or appropriate, it may then be reasonable to consider more selective COX-2 inhibition; however, this should be coupled with the realization that effective pain relief may come at the cost of a small but real increase in risk for cardiovascular or cerebrovascular complications. Recently published results of three randomized, placebo-controlled clinical trials, although not primarily designed to evaluate the effects of COX-2 inhibitors on cardiovascular outcomes, provide some estimates of absolute risk associated with COX-2 inhibitor use in various populations. The APC trial included patients with a history of colorectal neoplasia who were given two different doses of celecoxib or placebo. There was a 1% composite cardiovascular end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or nonfatal heart failure in the placebo group, compared with a 2.3% composite cardiovascular end point in patients receiving a total dose of 400 mg per day celecoxib and a 3.4% composite cardiovascular end point in those taking 800 mg celecoxib per day.14 The APPROVe trial included patients with a history of colorectal adenomas who received long-term rofecoxib or placebo. An increased risk of thrombotic events was observed in the treatment group after 18 months of treatment (0.78 events/100 patient-years versus 1.5 events/100 patient-years in the rofecoxib group).6 Finally, a study in post-CABG patients compared valdecoxib/parecoxib with placebo and found that cardiovascular events were more frequent in the treatment group (2.0% versus 0.5% for the placebo group).15
What Patient Characteristics Should Be Considered?
Patients with a history or risk of GI bleeding, especially in relationship to aspirin or other nonspecific NSAID use, may be given acetaminophen initially. Alternatively, proton-pump inhibitors may diminish the risk of recurrent GI bleeding in subjects who require low-dose aspirin.16,17 If these alternatives are not possible, then it may be reasonable to consider a COX-2 inhibitor, if the potential benefits of treatment are felt to outweigh the potential cardiovascular risks. Patients who can tolerate nonspecific NSAIDs but find them insufficient also could consider a COX-2 inhibitor. Patients with or at risk for active atherosclerotic processes, including those with recent bypass surgery, unstable angina or myocardial infarction, or ischemic cerebrovascular events, may have greater increases in absolute risk for adverse cardiovascular effects when given a COX inhibitor. In these patients, prudence dictates extra caution in the use of COX-2 inhibitors, which should include recommended doses only. Every effort should be made to assess and treat modifiable risk factors before and during NSAID treatment. COX inhibitors can lead to impaired renal perfusion, sodium retention, and increases in blood pressure. The extent to which these effects may contribute to adverse cardiovascular effects of COX-2 is unclear. However, renal function and blood pressure should be monitored in subjects taking COX-2 inhibitors and extra caution should be taken when giving these drugs to subjects with preexisting hypertension, renal disease, and heart failure.
Does Selectivity Matter to Patients Who Use a COX-2 Inhibitor?
In theory, the relative degree of COX-1 versus COX-2 inhibition may alter the adverse cardiovascular effect profile of the COX inhibitors, with valdecoxib being the most COX-2 selective of the available agents; however, the available data have implicated several COX-2 inhibitors with varying degrees of COX-2 selectivity. Thus, until more data are available, it is not entirely clear how much weight should be placed on COX-2 selectivity.
Can Patients Taking Aspirin for Cardioprotection Also Use NSAIDs or Selective COX-2 Inhibitors for Pain Relief?
There is evidence that ibuprofen, but not the COX-2 inhibitor rofecoxib, acetaminophen, or diclofenac,18 interferes with the ability of aspirin to irreversibly acetylate the platelet COX-1 enzyme, and it would be expected, although it has not been proven, that this would reduce the protective effect of aspirin on risk for atherothrombotic events.
Current evidence indicates that selective COX-2 inhibitors have important adverse cardiovascular effects including increased risk for myocardial infarction, stroke, heart failure, and hypertension. The risk for these adverse effects are likely greatest in patients with a prior history of, or at high risk for cardiovascular disease. In these patients, use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives; and then, only in the lowest dose and for the shortest duration necessary. More long-term data are needed to fully evaluate the extent to which these important adverse cardiovascular effects may be offset by other beneficial effects of these medications. More data are also needed concerning the cardiovascular safety of conventional NSAIDs. Until such data are available, the use of any COX inhibitor, including over-the-counter NSAIDs, for long periods of time should only be considered in consultation with a physician. ⇓
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on February 7, 2005. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0318. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-528-4121, fax 410-528-4264, or e-mail email@example.com. To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.
Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifier=3023366.
US Food and Drug Administration. Public Health Advisory: Non-Steroidal Anti-Inflammatory Drug Products (NSAIDS). Available at: http://www.fda.gov/cder/drug/advisory/nsaids.htm. Accessed February 4, 2005.
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352. Available at: http://content.nejm.org/cgi/content/abstract/NEJMoa050493v1. Accessed February 15, 2005.
Burleigh ME, Babaev VR, Oates JA, Harris RC, Gautam S, Riendeau D, Marnett LJ, Morrow JD, Fazio S, Linton MF. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation. 2002; 105: 1816–1823.
Rott D, Zhu J, Burnett MS, Zhou YF, Zalles-Ganley A, Ogunmakinwa J, Epstein SE. Effects of MF-tricyclic, a selective cyclooxygenase-2 inhibitor, on atherosclerosis progression and susceptibility to cytomegalovirus replication in apolipoprotein-E knockout mice. J Am Coll Cardiol. 2003; 41: 1812–1819.
Pratico D, Tillmann C, Zhang ZB, Li H, FitzGerald GA. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice. Proc Natl Acad Sci U S A. 2001; 98: 3358–3363.
Belton OA, Duffy A, Toomey S, Fitzgerald DJ. Cyclooxygenase isoforms and platelet vessel wall interactions in the apolipoprotein E knockout mouse model of atherosclerosis. Circulation. 2003; 108: 3017–3023.
Bea F, Blessing E, Bennett BJ, Kuo CC, Campbell LA, Kreuzer J, Rosenfeld ME. Chronic inhibition of cyclooxygenase-2 does not alter plaque composition in a mouse model of advanced unstable atherosclerosis. Cardiovasc Res. 2003; 60: 198–204.
Egan KM, Wang M, Lucitt MB, Zukas AM, Pure E, Lawson JA, FitzGerald GA. Cyclooxygenases, thromboxane, and atherosclerosis: plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation. 2005; 111: 334–342.
Solomon SD, McMurray JJV, Pfeffer MA, Wittes J, Fowler R, Finn P, Anderson WF, Zauber A, Hawk E, Bertagnolli M. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352. Available at: http://content.nejm.org/cgi/content/abstract/NEJMoa050405v1. Accessed February 15, 2005.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352. Available at: http://content.nejm.org/cgi/content/abstract/NEJMoa050330v1. Accessed February 15, 2005.
Chan FK, Chung SC, Suen BY, Lee YT, Leung WK, Leung VK, Wu JC, Lau JY, Hui Y, Lai MS, Chan HL, Sung JJ. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001; 344: 967–973.