online before print March 21, 2005, doi:10.1161/01.CIR.0000160005.90598.41
© 2005 American Heart Association,
AHA Science Advisory (American Heart Association)
The Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
A Science Advisory From the American Heart Association
Joel S. Bennett, MD; Alan Daugherty,
PhD; David Herrington, MD, MHS; Philip Greenland, MD; Harold Roberts, MD; Kathryn A. Taubert, PhD
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
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.
MECHANISM OF ACTION: [T]he 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. [The comparison
is between a coated medication which dissolves in the intestines and that of uncoated—usually aspirin--which with prolonged
usage in high doses produces a statistically significant upper GI issues—heartburn and bleeding. Coated aspirin is not used in these comparisons—jk]
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 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.
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.
RISK RATIOS: 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 [1% VS 2,3% and 3.4% for the higher dosage of celecoxib, and similar numbers
for other studies when comparing to placebo; viz., a three fold increase—jk]
- 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.
- Bunting S, Gryglewski R, Moncada S, Vane JR.
Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric
and coeliac arteries and inhibits platelet aggregation. Prostaglandins. 1976; 12: 897–913.[CrossRef][Medline]
GA, Smith B, Pedersen AK,
Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J
Med. 1984; 310: 1065–1068.[Abstract]
- FitzGerald GA. Coxibs and cardiovascular disease.
N Engl J Med. 2004; 351: 1709–1711.[Free
- Topol EJ. Failing the public health—rofecoxib,
Merck, and the FDA. N Engl J Med. 2004; 351: 1707–1709.[Free
- 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.[Abstract/Free Full Text]
- 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.[CrossRef][Medline]
- 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.[Abstract/Free Full Text]
- 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.[Abstract/Free Full Text]
- Olesen M, Kwong E, Meztli A, Kontny F, Seljeflot
I, Arnesen H, Lyngdorf L, Falk E. No effect of cyclooxygenase inhibition on plaque size in atherosclerosis-prone mice. Scand
Cardiovasc J. 2002; 36: 362–367.[CrossRef][Medline]
- 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.[CrossRef][Medline]
- 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.[Abstract/Free Full Text]
- 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.[Abstract/Free Full Text]
- Lai KC, Lam SK, Chu KM, Wong BC, Hui WM, Hu
WH, Lau GK, Wong WM, Yuen MF, Chan AO, Lai CL, Wong J. Lansoprazole for the prevention of recurrences of ulcer complications
from long-term low-dose aspirin use. N Engl J Med. 2002; 346: 2033–2038.[Abstract/Free Full Text]
- Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara
AJ, DeMarco S, Tournier B, Vyas SN, FitzGerald GA. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N
Engl J Med. 2001; 345: 1809–1817.[Abstract/Free Full Text]