US Pharm. 2014;39(3):35-38.
ABSTRACT: Nonsteroidal anti-inflammatory drugs
(NSAIDs) are commonly used to treat pain associated with a variety of
medical conditions. Nonselective NSAIDs reversibly inhibit the enzyme
cyclooxygenase (COX) in both of its isoforms, COX-1 and COX-2. An
increased risk of cardiovascular events has been associated with the use
of NSAIDs, especially of COX-2 selective NSAIDs. Current evidence
suggests that naproxen, a nonselective NSAID, is associated with the
lowest risk of cardiovascular events. Therefore, naproxen is the NSAID
of choice in patients with high cardiovascular risk.
Cardiovascular disease is defined as any disease that
involves the heart, blood vessels, or both, many of which are related to
the process of atherosclerosis. Approximately 83 million American
adults are affected by one or more types of cardiovascular disease, and
of these patients, 40 million are 60 years of age or older.1
Many patients of varying ages utilize OTC and prescription
anti-inflammatory drugs to manage pain. Approximately 30 million
Americans use nonsteroidal anti-inflammatory drugs (NSAIDs) daily for
reasons ranging from cardioprotection and everyday aches and pains to
more serious complications such as rheumatoid arthritis, acute gout, and
other comorbid conditions.2
Patients at an increased risk for cardiovascular events
with concurrent usage of NSAIDs include patients with recent bypass
surgery, unstable angina, myocardial infarction (MI), ischemic
cerebrovascular events, or any other active athlerosclerotic process.
Patients who have cardiovascular disease and are taking NSAIDs,
especially cyclooxygenase-2 (COX-2) selective agents, are at a much
higher risk of having an MI than patients not taking these drugs.
Therefore, understanding the potential danger of the use of NSAIDs in
patients who have cardiovascular risk factors is essential.1,3
NSAIDs and Adverse Effects
As with any medication, NSAIDs are not without adverse
effects. The most commonly experienced side effects are nausea,
vomiting, diarrhea, constipation, decreased appetite, rash, dizziness,
headache, and drowsiness. The more severe side effects seen with NSAID
use are fluid retention, renal failure (associated with more chronic
use), liver failure, gastric ulcers, and increased or prolonged bleeding
following an injury or surgical procedure.1,3
Many of the adverse effects associated with NSAID use can
be explained by their effect on phospholipid metabolism. Membrane
phospholipids are broken down by phospholipase A2 to
arachidonic acid, the substrate for the COX enzymes. COX-1 is
constitutively expressed in the stomach, kidneys, and intestinal
endothelium, where it leads to vasoconstriction and platelet
aggregation. COX-2 is upregulated during times of inflammation, where it
causes vasodilation and inflammation via the migration of macrophages,
leukocytes, and fibroblasts. It is this balance between the two enzymes
that is ultimately disrupted upon administration of NSAIDs (FIGURE 1).1,4
The decision about which NSAID to use will vary among
patients, and COX selectivity is one of the determining factors. NSAIDs
target both COX-1 and COX-2 enzymes. The rationale for the use of
selective COX-2 inhibitors stemmed from the negative gastrointestinal
(GI) effects of nonselective NSAIDs and aspirin. Selectivity for the
COX-2 enzyme proves to be gastroprotective, which is a major benefit for
pain management in patients with GI complications such as peptic ulcer
disease (PUD), gastroesophageal reflux disease (GERD), and GI bleeding.
However, the COX-2 selective inhibition exhibited by certain NSAIDs can
increase the risk of cardiovascular events in patients with preexisting
cardiovascular disease. This prothrombotic risk results from thromboxane
A2–mediated vasoconstriction and platelet aggregation, which
will remain unbalanced and unopposed when prostacyclin activity is
suppressed via COX-2 inhibition.1,4
On the other end of the spectrum, irreversible COX-1
inhibition has been shown to be cardioprotective, which is apparent with
low-dose aspirin. Nonselective NSAIDs inhibit both COX-2 and COX-1.
Because COX selectivity varies among the nonselective NSAIDs, so will
the NSAID-associated cardiovascular risk.1,4
Review of Literature
Rofecoxib, a COX-2 inhibitor, has been associated with
coronary and cardiovascular death, even in small doses. It was concluded
in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial that
there was a great concern for increased cardiovascular risk with
rofecoxib.5 It was the Adenomatous Polyp Prevention on Vioxx
(APPROVe) trial that ultimately led to the discontinuation of rofecoxib
from the U.S. market because it demonstrated the increased risk of acute
MI at both low and high doses.6 Current literature estimates
a fivefold increase in thromboembolic events in patients taking
rofecoxib 50 mg/day compared to naproxen, and a twofold increase in
patients taking 25 mg/day compared to placebo.7-9 Shortly
after the FDA’s removal of rofecoxib from the market, valdecoxib soon
followed suit due to increased risk of MI and stroke.10
In 2005, the FDA concluded that the health benefits of
celecoxib outweigh the potential risk in certain informed patient
populations.11 As such, celecoxib was left on the market.
Pfizer was advised by the FDA to revise the celecoxib label to add a
boxed warning and a Medication Guide. The boxed warning states that
celecoxib may cause increased risk of serious cardiovascular thrombotic
events, MI, and stroke. Celecoxib increases risk at doses higher than
200 mg/day. The risk, if any, that comes with lower doses of celecoxib
is not yet clear. The Medication Guide is to be given to patients at the
time the drug is dispensed in order to inform them that celecoxib is
associated with an increased risk of cardiovascular events and should
not be used in patients with high cardiovascular risk.8,12,13
Of note, several other NSAIDs increase cardiovascular risk
including the semiselective NSAIDs diclofenac and meloxicam, and the
nonselective NSAIDs ibuprofen and naproxen (FIGURE 2).3
Several meta-analyses and systematic reviews indicate that diclofenac
has demonstrated the highest cardiovascular risk of any of the
nonselective NSAIDs.7,8,12,13 Additionally, in a large
retrospective cohort study conducted by Ray et al, when compared to
≥1,000 mg/day of naproxen, diclofenac was associated with an increased
risk for MI, stroke, and all-cause mortality in doses <150 mg/day.8 This comes as no surprise when considering the degree of COX-2 selectivity that diclofenac possesses.3 Due to the limited number of trials assessing meloxicam, cardiovascular risk associated with its use remains unknown.14
An evidence-based review of the cardiovascular risk of NSAIDs by
Farkouh and Greenberg suggests that ibuprofen is associated with a
cardiovascular risk comparable to that of celecoxib.7 In
several head-to-head clinical trials, naproxen was not associated with
an increased cardiovascular risk in patients with preexisting
cardiovascular disease when compared to other nonselective NSAIDs and
COX-2 inhibitors. Naproxen has been determined to be the preferred
nonselective NSAID for patients with high cardiovascular risk.8,15
In addition to recognizing the cardiovascular risk profile
and dose relationship of each NSAID, it is also important to review the
evidence with respect to the timing and duration of therapy. A
nationwide cohort study of patients with a first-time MI demonstrated
that short-term and long-term use of NSAIDs and COX-2 inhibitors
increased the risk of death or recurrent MI.12 A follow-up
analysis of this nationwide cohort concluded that there is an increased
risk of death and coronary death or nonfatal recurrent MI with the use
of any NSAID that persists for at least 5 years after the first MI.13
Overall, the evidence suggests advising caution against both short-term
and long-term use of NSAIDs and selective COX-2 inhibitors in patients
with high risk of cardiovascular disease.
The Prospective Randomized Evaluation of Celecoxib
Integrated Safety vs. Ibuprofen or Naproxen (PRECISION) trial is
currently under way.16 It is a randomized, double-blind,
parallel-group study comparing the cardiovascular risk associated with
celecoxib to that of the two most commonly prescribed nonselective
NSAIDs (naproxen and ibuprofen) in patients with either osteoarthritis
or rheumatoid arthritis. The primary outcome of the study is the first
occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke.
Cardiovascular, GI, and renal side effects as well as symptomatic relief
will be assessed in the study. The trial is set to be completed in
September 2015 and may provide additional evidence for the use of NSAIDs
in patients with cardiovascular risk.16
American Heart Association Stance
In 2007, the American Heart Association (AHA) addressed
the concern that selective COX-2 inhibition may potentiate a
cardiovascular event in patients who are at an increased risk. The AHA
states that physicians and patients must weigh the risks and benefits of
each agent before choosing a treatment plan for pain relief. Patients
should be treated only for the shortest amount of time and with the
lowest dosage of drug necessary to gain symptom relief.13,17
A stepwise approach is suggested, beginning with the
agents that have the lowest associated cardiovascular risk and moving to
the agents with higher risk if treatment failure occurs. Non-NSAID
products, such as acetaminophen or nonacetylated salicylates, are the
preferred agents in patients with high cardiovascular risk. If these
treatments are not tolerated or fail to control pain, the use of NSAIDs
may be warranted. Patients beginning NSAID therapy should start with a
nonselective NSAID, such as ibuprofen or naproxen. However, the
literature suggests naproxen as the nonselective NSAID of choice for
these patients. If pain control is not established with nonselective
NSAIDs, the next trial should be with an agent that is semiselective for
COX-2, such as meloxicam or diclofenac.17
Finally, if all the above treatments have failed, the
patient may consider treatment with the selective COX-2 inhibitor
celecoxib. Celecoxib use in patients at risk for thrombotic events
should be reserved for patients who have no other appropriate
Concurrent use of nonselective NSAIDs with aspirin may
decrease the cardioprotective profile normally seen with aspirin use.
This is due to competitive inhibition of the receptor-binding site of
the COX-1 enzyme. The Therapeutic Arthritis Research and
Gastrointestinal Event Trial (TARGET) concluded that ibuprofen was shown
to negate the cardioprotective effects of aspirin.7 Although
no cardiovascular interaction has been seen with concomitant use of
celecoxib and aspirin, administration of aspirin with a selective COX-2
inhibitor may negate the gastroprotective effects of selective COX-2
inhibition. Despite these concerns, patients using low-dose aspirin for
cardioprotection may take NSAIDs. Aspirin’s cardioprotective profile may
help to decrease the cardiovascular risk associated with NSAID or COX-2
inhibitor use. Furthermore, the addition of a proton pump inhibitor
(PPI) may be warranted in certain patients with high GI risk to prevent
ulcers and other GI side effects associated with concurrent aspirin and
NSAID or COX-2 inhibitor use.14,17,18
During treatment with NSAIDs, patients should be closely
monitored for increases in blood pressure, signs of edema, decreasing
renal function, and GI bleeding. If any of these adverse effects occur, a
decrease in dose or a change in drug may be warranted. With each
patient case the risks and benefits of treatment should be considered
before beginning any one agent. It should be noted that all NSAIDs,
including COX-2 inhibitors, can raise blood pressure in some patients.
When initiating any NSAID in a patient with high cardiovascular risk, it
is important to monitor blood pressure. Concurrent use of NSAIDs with
antihypertensive medications has been associated with a decrease in the
blood pressure lowering effects of the antihypertensive therapy.1,7,17
The significance of pharmacist-patient communication is
crucial in informing patients about the risks associated with use of
NSAIDs. It is important for pharmacists to monitor patient profiles for
NSAID usage as well as to counsel patients with existing cardiovascular
disease about the use of OTC NSAIDs. Due to the wide availability of OTC
NSAID products, patients may assume they are safe for all and be
unaware of the increased cardiovascular risk. These situations provide
an opportunity for pharmacist intervention to educate patients on the
risk and inform them of preferred alternative therapies for pain
management, such as acetaminophen, capsaicin, and other topical
Notably, healthcare professionals should keep in mind that
for patients with arthritis or other comorbid conditions who require
NSAID therapy, naproxen appears to be the safest from a cardiovascular
perspective. For patients at high risk of NSAID-related GI tract
complications, naproxen plus a PPI is less costly, safer, and as
effective as low-dose celecoxib. The cardiovascular risk with NSAIDs
appears to increase as the dosage and duration of therapy increase.
Patients receiving NSAID therapy should be advised to use the lowest
effective dose for the shortest duration of time.12,17
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Group. Comparison of upper gastrointestinal toxicity of rofecoxib and
naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520-1528.
6. Garcia Rodriguez LA, Tacconelli S, Patrignani P. Role
of dose potency in the prediction of risk of myocardial infarction
associated with nonsteroidal anti-inflammatory drugs in the general
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8. Ray WA, Varas-Lorenzo C, Chung CP, et al.
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after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes. 2009;2:155-163.
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cardiac surgery. N Engl J Med. 2005;352:1081-1091.
Public Health Advisory. FDA
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Long-term cardiovascular risk of NSAID use according to time passed
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16. Prospective Randomized Evaluation of Celecoxib
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ClinicalTrials.gov. November 21, 2013.
http://clinicaltrials.gov/ct/show/NCT00346216?order=4. Accessed November
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18. Kearney PM, Baigent C, Godwin J, et al. Do selective
cyclo-oxygenase-2 inhibitors and traditional nonsteroidal
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Meta-analysis of randomized trials. BMJ. 2006;332:1302-1308.
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