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Association Between Naproxen Use and Protection Against Acute Myocardial Infarction
Elham Rahme, PhD;
Louise Pilote, MD, MPH, PhD;
Jacques LeLorier, MD, PhD, FRCPC
Arch Intern Med. 2002;162:1111-1115.
ABSTRACT
| |
Background The association between the use of nonsteroidal anti-inflammatory drugs
(NSAIDs) and acute myocardial infarction (AMI) is unclear. Nonsteroidal anti-inflammatory
drugs vary in their antithrombotic properties, with naproxen having a particularly
effective antithrombotic potential.
Objective To compare the effect of naproxen vs other NSAIDs in the prevention
of AMI in an older population.
Methods Population-based, matched case-control study. Patients (aged  65
years) in Quebec had been hospitalized for AMI between January 1, 1992, and
December 31, 1994. The admission date for AMI was considered the index date.
Control subjects were randomly selected from a Quebec drug and physician claims
database. For each case, a control was matched with the same index date, age
(within 2 years), and sex. Cases and controls were required to have at least
1 year of pharmaceutical and medical records before the index date to identiify
risk factors for AMI and exposure to naproxen or other nonaspirin NSAIDs.
Concurrent exposure to a medication was defined as exposure to that medication
at the index date. Logistic regression analyses were used to evaluate the
association between the use of naproxen and other NSAIDs in the prevention
of AMI, adjusting for potential confounders.
Results Included in the study were 4163 cases and 14 160 controls. Determinants
(adjusted odds ratios [95% confidence intervals]) of AMI included use in the
prior year of anticoagulants (0.76 [0.64-0.90]), nitrates (2.01 [1.86-2.17]),
antidiabetic agents (1.72 [1.56-1.90]), antihypertensive agents (1.36 [1.28-1.45]),
and lipid-lowering agents (0.83 [0.75-0.91]), as well as concurrent exposure
to naproxen vs other NSAIDs (0.79 [0.63-0.99]).
Conclusion Compared with other NSAIDs, concurrent exposure to naproxen has a protective
effect against AMI.
INTRODUCTION
NONSTEROIDAL anti-inflammatory drugs (NSAIDs) are effective for the
management of inflammatory and arthritic conditions and have been one of the
most widely used classes of drugs worldwide.1-5
In vivo investigations have shown a beneficial effect of other NSAIDs on platelet
functions,6 suggesting that these agents may
prevent the thrombotic complications of cardiovascular diseases, such as myocardial
infarction (MI).
The cyclooxygenase-2 (COX-2) inhibitors, or coxibs, form a group of
agents that have the anti-inflammatory effect of NSAIDs, with a lower potential
for causing upper gastrointestinal toxicity.7-14
Coxibs have been associated with MI7, 15;
however, this association remains controversial.16
The hypothesis that naproxen is a stronger antiplatelet agent compared with
other NSAIDs has been suggested in a study7
comparing rofecoxib with naproxen.
Given the widespread use of coxibs and NSAIDs among older populations,
it is important to examine, at the population level, the association between
naproxen and other NSAID exposure and hospitalization for acute MI (AMI).
Government health plan databases, such as the database of the Quebec Health
Care Fund administered by the Régie de l'assurance
maladie du Québec (RAMQ), Quebec City,
are a source of patient-specific data.17
The objective of this study was to compare the effect of naproxen vs
other NSAIDs in the prevention of AMI in older persons.
SUBJECTS AND METHODS
DATA SOURCE
In Quebec, all persons aged 65 years or older are eligible for health
care coverage by RAMQ. The fund covers the costs
of prescription drugs, outpatient physician visits, and other medical services
offered in private clinics or hospitals. The RAMQ
database has been described in detail elsewhere.17-18
A hospital discharge summary database maintained by Med-Echo, a government agency, is also available in Quebec. Med-Echo records provide information on hospitalized patients, including
discharge diagnosis, comorbid conditions, and dates of admission and discharge.
For all Quebecois who are permanent residents, hospitalizations are covered
by RAMQ, and the dates are captured in the Med-Echo database. The data in the Med-Echo and RAMQ databases are linked by patient
identification number. The 2 databases have been used in other epidemiological
studies.17-20
STUDY POPULATION
The study population was derived from the RAMQ
and Med-Echo databases, using data recorded for all
patients aged 65 years or older between January 1, 1988, and December 31,
1994.
DESIGN
The design was a 1:1 matched, population-based, case-control study.21
CASE SELECTION
Medical, demographic, and pharmaceutical records on all patients aged
65 years or older who had a diagnosis of AMI (International
Classification of Diseases, Ninth Revision [ICD-9]), code 410) between
1988 and 1994 were obtained from RAMQ. All hospital
discharge summaries of these patients during the same period were obtained
from Med-Echo. Those with an AMI discharge diagnosis
date between January 1, 1992, and December 31, 1994, were retained as potential
cases. The date of admission for each case was termed the index date. For each of these patients, medical records of the 4 years
before hospitalization were examined for prior AMI. Those with a prior AMI
within that period were excluded. To further exclude cases with preexisting
events, Med-Echo records for the potential cases
were linked to those obtained from RAMQ; the RAMQ records were searched for ICD-9 code 412 ("old" MI diagnoses); and all patients with this diagnosis
during the year before their index date were excluded. The remaining patients
who had at least 1 year of documented observation in the database before their
index date constituted the cases.
CONTROL SELECTION
Control subjects were selected from a random sample of 82 754 patients
obtained from the RAMQ database. The sample comprised
10% of all patients who were aged 65 years or older between 1988 and 1994
and who filled at least 1 prescribed drug or had at least 1 medical service
during that period. From this sample, we identified, for each case, all subjects
who were of the same sex, within 2 years of the same age at the case index
date, and who had at least 1 year of medical and pharmaceutical data before
the case index date. From these subjects, 1 control was randomly selected
for each case. The index date of the case was assigned to its matched control.
The control for a case was selected using the method of sampling with replacement.
Therefore, a person could serve as a control for more than 1 case. All controls
used in the analysis were under observation (ie, active in the RAMQ database and still alive) at the index date.
POTENTIAL DETERMINANTS OF AMI
Patient demographics and medical and prescription records for cases
and controls were searched for data from the year before the index date, to
identify potential determinants of MI. The following potential determinants
were assessed and included in the analysis:
Medications
Prior use of anticoagulants, nitrates, lipid-lowering agents, antidiabetic
agents, and antihypertensive agents was documented.
Existing Cardiovascular Disease
Ischemic heart disease (ICD-9 codes 410-414),
congestive heart failure (codes 428-429), prior visits to cardiologists, and
prior diagnoses of cerebrovascular diseases (codes 430-438) were indicative
of existing cardiovascular disease.
Comorbidity Factors
All hospitalizations and the number of medical encounters during the
year before the index date and the chronic disease score were assessed. The
chronic disease score for a patient was derived from a weighted summation
of the number of drugs filled during the year before the index date.22 Classes of drugs were assigned scores (0 to 5) according
to the severity of the disease for which they were prescribed, with higher
scores indicating more severe conditions. The sum of the scores of drugs the
patient took during the year preceding the index date was the chronic disease
score. Nonsteroidal anti-inflammatory drugs and the drugs listed as key variables
in the "Medications" subsection were excluded from the calculation of the
chronic disease score (to prevent colinearity).
EXPOSURE CLASSIFICATION
Medical records preceding the index date were searched for filled prescriptions
for naproxen, nonaspirin NSAIDs (excluding naproxen), and aspirin. Each prescription
was assigned a duration, using the number of days' supply as indicated in
the database. Four exposure types were assessed:
Concurrent Exposure
Concurrent exposure referred to prescriptions with a duration that covered
or overlapped with the index date.
Chronic Exposure
Chronic exposure referred to prescriptions filled at least twice and
with 60 or more consecutive days of prescription duration. For this category,
patients were considered to be exposed for 125% days' supply as recorded in
the database23 to allow for a gap between prescriptions
not exceeding 25% of the duration of the first one (Figure 1).
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Example of a patient's interrupted–long-term exposure to naproxen
12 months before the index date. The patient had 62 (10 + 2 + [30-5]
+ 20 + 20/4) consecutive days of exposure but was not exposed at the index
date.
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Concurrent-Chronic Exposure
Concurrent-chronic exposure was chronic exposure and exposure at the
index date. This category was the subject of the primary analysis.
Interrupted-Chronic Exposure
Interrupted-chronic exposure was chronic exposure without exposure at
the index date.
STATISTICAL ANALYSIS
Descriptive statistics (means and proportions) were used to evaluate
patient characteristics at the index date. The association between use of
naproxen and other NSAIDs (excluding naproxen) and hospitalization for AMI
was assessed using 3 conditional logistic regression analyses appropriate
for 1:1 matched case-control studies,24 adjusting
for the same potential confounders. The primary analysis examined the effect
of concurrent-chronic exposure to naproxen vs other NSAIDs (excluding naproxen)
on outcomes. Additional analyses examined the effects of (1) concurrent exposure
to naproxen and any concurrent NSAID (excluding naproxen) and (2) interrupted-chronic
exposure to naproxen vs other NSAIDs (excluding naproxen). The potential confounders
adjusted for in the models included prior use of anticoagulants, nitrates,
lipid-lowering agents, antidiabetic agents, or antihypertensive agents; prior
cardiovascular diseases; and the presence of comorbidity factors. Commercially
available statistical software (SAS, version 8; SAS Institute, Cary, NC) was
used to carry out the analyses.
RESULTS
PATIENT CHARACTERISTICS
During the study, 14 163 patients had an AMI and formed the case
group. The control group comprised 14 160 persons. In the year preceding
the index date, more cases than controls had been hospitalized, had office
visits, and had higher chronic disease scores (Table 1). In addition, the prevalence of AMI risk factors was higher
in cases than in controls. Prescriptions for nitrates, antihypertensive agents,
antidiabetic agents, anticoagulants, and aspirin were more frequently filled
by cases than by controls. More cases than controls had been diagnosed as
having cardiovascular diseases or had visited a cardiologist in the year before
the index date. Exposure history to naproxen and other NSAIDs was more common
in cases than in controls (Table 2).
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Table 1. Patient Characteristics at Index Date*
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Table 2. Exposure to Naproxen or Other Nonsteroidal Anti-inflammatory
Drugs (NSAIDs)*
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ASSOCIATION BETWEEN NAPROXEN USE AND HOSPITALIZATION FOR AMI
Table 3 displays the results
of the primary analysis, which used a conditional logistic regression model
to compare the association (odds ratio [95% confidence interval]) between
AMI and concurrent-chronic exposure to naproxen and other NSAIDs, adjusting
for baseline factors. Patients who filled prescriptions for nitrates (2.01
[1.86-2.17]), antidiabetic agents (1.72 [1.56-1.90]), and antihypertensive
agents (1.36 [1.28-1.45]) were at significantly higher risk for AMI compared
with those not prescribed these agents. Patients who were exposed to aspirin
at the index date were at higher risk of AMI than those not exposed (1.17
[1.07-1.28]). There was an interaction effect between prior ischemic heart
disease and aspirin at the index date. Among those who had ischemic heart
disease diagnoses before the index date, those exposed to aspirin had a lower
incidence of AMI than those not exposed to aspirin (0.85 [0.77-1.00]). Patients
who were dispensed lipid-lowering agents (0.83 [0.75-0.91]) and those dispensed
anticoagulants (0.76 [0.64-0.90]) had a lower incidence of AMI than those
not dispensed these agents. Concurrent-chronic users of naproxen had a lower
incidence of AMI than concurrent-chronic users of other NSAIDs (0.64 [0.48-0.86]).
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Table 3. Conditional Logistic Regression Model to Determine the Factors
Associated With Hospitalization for Acute Myocardial Infarction*
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Secondary analyses showed that (1) the incidence of AMI association
with interrupted-chronic exposure to naproxen was not significantly different
from that of interrupted-chronic exposure to other NSAIDs (0.98 [0.73-1.33])
and (2) the incidence of AMI in concurrent users of naproxen was significantly
lower than that of concurrent users of other NSAIDs (0.79 [0.63-0.99]). In
these secondary analyses, estimates of the effect of baseline factors on AMI
were similar to those in the primary analysis for all baseline factors.
COMMENT
This study was designed to examine the association between naproxen
use and hospitalization for AMI in comparison with other NSAIDs, using a database
of older Quebecois. We used a case-control design that included all those
who had been hospitalized for AMI (14 163 patients) during 3 years. Given
the same risk susceptibility, exposure to naproxen had a protective effect
against AMI compared with the other nonaspirin NSAIDs. This effect seemed
to be present only with concurrent naproxen exposure and was strongest in
chronic users. This is consistent with the fact that the antiplatelet effect
of naproxen is brief and suggests that persistent use is required for cardioprotection.
Conventional NSAIDs inhibit 2 forms of COX, COX-1 and COX-2.10 Cyclooxygenase-1 is constitutively expressed in platelets,
gastric mucosa, and most tissues, where it maintains physiological functions
such as vascular homeostasis and gastric cytoprotection. Cyclooxygenase-2
is predominantly induced at sites of inflammation throughout the body to generate
prostaglandin, believed to mediate pathologic processes such as pain and inflammation.25-26 Naproxen, but not aspirin, meclofenamate
sodium, or indomethacin, has been found to protect ischemic myocardium caused
by coronary occlusion in animals.27 In contrast,
another study28 found no association between
nonaspirin NSAID use and reduced risk for AMI among women.
Our findings indirectly support the results of Van Hecken et al,6 showing that naproxen is a stronger inhibitor of COX-1
than either diclofenac or ibuprofen. Our results partially explain the discrepancy
between the findings by Bombardier et al,7
in which the incidence of MI was higher in rofecoxib users than in naproxen
users, and studies by Day8 and Cannon9 and their colleagues, in which the incidence of MI
in rofecoxib users was similar to that in ibuprofen or diclofenac users. Another
case-control study28 has found no cardioprotective
effect of NSAIDs. This study used a nested case-control design in women after
menopause. Our study design differed in that it compared patients concurrently
exposed to naproxen with those concurrently exposed to other NSAIDs, thus
reducing the selection bias that is present in the comparison between NSAID
users and nonusers.
The beneficial effect of aspirin in the prevention of MI is well known.29-31 Patients who have
had an MI or who are considered at risk for such an event should be prescribed
a daily low dosage of aspirin. Aspirin use can therefore be a marker for the
presence of MI risk factors and is also an effect modifier for that risk factor.
The beneficial effect of aspirin to prevent MI is immediate. Therefore, only
concurrent exposure to aspirin was considered in this study. Unlike aspirin,
the effect of nonaspirin NSAIDs on MI is unknown, and patients prescribed
naproxen are not expected to differ from those prescribed other nonaspirin
NSAIDs (excluding naproxen) in MI risk susceptibility. Therefore, any difference
in AMI occurrence between the 2 groups was attributed to exposure to naproxen
or other NSAIDs.
This analysis was conducted using a large population-based, validated
medical database. Patients with uncontrolled hypertension or those at high
risk for MI are typically excluded from clinical trial research.16
Use of administrative databases provide the advantage of a large sample size,
generalizability, and the broad inclusion of patients with multiple AMI risk
factors, who are typically excluded from clinical trials.
This study had several limitations. First, important risk factors such
as cigarette smoking and obesity could not be assessed. These factors could
be differential between users and nonusers of NSAIDs. In addition, cardiovascular
morbidity is increased in autoimmune diseases such as rheumatoid arthritis
that necessitate chronic use of NSAIDs.16 Therefore,
a direct comparison between NSAID users and nonusers was not performed. However,
in theory, naproxen and other NSAID users should not differ in AMI risk susceptibility.
By comparing the AMI risk in those exposed to naproxen with that of those
exposed to other NSAIDs, we have controlled for factors that are nondifferential
between the 2 groups, including cigarette smoking and obesity. Second, patients
who died of MI before reaching the hospital are not captured in the Med-Echo database. However, we have no reason to believe
that those exposed to naproxen were at greater risk of dying of MI before
reaching the hospital than those exposed to the other nonaspirin NSAIDs. Other
potential limitations of the study include uncertainty about actual medications
taken and unknown concurrent use of over-the-counter drugs (especially aspirin,
naproxen, and ibuprofen). However, Santé Québec (a government public health agency [written communication, 1992-1993])
reports that, during the years of the study, older Quebecois acquired the
following agents over the counter (given as proportions of the total numbers
of those who used the agents): acetaminophen (5.5%), NSAIDs (90.5%), and aspirin
(0.3%).
In summary, concurrent exposure to naproxen was cardioprotective compared
with other nonaspirin NSAIDs. Our study design did not permit direct comparison
of the effect of aspirin vs naproxen on AMI. Therefore, our results apply
only to patients in need of NSAID therapy and do not support the use of naproxen
as a primary cardiovascular prophylaxis. Given the widespread use of NSAIDs
among older populations, these patients may require close monitoring when
using these drugs. In a population such as the one included in this study,
physicians should weigh the cardiac benefit of naproxen vs its gastrointestinal
toxicity.
AUTHOR INFORMATION
Accepted for publication January 31, 2002.
This study was supported by Merck & Co, Inc, Whitehouse Station,
NJ.
Corresponding author and reprints: Elham Rahme, PhD, Division of
Clinical Epidemiology, Montreal General Hospital, 1650 Cedar Ave, Room L10-408,
Montreal, Quebec, Canada H3G 1A4 (e-mail: elham.rahme{at}mcgill.ca).
From the Departments of Epidemiology and Biostatistics (Dr Rahme) and
Medicine (Dr Pilote), McGill University; Division of Clinical Epidemiology,
Montreal General Hospital (Drs Rahme and Pilote); and Research Center, Centre
Hospitalier de l'Université de Montréal–Hôtel-Dieu
(Dr LeLorier), Montreal, Quebec. Dr LeLorier has served as a paid speaker
for Merck & Co, Inc.
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J Am Coll Cardiol 2005;45:1295-1301.
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The Risk for Myocardial Infarction with Cyclooxygenase-2 Inhibitors: A Population Study of Elderly Adults
Levesque et al.
ANN INTERN MED 2005;142:481-489.
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Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial
Bresalier et al.
NEJM 2005;352:1092-1102.
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Coxibs, Science, and the Public Trust
Solomon and Avorn
Arch Intern Med 2005;165:158-160.
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Selective Cyclooxygenase-2 Inhibition and Cardiovascular Effects: An Observational Study of a Medicaid Population
Shaya et al.
Arch Intern Med 2005;165:181-186.
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Treating Osteoarthritis With Cyclooxygenase-2-Specific Inhibitors: What Are the Benefits of Avoiding Blood Pressure Destabilization?
Grover et al.
Hypertension 2005;45:92-97.
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Discontinuation of Nonsteroidal Anti-inflammatory Drug Therapy and Risk of Acute Myocardial Infarction
Fischer et al.
Arch Intern Med 2004;164:2472-2476.
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Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Patrono et al.
Chest 2004;126:234S-264S.
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Nonsteroidal Antiinflammatory Drugs and the Risk of Myocardial Infarction in the General Population
Garcia Rodriguez et al.
Circulation 2004;109:3000-3006.
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Over-the-Counter Pain Reliever and Aspirin Use Within a Sample of Long-term Cyclooxygenase 2 Users
Cox et al.
Arch Intern Med 2004;164:1243-1246.
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Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults
Solomon et al.
Circulation 2004;109:2068-2073.
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Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic
WARNER and MITCHELL
FASEB J. 2004;18:790-804.
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Use of Aspirin and Ibuprofen Compared With Aspirin Alone and the Risk of Myocardial Infarction
Patel and Goldberg
Arch Intern Med 2004;164:852-856.
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Clinical Pharmacology of Platelet, Monocyte, and Vascular Cyclooxygenase Inhibition by Naproxen and Low-Dose Aspirin in Healthy Subjects
Capone et al.
Circulation 2004;109:1468-1471.
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The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin
Kimmel et al.
J Am Coll Cardiol 2004;43:985-990.
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The case for an adverse interaction between aspirin and non-steroidal anti-inflammatory drugs: Is it time to believe the hype?
Curtis and Krumholz
J Am Coll Cardiol 2004;43:991-993.
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Nonsteroidal Anti-Inflammatory drugs and cardiovascular risk
Howard and Delafontaine
J Am Coll Cardiol 2004;43:519-525.
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Cyclooxygenase-2 Inhibitors: Are They Really Atherothrombotic, and If Not, Why Not?
Hankey and Eikelboom
Stroke 2003;34:2736-2740.
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Effects of Cyclooxygenases Inhibitors on Vasoactive Prostanoids and Thrombin Generation at the Site of Microvascular Injury in Healthy Men
Tuleja et al.
Arterioscler. Thromb. Vasc. Bio. 2003;23:1111-1115.
ABSTRACT
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Cyclooxygenase-2 Inhibitors
Gajraj
Anesth. Analg. 2003;96:1720-1738.
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Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors
Hawkey and Langman
Gut 2003;52:600-608.
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Effect of Selective Cyclooxygenase 2 Inhibitors and Naproxen on Short-term Risk of Acute Myocardial Infarction in the Elderly
Mamdani et al.
Arch Intern Med 2003;163:481-486.
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Lack of Cardioprotective Effect of Naproxen
Mukherjee et al.
Arch Intern Med 2002;162:2637-2637.
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Cyclooxygenase-2 Inhibitors and Myocardial Infarction
Goldstein
Arch Intern Med 2002;162:2639-2639.
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Aspirin Use May Change Cost-effectiveness of COX-2 Inhibitors
Pickard et al.
Arch Intern Med 2002;162:2637-2639.
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Risk of Myocardial Infarction Associated With Selective COX-2 Inhibitors: Questions Remain
Juni et al.
Arch Intern Med 2002;162:2639-2642.
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JournalScan
Malik
Heart 2002;88:207-208.
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Cyclooxygenase-2 Inhibition and Cardiovascular Events
Pitt et al.
Circulation 2002;106:167-169.
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What's all the fuss? Safety concerns about COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex)
Wooltorton
CMAJ 2002;166:1692-1693.
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Selective COX-2 Inhibitors, NSAIDs, Aspirin, and Myocardial Infarction
Dalen
Arch Intern Med 2002;162:1091-1092.
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The Risk for Myocardial Infarction with Cyclooxygenase-2 Inhibitors: A Population Study of Elderly Adults
Levesque et al.
ANN INTERN MED 2005;142:481-489.
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