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Lower Risk of Thromboembolic Cardiovascular Events With Naproxen Among Patients With Rheumatoid Arthritis
Douglas J. Watson, PhD;
Thomas Rhodes, MS;
Bing Cai, MS;
Harry A. Guess, MD, PhD
Arch Intern Med. 2002;162:1105-1110.
ABSTRACT
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Background Naproxen strongly inhibits platelet aggregation.
Objective To examine the risk of acute thromboembolic cardiovascular events (TCEs)
(myocardial infarction, sudden death, and stroke) with current naproxen use
among patients with rheumatoid arthritis.
Methods We studied patients aged 40 to 79 years with rheumatoid arthritis in
the British General Practice Research Database, excluding those with a prior
TCE and potentially confounding conditions. We matched up to 4 controls by
sex, age, and site of medical practice to cases with first incident TCEs.
The case diagnosis date was designated as the index date for each case and
his or her controls. We categorized naproxen according to the most recent
prescription prior to the index date as being current ( 30 days), past
(>30 days but <365 days), or none ( 365 days before index date). Using
conditional logistic regression, we conducted a matched case-control
analysis with adjustment for potential confounders.
Results We identified 809 cases. Current naproxen use was more common among
controls (5.7%) than cases (3.2%). Adjusting for calendar year of treatment
start, systemic corticosteroid use, diabetes, and comorbidity, we found that
the odds ratio (95% confidence interval) for current naproxen use was 0.61
(0.39-0.94) while that for past use was 0.87 (0.65-1.16). Secondary and sensitivity
analyses supported these results.
Conclusions In this case-control study, patients with rheumatoid arthritis and a
current prescription for naproxen had a reduced risk of acute major TCEs relative
to those with no naproxen prescription in the past year. These results are
consistent with the ability of naproxen to inhibit platelet aggregation.
INTRODUCTION
PLATELET AGGREGATION plays a central role in the pathophysiology of
thromboembolic cardiovascular events (TCEs) such as myocardial infarction
(MI) and stroke.1 Platelet activation and aggregation
are mediated through the cyclooxygenase (COX) 1 isoform. Aspirin, an irreversible
inhibitor of COX-1, profoundly inhibits platelet aggregation, prolongs bleeding
time,2 and has been shown to reduce the incidence
of serious TCEs in patients presenting with an acute coronary syndrome3 and in patients with a history of MI,4
angina pectoris,5 or stroke.4
Theoretically, some nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs),
which are nonselective inhibitors of both COX-1 and COX-2, could also have
an antithrombotic effect via inhibition of platelet activity. In particular,
naproxen has been shown to confer clinically important levels of platelet
inhibition.6-7 In addition, the
product circular for naproxen in the United States and other countries states
that naproxen reduces platelet aggregation, prolongs bleeding time, and is
associated with a risk of bleeding.8
The present study used a British population-based clinical database
to estimate the risk of an acute major TCE in patients with rheumatoid arthritis
(RA) using naproxen relative to those not using naproxen. Patients with RA
were selected for study because of the likely high compliance with naproxen
therapy.
SUBJECTS AND METHODS
The General Practice Research Database (GPRD) represents a 6% sample
of the population of England and Wales from general practices in Britain.
Data are collected and recorded according to agreed-on standards and include
demographic details, prescriptions, clinical diagnoses, and hospital referrals.
Data concerning the use of over-the-counter medications are not available
in the database. Data from a practice are incorporated in the GPRD only after
that practice has been approved as "up-to-standard." A number of studies have
confirmed the validity of the diagnostic and prescription data contained in
the GPRD.9-13
The scientific and ethical review group that oversees analyses using the GPRD
approved the protocol for the present study.
We used a case-control study design among patients enrolled in up-to-standard
GPRD practices. To avoid practices where data might be incompletely recorded,
we excluded practices in which 20% or more of the patients had no recorded
health care visits. Patients with 1 or more diagnoses consistent with RA and
1 or more prescriptions for an NSAID, a disease-modifying antirheumatic drug
(DMARD), or a systemic corticosteroid were eligible for the study. We excluded
patients younger than 40 or older than 79 years at study start, those with
a previous TCE, and those with medical conditions that might confound the
association of interest, including cancer (other than basal cell of the skin),
vasculitis, coagulopathy, renal disease, liver failure, or alcohol or drug
abuse at any time prior to study start. In addition, we excluded patients
with a prescription for flurbiprofen14 (indobufen15 was not available in Britain during the years studied)
or anticoagulants and/or antiplatelet agents (prescription for aspirin at
any dosage, clopidogrel bisulfate, ticlopidine hydrochloride, dipyridamole,
or heparin) during the year prior to study start. We also excluded patients
with such prescriptions 30 days or less prior to their index date.
The primary end point was the first diagnosis of an acute TCE, defined
as MI, sudden death, or cerebrovascular event. Cerebrovascular events included
stroke, subarachnoid hemorrhage, and subdural hematoma but excluded transient
ischemic attack. Since hemorrhagic and ischemic cerebrovascular events cannot
always be distinguished clinically nor by the diagnoses in the database, we
included both in the primary end point. The date of the first incident end
point in a given patient was termed the index date. We matched up to 4 controls
to cases by sex, age within 5 years, and medical practice. When no control
could be matched within the same practice, we randomly selected controls matched
on sex and age from other practices. A control's index date was the same calendar
date as the index date for the matched case.
We sent the general practitioners a questionnaire concerning all exposed
cases and a 10% sample of both the unexposed cases and controls to verify
the RA and TCE diagnoses in the database. Among the returned questionnaires,
the RA diagnosis was confirmed in 80%, 74%, and 77% of the exposed cases,
unexposed cases, and controls, respectively. The TCE diagnoses were confirmed
in 80% of the exposed cases and in 78% of the unexposed cases.
Exposure to naproxen was based on the timing of prescriptions relative
to the index date. Current naproxen use was defined
as a prescription with a start date 30 days or less prior to the index date. Past naproxen use was defined as a prescription with an
end date more than 30 days but 365 days or less prior to the index date, while no naproxen was no prescription with an end date more than
365 days prior to the index date. Use of NSAIDs other than naproxen was evaluated
as a potential confounder in the primary analysis and was considered in secondary
analyses as an exposure of interest.
We evaluated and controlled for potential confounders or effect modifiers
other than the matching factors as needed in the analysis. These included
the calendar year the patient started the study (1988-1991, 1992-1995, 1996-1999);
smoking; prescription for DMARD, systemic corticosteroid, or estrogen 90 days
or less (but >30 days) prior to the index date; diagnosed or treated diabetes;
and other medical comorbidity (referral, admission, or emergency visit for
medical or surgical condition 6 months but >30 days prior to the index
date). For cardiovascular (CV) disease risk, we created an indicator variable
for each of the following conditions: hypercholesterolemia, hypertension,
congestive heart failure, angina pectoris, and cardiac conduction disorder.
Each condition was considered present if the patient had a recorded diagnosis
or was prescribed a medication for the condition at any time more than 30
days prior to the index date. We then used the indicator variables to compute
a single summary CV risk score. The distribution of the risk score was highly
skewed; therefore, we used a value of zero as a cutoff point to divide the
study population into those with and those without a positive CV risk score.
Because age is associated with CV risk factors, we created an interaction
term for the product of CV risk score and age at index date (<65 vs 65
years). We then used the CV risk score and the interaction term with age in
further modeling in place of the individual terms comprising the risk score.
Using conditional logistic regression, we conducted a matched case-control
analysis. We initially included all potential 2-way interactions between the
covariates and current naproxen use in the model. Using a backward stepwise
procedure, we examined the contribution of the interactions and covariates,
and those associated with the outcome (P<.05)
were retained in the final model.
We performed analyses of the effect of current naproxen use for the
composite primary end point and for MI events separately. We also conducted
secondary analyses using identical methods as outlined above to examine the
effect of current naproxen use compared with current non-naproxen NSAID use
on all TCEs and on MI specifically. Last, we also did analyses to examine
the effect of current non-naproxen NSAIDs, ibuprofen, and diclofenac use (each
evaluated separately) compared with no use on all TCEs and MI specifically
among patients who did not have prescriptions for naproxen.
To corroborate the results, we repeated the analyses for all TCEs and
for MI using a prospective cohort study design. We used similar methods to
those in the case-control approach to identify the study cohort and determine
the study start and stop dates for each subject. We identified courses of
naproxen therapy. We defined the start of a course as the date the prescription
was written and the end of a course as the sum of the start date plus the
duration of the prescription plus 15 days. For patients with missing data
on duration of a prescription, we assigned the median value for the entire
study population. We considered a patient to be a current user from the start
date for a given course until the earliest of the end date for that course
or end of follow-up. If another prescription for naproxen was given before
either of these dates, we counted the course of therapy as continuing until
the earliest of the end date of the last course without a new prescription
or end of follow-up.
Patients may have had more than 1 period of current naproxen use. Following
the end of a course of naproxen, we considered a patient a past user until
a new course of naproxen began or the end of follow-up, whichever came first.
We classified patients without a naproxen prescription from study start until
end of follow-up as not exposed to naproxen, and these patients served as
the control group for the analysis. For the controls, we assessed the same
potential confounders and effect modifiers, as determined by their presence
during the year prior to study start, as in the case-control analysis. We
conducted a survival analysis using Cox regression models, selecting covariates
for analysis and eligibility in the final models in the same manner as in
the case-control analysis. We included current naproxen use (yes, no) in the
model as a time-dependent variable. We estimated both unadjusted and adjusted
risk ratios for current naproxen vs never use, and used a likelihood ratio
test to test the null hypothesis that the hazard ratio for current use was
1.0.
RESULTS
A total 31 614 patients met the study criteria for RA, of whom
14 677 (46.4%) were excluded, leaving 16 937 patients eligible for
the analysis (Table 1). Of these,
809 had a first incident TCE (435 MIs, 27 sudden deaths, 347 cerebrovascular
events) and comprised the cases for the analysis. A total of 2285 controls
were matched to the 809 cases for the primary analysis. Current naproxen use
was seen in 26 cases (3.2%) vs 130 controls (5.7%), while the proportions
of patients with past and no naproxen use were similar between cases and controls
(Table 2). The distributions of
age at study start and sex were similar for cases and controls. Cases were
more likely to have an earlier study start date, to smoke, to have used systemic
corticosteroids, and to have a positive CV risk score, diabetes, and/or other
comorbidity.
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Table 1. Patient Accounting
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Table 2. Patient Characteristics (Cohort Including All Thromboembolic
Events)
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We also examined the characteristics of patients with current naproxen
use compared with those with no naproxen use in the past year. Among cases,
current naproxen users were more likely to be 65 years or older (80.8% vs
65.9%) and to use DMARDs (50.0% vs 33.1%), and less likely to use steroids
(26.9% vs 33.1%), have a positive CV risk score (46.2% vs 57.2%), or to have
a comorbidity (3.9% vs 19.7%). Among controls, current naproxen users were
more likely to use DMARDs (43.9% vs 32.5%), less likely to use steroids (18.5%
vs 25.1%), and slightly less likely to have a positive CV risk score (40.8%
vs 44.1%).
The odds ratios (ORs) (and 95% confidence intervals [CIs]) for current
and past naproxen use matched on age, sex, and practice but without adjustment
for other potential confounders were 0.57 (0.37-0.88) and 0.90 (0.68-1.19),
respectively. The contribution of the 2-way interactions with current naproxen
use (as a group) did not significantly contribute to the fit of the multivariate
model (P = .12). In the final model, the OR (95%
CI), adjusting for calendar year of patient start, systemic corticosteroid
use, diabetes, and comorbidity, for current naproxen use was 0.61 (0.39-0.94)
while that for past naproxen use was 0.87 (0.65-1.16) (Table 3).
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Table 3. Conditional Logistic Regression Results of Matched Case-Control
Analysis of the Association of Naproxen Use With All Thromboembolic Events*
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The associations of the other drug therapies with all TCEs are given
in Table 4. The risk of an event
with current naproxen use as opposed to current use of non-naproxen NSAIDs
as a group was 0.65 (0.34-1.24). Other results given in Table 4 are those of current and past use of non-naproxen NSAIDs
as a group, ibuprofen, and diclofenac compared with no use of these agents
among patients not using naproxen. The ORs (95% CIs) for current use were
1.16 (0.92-1.46) for non-naproxen NSAIDs, 1.05 (0.64-1.73) for ibuprofen,
and 1.68 (1.25-2.27) for diclofenac.
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Table 4. Conditional Logistic Regression Results of Secondary Matched
Case-Control Analyses of Drug Therapies and All Thromboembolic Events*
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For MI, the ORs (95% CIs) for current and past naproxen use matched
on age, sex, and practice but without adjustment for other potential confounders
were 0.53 (0.28-0.97) and 0.90 (0.61-1.32), respectively. The results of multivariable
analyses of MI are given in Table 5.
The ORs (95% CIs) for current and past use of naproxen with adjustment for
calendar year of study start, systemic corticosteroid use, comorbidity, and
CV risk score were 0.57 (0.31-1.06) and 0.90 (0.60-1.34), respectively. The
risk of MI with current use of naproxen as opposed to non-naproxen NSAIDs
as a group was 0.40 (0.13-1.20). Other results given in Table 5 are those of current and past use of non-naproxen NSAIDs
as a group, ibuprofen, and diclofenac compared with no use of these agents
among patients not using naproxen. The ORs (95% CIs) for current use were
1.47 (1.00-2.16) for non-naproxen NSAIDs, 0.74 (0.35-1.55) for ibuprofen,
and 1.68 (1.14-2.49) for diclofenac.
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Table 5. Conditional Logistic Regression Results of Matched Case-Control
Analysis of the Association of Naproxen and Other Drug Therapies With Myocardial
Infarction*
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The survival analysis in the cohort study yielded similar results, although
with some loss of precision. The hazard ratio (95% CI) for the crude association
of current naproxen with all TCEs was 0.55 (0.28-1.11); in the final adjusted
model it was 0.53 (0.22-1.28) (Table 6).
The crude association (95% CIs) of current naproxen use with MI was 0.26 (0.06-1.04);
in the final adjusted model it was 0.38 (0.10-1.54) (Table 7).
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Table 6. Results of Survival Analysis of Prospective Cohort Analysis
of the Association of Naproxen Use With All Thromboembolic Events*
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Table 7. Results of Survival Analysis of Prospective Cohort Analysis
of the Association of Current Naproxen Use With Myocardial Infarction
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COMMENT
The results of this study suggest that patients with RA currently using
naproxen have a lower risk for TCEs relative to those with no naproxen use
in the past year. However, risk was not lower with past use of naproxen, suggesting
that any effect of naproxen is likely to be short-lived. A lower risk with
current naproxen use was also found when MIs were analyzed separately, although
this result was not statistically significant. As in the primary analysis,
current use of non-naproxen NSAIDs was not associated with a reduced risk
of MI. Analyses comparing current use of naproxen with current use of non-naproxen
NSAIDs and a sensitivity analysis using a different analytical approach were
both consistent with the primary results, although these analyses had less
precision than the primary analysis.
The negative association of TCEs with naproxen use is in the expected
direction based on preclinical and pharmacologic data suggesting that naproxen
has a strong antiplatelet effect.6-8
The present study also did not show a protective effect for TCEs with current
use of ibuprofen or diclofenac, which have a less profound effect on platelet
activity6; nor did it show an effect of current
use of non-naproxen NSAIDs combined among patients not using naproxen.
It is possible that the finding of a lower risk of MI with current naproxen
use is due to a lower baseline risk of events. We examined the distributions
of baseline characteristics of current naproxen users compared with nonusers,
and did not find any major differences in baseline risk. Nevertheless, it
is possible that there could be residual confounding due to factors not fully
accounted for in our analysis.
The definition of RA for this study was based on general practitioner–recorded
GPRD codes related to diagnoses and clinical findings commonly found in RA.
We validated the RA diagnosis in a sample of the subjects and found that the
diagnosis was confirmed in 80%, 74%, and 77% of the exposed cases, unexposed
cases, and controls, respectively. In addition, the accuracy of the diagnosis
data in the GPRD has been studied previously and found to be acceptable for
research purposes.12-13 On repeating
the analysis using a more restrictive list of RA diagnoses, we obtained similar
results (data not shown), suggesting that the results were not sensitive to
the choice of RA diagnostic codes.
Data on actual use of medications and compliance with dosing instructions
are not available in the GPRD. However, patients with RA often require long-term
daily therapy for pain and inflammation and thus are more likely to be compliant
with NSAID regimens than other patients. In addition, we defined current naproxen
therapy as a prescription within 30 days, and the use of short prescription
time reduces misclassification error.16 The
fact that current exposure to naproxen in this study showed a stronger protective
effect than did past exposure would seem to corroborate this approach.
The end points in this study were recorded diagnoses related to MI,
sudden death, or cerebrovascular events. We validated the end point diagnosis
in 80% of the exposed cases and in 78% of the unexposed cases. In addition,
others have used similar MI diagnosis lists and confirmed a similar percentage.17 The cause of sudden death, although often not documented,
is usually CV disease, and this diagnosis is frequently included in CV outcome
studies. The cerebrovascular end points included both ischemic and hemorrhagic
diagnoses, despite the fact that an antiplatelet effect of naproxen might
protect against the former and increase the hazard for the latter. We included
both types because it is sometimes difficult to distinguish the 2 types clinically,
and because most such events are ischemic. Nevertheless, we performed a sensitivity
analysis restricting cerebrovascular diagnoses to those most likely on inspection
of diagnostic codes to reflect an ischemic etiology, and this analysis yielded
similar results (data not shown).
Currently, there are a few published studies of a potential antithrombotic
effect of naproxen. In a case-control study, Rahme et al18
examined the association of naproxen use and hospitalization for acute MI
among elderly Canadian men and women. They found the risk of hospitalization
for acute MI to be lower among long-term users of naproxen than among long-term
users of other nonaspirin NSAIDs (OR, 0.65; 95% CI, 0.48-0.97). Solomon et
al19 performed a case-control study of NSAID
use and MI and found that although use of any NSAID was not associated with
the outcome, use of naproxen was associated with a reduction in the risk of
MI compared with nonusers (OR, 0.84; 95% CI, 0.72-0.98). In a cohort study
of new users of nonaspirin NSAIDs, Ray et al20
found that the risk of acute MI among current users of naproxen was essentially
the same as among nonusers (RR, 1.03; 95% CI, 0.98-1.08), but somewhat lower
than among current users of ibuprofen (RR, 0.83; 95% CI, 0.69-0.98).
In summary, the present study found that patients with RA aged 40 to
79 years who had recently received a prescription for naproxen had a lower
risk of TCEs than patients who had not had a prescription for naproxen in
the prior year. These results are consistent with the antiplatelet effect
of naproxen. Sensitivity analyses, including a cohort analysis, were generally
consistent with, but less precise than, the primary results.
AUTHOR INFORMATION
Accepted for publication February 14, 2002.
This study was funded by Merck & Co Inc, Whitehouse Station, NJ.
This study was presented at the American College of Rheumatology Annual
Scientific Meeting, San Francisco, Calif, November 14, 2001.
Corresponding author and reprints: Douglas J. Watson, PhD, Department
of Epidemiology, Merck Research Laboratories, 10 Sentry Pkwy (BL1-7), Blue
Bell, PA 19422 (e-mail: watsond{at}merck.com).
From Merck Research Laboratories, Blue Bell, Pa. All authors are employees
of Merck & Co Inc and may own stock in the company.
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Ann Rheum Dis 2006;65:7-13.
ABSTRACT
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Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis
Hippisley-Cox and Coupland
BMJ 2005;330:1366.
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Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study
Hudson et al.
BMJ 2005;330:1370.
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Impact of Nonsteroidal Antiinflammatory Drugs on the Cardioprotective Effects of Aspirin
Corman et al.
The Annals of Pharmacotherapy 2005;39:1073-1079.
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Risk of Hospitalization for Myocardial Infarction Among Users of Rofecoxib, Celecoxib, and Other NSAIDs: A Population-Based Case-Control Study
Johnsen et al.
Arch Intern Med 2005;165:978-984.
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Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects
Capone et al.
J Am Coll Cardiol 2005;45:1295-1301.
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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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The Risk for Myocardial Infarction with Cyclooxygenase-2 Inhibitors: A Population Study of Elderly Adults
Levesque et al.
ANN INTERN MED 2005;0:0000605-200504050-00113-65e.
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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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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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Tackling ischaemic heart disease in rheumatoid arthritis
Kitas and Erb
Rheumatology (Oxford) 2003;42:607-613.
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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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Efficacy and safety of COX 2 inhibitors
Jones
BMJ 2002;325:607-608.
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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.
FULL TEXT
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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