[e-drug] Cox-2, NSAIDS, cardiovascular risk: the seduction of common sense

["Andy Gray" <graya1@ukzn.ac.za>]

E-DRUG: Cox-2, NSAIDS, cardiovascular risk: the seduction of common sense
-------------------------------------------------------------------------

[In a rare move JAMA has made available pre-publication versions of two
meta-analyses and an accompanying editorial for free as full text. The
hard-hitting editorial by David Graham is below. The two meta-analyses
are at http://jama.ama-assn.org/cgi/content/full/296.13.jrv60015v1 and
http://jama.ama-assn.org/cgi/content/full/296.13.jrv60011v1
(abstracts below). The NYT has coverage at
http://www.nytimes.com/aponline/us/AP-Safest-Painkillers.html?_r=1&oref=slogin

- any comments on this advice: "''If something has helped you in the
past and you haven't experienced an adverse reaction with it, stay with
that drug,'' advises Larry Sasich, a pharmacy school instructor and
consultant to Public Citizen's Health Research Group."? Or on Graham's
suggestion that patients at risk of GI problems use naproxen plus a PPI
as first-line or that those at risk of cardiac problems (or all elderly
patients?) use naproxen in the first instance? The FDA NSAID guide is at
http://www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdf. 
Copied as fair use. Andy

[Also note that the last study raises serious questions about the safety
of diclofenac, which is present on many essential drug lists. Should
it be replaced by naproxen (+PPI?) for patients at risk? WB]
~~~

http://jama.ama-assn.org/cgi/content/full/296.13.jed60058v1
Editorial   
COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk 
The Seduction of Common Sense 
David J. Graham, MD, MPH 

JAMA. 2006;296:(doi:10.1001/jama.296.13.jed60058). 

" . . . (A) long habit of not thinking a thing wrong, gives it a
superficial appearance of being right, and raises at first a formidable
outcry in defence of custom. But the tumult soon subsides. Time makes
more converts than reason."-Thomas Paine, Common Sense, 1776

The concept was appealing in its simplicity. Traditional nonsteroidal
anti-inflammatory drugs (NSAIDs) inhibited both isoforms of the enzyme
cyclooxygenase responsible for the first step in the conversion of
arachidonic acid into a variety of prostaglandins, thromboxanes, and
leukotrienes throughout the body.1 The anti-inflammatory and
pain-relieving effects of NSAIDs resulted from inhibition of
prostaglandin synthesis mediated by cyclooxygenase 2 (COX-2) at the site
of tissue injury, while gastrointestinal tract complications were due to
inhibition of prostaglandin synthesis mediated by cyclooxygenase 1
(COX-1) in the gastrointestinal mucosa. The allure of COX-2 inhibitors
was the prospect of treating pain without gastrointestinal toxicity.1
Celecoxib and rofecoxib were the first of these new agents to gain
approval and, with heavy promotion and direct-to-consumer advertising,
quickly became the most widely prescribed NSAIDs in the United States. 

Lurking in the background was the concern that selective COX-2
inhibition might suppress endothelial cell synthesis of prostacyclin,
leaving platelet thromboxane A2 mediated by COX-1 relatively
unopposed.2-3 With loss of the antiplatelet and vasodilatory effects of
prostacyclin, a relative excess of thromboxane A2 would favor
vasoconstriction, platelet aggregation, and thrombosis.2-3 Disturbing
red flags for cardiovascular risk were noted in the preapproval
application for rofecoxib submitted to the US Food and Drug
Administration (FDA) in November 1998, but were dismissed because of the
FDA's practice of requiring "complete certainty" before acting on safety
concerns.4 Indeed, as noted by Psaty and Furberg,5 "Safety signals were
recognized by the medical officer of the Food and Drug Administration
(FDA) who observed that in 6-week studies, thromboembolic events are
more frequent in patients receiving rofecoxib [12 (0.6%) of 1780] than
placebo [1 (0.24%) of 412]." 

Within months of rofecoxib's approval in May 1999, the Vioxx
Gastrointestinal Outcomes Research (VIGOR) trial reported a 50%
reduction in serious gastrointestinal outcomes, but a 5-fold increase in
thromboembolic cardiovascular events (primarily acute myocardial
infarction [MI]) among patients treated with 50 mg/d of rofecoxib
compared with 1000 mg/d of naproxen.6 For nearly 2 years after these
results became known, rofecoxib's label remained unchanged while the
company aggressively marketed the drug, claiming that it did not
increase the risk of MI and that naproxen was cardioprotective.6-8
During this period, the FDA warned the company that its promotion of
rofecoxib made "unsubstantiated claims," "promoted off-label use," and
was "false, lacking in fair balance, or otherwise misleading."8
Meanwhile, a Pfizer study of celecoxib in Alzheimer disease, which was
completed in 2000 but not revealed until January 2005, showed an
increase in cardiovascular risk with that drug.9 

Then, in 2004, Merck withdrew rofecoxib from the market after its
Adenomatous Polyp Prevention on Vioxx (APPROVe) trial showed a 2-fold
increase in cardiovascular risk with 25 mg/d of rofecoxib compared with
placebo.10 Based on an unplanned post hoc analysis, the company claimed
that risk increased only after 18 months of continuous use,10-11 which
if true, would reduce the company's liability substantially because most
rofecoxib use was for much shorter periods. Against this backdrop,
public concern was heightened by announcements that celecoxib,
valdecoxib, and naproxen might also increase MI risk.12-14 For example,
analysis of the Adenoma Prevention with Celebrex study showed at least a
tripling of risk for 400 mg of celecoxib twice daily.12 Subsequently,
the FDA labeled all COX-2 selective and nonselective NSAIDs as
increasing cardiovascular risk,15 adding to public anxiety and
confusion. 

In 2006, Merck announced that it had performed an incorrect statistical
test in its post hoc analysis of the APPROVe trial.16 More importantly,
the analysis was performed improperly because it relied on a censoring
rule that violated widely accepted intention-to-treat principles.17-18
When analyzed appropriately, cardiovascular risk was decidedly present
early in rofecoxib therapy.17 The New England Journal of Medicine
published a correction to the original report of APPROVe, removing all
reference to an 18-month threshold for cardiovascular risk, thereby
indicating that risk was increased from the start of therapy and
continued through the period of the study.19 

In this issue of JAMA, 2 systematic reviews20-21 provide clarity on a
topic that has been dominated more by disinformation than reason. Zhang
and colleagues20 addressed the important but underappreciated issue of
renal effects with COX-2 selective NSAIDs. Their review and
meta-analysis of 114 clinical trials involving 116 094 patients revealed
that rofecoxib was associated with increased risk of peripheral edema,
hypertension, and renal dysfunction at low and high doses. Risk of
cardiac arrhythmias was also increased, and while the number of events
was small, ventricular fibrillation, cardiac arrest, and sudden cardiac
death accounted for most arrhythmia events. No such effects were present
with celecoxib, valdecoxib, or etoricoxib. Moreover, in a
time-cumulative analysis, the authors suggest that the risk of
peripheral edema and hypertension associated with rofecoxib was evident
by 2000, and the risk of arrhythmia was evident by 2004. 

In their systematic review of observational studies, McGettigan and
Henry21 focused on the cardiovascular (primarily MI) risk of COX-2
selective and nonselective NSAIDs. Among their most important findings,
cardiovascular risk was increased with rofecoxib as well as with
diclofenac, indomethacin, and probably meloxicam. Rofecoxib risk was
increased at low and high doses and was evident during the first 30 days
of use. Importantly, naproxen was not cardioprotective. With a pooled
relative risk (RR) of 0.97 (95% confidence interval [CI], 0.87-1.07),
naproxen neither increased nor decreased risk. Although the RR for
ibuprofen was not statistically significantly increased compared with
that for naproxen, the lower bound of its 95% CI approached 1 (RR, 1.07;
95% CI, 0.97-1.18), which is less than reassuring. 

Of note, rofecoxib, diclofenac, and meloxicam are COX-2 selective
inhibitors1 and this common characteristic may account for their
increased risk, although it does not necessarily explain all of these
observations. Celecoxib is also COX-2 selective (but less so than
rofecoxib) and, in the review by McGettigan and Henry,21 while
cardiovascular risk was increased at a dose above 200 mg/d, risk at 200
mg/d was not increased. Nonetheless, it may be prudent to regard
celecoxib with caution in light of 4 recent studies published since
their meta-analysis was completed. Andersohn et al22 reported an
increased MI risk with celecoxib (RR, 1.56; 95% CI, 1.22-2.00) in
addition to increased risks with the COX-2 selective drugs rofecoxib,
diclofenac, etoricoxib, and valdecoxib. Brophy et al23 found that MI
risk with celecoxib was increased among patients without, but not with,
a past history of MI. Gislason et al24 found that in patients following
hospitalization for a first MI, rofecoxib was associated with a 2.5-fold
(25 mg/d) and 5.3-fold (>25 mg/d) increase in risk of death and a
1.7-fold (25 mg/d) increase in reinfarction. Celecoxib was associated
with a 1.9-fold (200 mg/d) and 4.7-fold (>200 mg/d) increase in risk of
death and a 1.5-fold and 1.6-fold increased risk of reinfarction at
lower and higher doses, respectively. The risk of death with ibuprofen
was increased 2.2-fold at doses higher than 1200 mg/d and reinfarction
was increased at doses below and above 1200 mg/d.24 Also,
Helin-Salmivaara et al25 found an increased risk of first-time MI with
rofecoxib and etoricoxib but not celecoxib, as well as increased risk
with diclofenac, indomethacin, ibuprofen, and naproxen. 

A 2004 cumulative meta-analysis by Juni et al26 showed that rofecoxib
increased cardiovascular risk at low and high doses and that risk was
increased early in therapy. In a recently reported meta-analysis of 138
randomized trials covering all NSAIDs, Kearney et al27 found that for 37
trials with rofecoxib (85% at 25 mg/d), acute MI risk was increased (RR,
1.73; 95% CI, 1.09-2.82) compared with placebo. With celecoxib (41
trials), the RR was 2.70 (95% CI, 1.30-6.29), which was driven by 21
studies at doses of 400 mg/d or higher. Combined vascular event risk
(primarily MI) compared with placebo was also increased for diclofenac
(RR, 1.63; 95% CI, 1.12-2.37) and approached statistical significance
for ibuprofen (RR, 1.51; 95% CI, 0.96-2.37).27 Risk was not increased
with naproxen (RR, 0.92; 95% CI, 0.67-1.26).27 

What does this all mean? First, rofecoxib increases the risk of acute
MI at low and high doses. This risk begins early in therapy, probably
with the first dose. There is no initial 18-month period of immunity
from risk.17-19,21, 26 Celecoxib also increases risk at doses higher
than 200 mg/d; at lower doses, the potential risk is less clear. Several
other NSAIDs increase risk, including the COX-2 selective NSAIDs
diclofenac and meloxicam, and the nonselective NSAID indomethacin, and
probably ibuprofen. Meta-analyses of randomized clinical trials and
observational studies agree that naproxen is neutral for MI risk. 

What should physicians do? For most patients with arthritis or other
conditions who require chronic pain relief, naproxen appears to be the
safest NSAID choice from a cardiovascular perspective. For patients at
high risk of NSAID-related gastrointestinal tract complications,
naproxen plus a proton pump inhibitor is less costly and as
effective,28-29 and probably safer, than low-dose celecoxib. Additional
studies exploring the benefits and risks of this approach are urgently
needed. Third-party payers and managed care organizations may wish to
fund such studies, given the huge sums they spend on COX-2 inhibitors.
The nation's largest third-party payer, the federal government, should
also be interested. If COX-2 inhibitors cost substantially more, confer
substantially greater cardiovascular risk, and offer no unique and
meaningful gastrointestinal tract benefit over generic naproxen plus
proton pump inhibitor, is there any point to the continued use of these
drugs? Another critical area for research relates to the use of low-dose
aspirin in the setting of COX-2 selective and nonselective NSAID use. It
is unclear whether aspirin mitigates or abolishes NSAID-related MI risk,
and, if so, how it may affect gastrointestinal tract risk. The
concomitant use of aspirin would appear to contradict the premise
underlying selective COX-2 inhibitor use. 

Another key issue is to account for the long delay in defining the
risks and benefits of COX-2 inhibitors. Part of the problem lies with
FDA policies, practices, and procedures that lead it to ignore potential
safety problems. Despite a priori concerns2-3 and disconcerting evidence
in the preapproval application,4-5 the FDA approved rofecoxib, stating
it lacked "complete certainty" that the drug increased cardiovascular
risk.4 Such a standard does not protect consumers, is prejudicially
favorable to industry and its financial interests, rewards drug
companies for not aggressively pursuing safety questions, and guarantees
that some drugs with major safety problems will be approved and, once
approved, will remain on the market, even in the face of extensive
patient harm. The failure to immediately withdraw high-dose rofecoxib
from the market following publication of the results of the VIGOR trial,
and to study quickly and intensively its cardiovascular risks at lower
doses, increased the number of patients harmed by the drug as well as
the profits made from its continued marketing. Only Congress can help
prevent this from happening again by enacting legislation to create a
separate and independent Center for Post-Marketing Safety within the
FDA, empowered with the authority to identify and effectively deal with
unsafe medicines and the companies that market them. 

In retrospect, had the VIGOR trial's cardiovascular findings for
rofecoxib been reported in comparison with naproxen (as was done for
gastrointestinal tract complications), it might have been more difficult
for the company to assert that naproxen was cardioprotective.5-8 Had the
company adhered to accepted scientific standards, it would have reported
that rofecoxib increased cardiovascular risk by a factor of 5 compared
with naproxen, not that risk with naproxen was one fifth that of
rofecoxib. Moreover, in the VIGOR trial, rofecoxib caused nearly 1 MI
for every complicated gastrointestinal tract event (mainly bleeding)
prevented, hardly a favorable benefit-to-risk profile. 

In 2001, Mukherjee et al30 raised a "cautionary flag" about an
increased risk of cardiovascular events with COX-2 inhibitors, and urged
caution in prescribing these agents to patients at risk for
cardiovascular morbidity. Unfortunately, many patients with underlying
cardiovascular risk continued to be treated with COX-2 inhibitors. The
typical patient treated with rofecoxib was older, frequently male, and
by virtue of age, probably had at least 1 other risk factor for
cardiovascular disease (ie, the target population for rofecoxib was not
at low risk). For tens of thousands of patients who experienced MI while
taking rofecoxib,31 the drug may have been the decisive risk factor,
over and above any other risk factors, that contributed to the
occurrence of this life-changing and potentially fatal event. 

Regarding naproxen, little skepticism about its purported
cardioprotective properties was expressed. If naproxen accounted for the
VIGOR results, it would have had to be at least 3 times more effective
than aspirin, a finding that seems implausible. The focus of the
scientific community on naproxen shifted attention from lower-dose
rofecoxib and efforts to establish its risk. Likewise, with APPROVe, an
improperly performed and misleading post hoc analysis enabled the
company to claim that cardiovascular risk began only after 18 months of
continuous rofecoxib use.10-11 Important considerations for which
skepticism was not expressed were that the post hoc analysis should have
been only hypothesis-generating, that statistical power was too low to
show an early risk, and that given rofecoxib's immediate suppression of
prostacyclin, risk would be expected to increase with the first dose and
remain elevated for the duration of therapy. 

With the recent announcement by Merck that it will press for US
approval of its COX-2 inhibitor NSAID etoricoxib,32 the FDA, academia,
and the medical research enterprise are once again faced with the
opportunity to forsake common sense by willfully accepting misdirection
and disinformation presented in the guise of science. An analysis of 3
randomized trials, collectively referred to as the Multinational
Etoricoxib and Diclofenac Arthritis Long-Term Program (MEDAL), was
reported to show that the risk of thrombotic cardiovascular events with
etoricoxib was not different from that for diclofenac (RR, 1.05; 95% CI,
0.93-1.19),32 with the implication being that etoricoxib is safe from a
cardiovascular perspective. The company used a noninferiority study
design, well-known to be especially poor at identifying differences in
safety risks between drugs, thereby stacking the deck in favor of its
drug. More importantly, in MEDAL, etoricoxib was compared with
diclofenac, a drug shown to substantially increase the risk of acute MI
in the meta-analysis of randomized trials by Kearney et al,27 and in the
meta-analysis of observational studies by McGettigan and Henry.21 By
inference, therefore, etoricoxib also must increase cardiovascular risk,
but that inference is not immediately apparent because of the way MEDAL
was designed, and by the way it appears that the findings are being
interpreted and positioned. 

This veiled and misleading ambiguity has much in common with the
stratagems used for VIGOR and APPROVe, where the true results were
opposite to those claimed and promoted. From the perspective of patient
safety and rational therapeutics, naproxen, not diclofenac, should have
been the reference drug in MEDAL.33 Had that been so, it is highly
likely that etoricoxib would have been shown to be no different than its
first-cousin rofecoxib with respect to cardiovascular risk. From a
business perspective, were etoricoxib to be exposed as another "naked
emperor," its US approval might be difficult, even by the FDA's
apparently industry-friendly standards. If the lessons of recent history
have been learned, the FDA's concerns will now be squarely focused on
patient safety rather than corporate profitability, and, ultimately,
common sense will prevail. 

AUTHOR INFORMATION  

Financial Disclosures: Dr Graham reported no financial conflicts of
interest, but reported that he was subpoenaed as a federal government
expert by plaintiffs, for the purpose of providing testimony (in May
2006) that may be used in a number of Vioxx-related lawsuits, and
reported that he received no compensation for this activity, other than
his federal salary. 

Disclaimer: The views expressed in this Editorial are the author's own
and do not reflect the official policy or position of the Food and Drug
Administration. 

Editorials represent the opinions of the authors and JAMA and not those
of the American Medical Association. 

Published online: September 12, 2006
(doi:10.1001/jama.296.13.jed60058). 

Editor's Note: Dr Graham is an employee of the US Food and Drug
Administration. This editorial was written by Dr Graham as an officially
approved outside activity in his private capacity and not as a Food and
Drug Administration employee. His contact information is publicly
available at http://directory.psc.gov/employee.htm and is as follows:
David J. Graham, MD, MPH, Office of Surveillance and Epidemiology, Food
and Drug Administration, 10903 New Hampshire Ave, WO22, Room 4314,
Silver Spring, MD 20993 (david.graham1@fda.hhs.gov). 

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23. Brophy J, Levesque L, Zhang B. The coronary risk of
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24. Gislason GH, Jacobsen S, Rasmussen JN, et al. Risk of death or
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acute myocardial infarction. Circulation. 2006;113:2906-2913.
25. Helin-Salmivaara A, Virtanen A, Vesalainen R, et al. NSAID use and
the risk of hospitalization for first myocardial infarction in the
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[published online ahead of print May 26, 2006]. Eur Heart J.
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26. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M.
Risk of cardiovascular events and rofecoxib: cumulative meta-analysis.
Lancet. 2004;364:2021-2029.  
27. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C.
Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal
anti-inflammatory drugs increase the risk of atherothrombosis?
meta-analysis of randomised trials. BMJ. 2006;332:1302-1308. 
28. Lai KC, Chu KM, Hui WM, et al. Celecoxib compared with lansoprazole
and naproxen to prevent gastrointestinal ulcer complications. Am J Med.
2005;118:1271-1278.   
29. Scheiman JM, Yeoman ND, Tally NJ, et al. Prevention of ulcers by
esomeprazole in at-risk patients using non-selective NSAIDs and COX-2
inhibitors. Am J Gastroenterol. 2006;101:701-710.   
30. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events
associated with selective COX-2 inhibitors JAMA. 2001;286:954-959. 
31. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial
infarction and sudden cardiac death in patients treated with COX-2
selective and non-selective NSAIDs. Lancet. 2005;365:475-481. 
32. Merck and Company Inc. Merck provides preliminary analyses of the
completed MEDAL program for Arcoxia (etoricoxib) [news release; August
23, 2006].
http://www.merck.com/newsroom/press_releases/research_and_development/2006_0
823.html.
Accessed August 29, 2006. 
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24, 2006:C1.
 
~~~
http://jama.ama-assn.org/cgi/content/full/296.13.jrv60015v1

Adverse Effects of Cyclooxygenase 2 Inhibitors on Renal and Arrhythmia
Events 
Meta-analysis of Randomized Trials 

Jingjing Zhang, MD, PhD; Eric L. Ding, BA; Yiqing Song, MD, ScD 

JAMA. 2006;296:(doi:10.1001/jama.296.13.jrv60015). 

ABSTRACT   

Context  Adverse effects of selective cyclooxygenase 2 (COX-2)
inhibitors on renal events and arrhythmia have been controversial, with
suggestions of a class effect. 

Objective  To quantitatively evaluate adverse risks of renal events
(renal dysfunction, hypertension, and peripheral edema) and arrhythmia
events and to explore drug class effects and temporal trends of apparent
effects of the COX-2 inhibitors: rofecoxib, celecoxib, valdecoxib,
parecoxib, etoricoxib, and lumiracoxib. 

Data Sources  A systematic search of EMBASE and MEDLINE (through June
2006), bibliographies, US Food and Drug Administration reports, and
pharmaceutical industry clinical trial databases. 

Study Selection  From relevant reports, 114 randomized double-blind
clinical trials were included. 

Data Extraction  Information on publication year, participant
characteristics, trial duration, drug, control, dose, and events were
extracted using a standardized protocol. 

Data Synthesis  Results were pooled via random-effects models and
meta-regressions. Of 116 094 participants from 114 trial reports
including 127 trial populations (40 rofecoxib, 37 celecoxib, 29
valdecoxib + parecoxib, 15 etoricoxib, and 6 lumiracoxib), there were a
total of 6394 composite renal events (2670 peripheral edema, 3489
hypertension, 235 renal dysfunction) and 286 arrhythmia events. Results
indicated significant heterogeneity of renal effects across agents (P
for interaction = .02), indicating no class effect. Compared with
controls, rofecoxib was associated with increased risk of arrhythmia
(relative risk [RR], 2.90; 95% confidence interval [CI], 1.07-7.88) and
composite renal events (RR, 1.53; 95% CI, 1.33-1.76); adverse renal
effects increased with greater dose and duration (both P.05). For all
individual renal end points, rofecoxib was associated with increased
risk of peripheral edema (RR, 1.43; 95% CI, 1.23-1.66), hypertension
(RR, 1.55; 95% CI, 1.29-1.85), and renal dysfunction (RR, 2.31; 95% CI,
1.05-5.07). In contrast, celecoxib was associated with lower risk of
both renal dysfunction (RR, 0.61; 95% CI, 0.40-0.94) and hypertension
(RR, 0.83; 95% CI, 0.71-0.97) compared with controls. Other agents were
not significantly associated with risk. Time-cumulative analyses
indicated that for rofecoxib the adverse risks for peripheral edema and
hypertension were evident by the end of year 2000 and for risk of
arrhythmia by 2004. 

CONCLUSIONS  In this comprehensive analysis of 114 randomized trials
with 116 094 participants, rofecoxib was associated with increased renal
and arrhythmia risks. A COX-2 inhibitor class effect was not evident.
Future safety monitoring is warranted and may benefit from an active and
continuous cumulative surveillance system. 

Published online: September 12, 2006
(doi:10.1001/jama.296.13.jrv60015). 

~~~
http://jama.ama-assn.org/cgi/content/full/296.13.jrv60011v1
Cardiovascular Risk and Inhibition of Cyclooxygenase 
A Systematic Review of the Observational Studies of Selective and
Nonselective Inhibitors of Cyclooxygenase 2 

Patricia McGettigan, MD, FRACP; David Henry, MB, ChB, FRCP 

JAMA. 2006;296:(doi:10.1001/jama.296.13.jrv60011). 

ABSTRACT   

Context  Evidence that rofecoxib increases the risk of myocardial
infarction has led to scrutiny of other nonsteroidal anti-inflammatory
drugs (NSAIDs). Regulatory agencies have provided variable advice
regarding the cardiovascular risks with older nonselective NSAIDs. 

Objective  To undertake a systematic review and meta-analysis of
controlled observational studies to compare the risks of serious
cardiovascular events with individual NSAIDs and cyclooxygenase 2
inhibitors. 

Data Sources  Searches were conducted of electronic databases
(1985-2006), scientific meeting proceedings, epidemiological research
Web sites, and bibliographies of eligible studies. 

Study Selection  Eligible studies were of case-control or cohort
design, reported on cardiovascular events (predominantly myocardial
infarction) with cyclooxygenase 2 inhibitor, NSAID use, or both with
nonuse/remote use of the drugs as the reference exposure. Of 7086
potentially eligible titles, 17 case-control and 6 cohort studies were
included. Thirteen studies reported on cyclooxygenase 2 inhibitors, 23
on NSAIDs, and 13 on both groups of drugs. 

Data Extraction  Two people independently extracted data and assessed
study quality with disagreements resolved by consensus. 

Data Synthesis  Data were combined using a random-effects model. A
dose-related risk was evident with rofecoxib, summary relative risk with
25 mg/d or less, 1.33 (95% confidence interval [CI], 1.00-1.79) and 2.19
(95% CI, 1.64-2.91) with more than 25 mg/d. The risk was elevated during
the first month of treatment. Celecoxib was not associated with an
elevated risk of vascular occlusion, summary relative risk 1.06 (95% CI,
0.91-1.23). Among older nonselective drugs, diclofenac had the highest
risk with a summary relative risk of 1.40 (95% CI, 1.16-1.70). The other
drugs had summary relative risks close to 1: naproxen, 0.97 (95% CI,
0.87-1.07); piroxicam, 1.06 (95% CI, 0.70-1.59); and ibuprofen, 1.07
(95% CI, 0.97-1.18). 

Conclusions  This review confirms the findings from randomized trials
regarding the risk of cardiovascular events with rofecoxib and suggests
that celecoxib in commonly used doses may not increase the risk,
contradicts claims of a protective effect of naproxen, and raises
serious questions about the safety of diclofenac, an older drug. 

Published online: September 12, 2006
(doi:10.1001/jama.296.13.jrv60011).