vioxx warning - blood clots - Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors

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Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors  

Debabrata Mukherjee, MD; E. Nissen, MD; J. Topol, MD

Atherosclerosis is a process with inflammatory features and selective

cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic

effects by virtue of inhibiting inflammation. However, by decreasing

vasodilatory and antiaggregatory prostacyclin production, COX-2 antagonists

may lead to increased prothrombotic activity. To define the cardiovascular

effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain

in patients without coronary artery disease, we performed a MEDLINE search

to identify all English-language articles on use of COX-2 inhibitors

published between 1998 and February 2001. We also reviewed relevant

submissions to the US Food and Drug Administration by pharmaceutical

companies.

Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal

Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term

Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials

with approximately 1000 patients each. The results from VIGOR showed that

the relative risk of developing a confirmed adjudicated thrombotic

cardiovascular event (myocardial infarction, unstable angina, cardiac

thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic

stroke, and transient ischemic attacks) with rofecoxib treatment compared

with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P = .002). There

was no significant difference in cardiovascular event (myocardial

infarction, stroke, and death) rates between celecoxib and nonsteroidal

anti-inflammatory agents in CLASS. The annualized myocardial infarction

rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher

than that in the placebo group of a recent meta-analysis of 23 407 patients

in primary prevention trials (0.52%): 0.74% with rofecoxib (P = .04 compared

with the placebo group of the meta-analysis) and 0.80% with celecoxib (P =

..02 compared with the placebo group of the meta-analysis).

The available data raise a cautionary flag about the risk of cardiovascular

events with COX-2 inhibitors. Further prospective trial evaluation may

characterize and determine the magnitude of the risk.

JAMA. 2001;286:954-959

Aspirin and nonsteroidal anti-inflammatory agents (NSAIDs) have proven

analgesic, anti-inflammatory, and antithrombotic properties but also have

significant gastric toxicity. The gastrointestinal toxicity appears to be

related to cyclooxygenase 1 (COX-1) inhibition.1 In 1990, Fu et al2 detected

a novel COX protein in monocytes stimulated by interleukin, and a year later

Kujubu et al3 identified a gene with considerable homology to COX-1.

Identification of this COX-2 protein rekindled the efforts of the

pharmaceutical industry to produce a safer analgesic and anti-inflammatory

drug via selective inhibition of COX-2, and this class of agents was

introduced in 1999. By October 2000, celecoxib and rofecoxib had sales

exceeding $3 billion in the United States, and a prescription volume in

excess of 100 million for the 12-month period ending in July 2000.4

The development of COX-2 inhibitors as anti-inflammatory agents without

gastric toxicity is based on the premise that COX-1 predominates in the

gastric mucosa and yields protective prostaglandins, whereas COX-2 is

induced in inflammation and leads to pain, swelling, and discomfort.

However, selective COX-2 inhibitors decrease vascular prostacyclin (PGI2)

production and may affect the balance between prothrombotic and

antithrombotic eicosanoids.5 Unlike the platelet inhibition afforded by

COX-1 inhibitors, COX-2 inhibitors do not share this salutary antithrombotic

property. In contrast, by decreasing vasodilatory and antiaggregatory PGI2

production, COX-2 antagonists may tip the balance in favor of prothrombotic

eicosanoids (eg, thromboxane A2) and may lead to increased cardiovascular

thrombotic events.6 However, atherosclerosis is a process with inflammatory

features7 and selective COX-2 inhibitors may potentially have

antiatherogenic effects by virtue of inhibiting inflammation. Herein,we

analyze the randomized trials that have been performed to determine whether

COX-2 inhibitors are associated with a protective or hazardous effect on the

risk of cardiovascular events.

METHODS

We used MEDLINE to identify all published, English-language, randomized,

double-blind trials of COX-2 inhibitors from January 1998 to February 2001.

Keywords used for our search included COX-2, cyclooxygenase, rofecoxib, and

celecoxib. We also searched the World Wide Web using the same keywords. A

number of studies8-17 focused only on the gastrointestinal effects of COX-2

inhibitors and did not assess cardiovascular events, most likely because

investigators were unaware of any cardiovascular adverse effects at that

time. These studies were not included in our analysis because there was no

reporting of cardiovascular adverse effects.

COX-2 inhibitors were approved in 1998 and there have been 2 major

postmarketing multicenter trials with these agents. These include the Vioxx

Gastrointestinal Outcomes Research study (VIGOR)18 and the Celecoxib

Arthritis Safety Study (CLASS).19 We also reviewed cardiovascular event

rates from Study 085 and Study 090, both submitted to the US Food and Drug

Administration (FDA).20 Table 1 summarizes the design of these trials. We

also compared the annualized myocardial infarction (MI) rates in the placebo

group of a recent meta-analysis of 4 aspirin primary prevention trials with

MI rates in the VIGOR and CLASS trials.

An October 12, 2000, Adverse Events Reporting System search limited to the

United States was conducted for rofecoxib and celecoxib using the following

MedDRA terms: central nervous system hemorrhages and cerebral accidents,

coronary artery occlusion, coronary artery embolism, myocardial infarction,

gastrointestinal arterial occlusion and infarction, and embolism,

thrombosis, and stenosis.21

Time-to-event analysis of cardiovascular events was performed based on

Kaplan-Meier estimates of cumulative event incidences. The relative risk

(RR) of rofecoxib with respect to naproxen was derived from an unstratified

model in which the number of events was at least 11; otherwise, RR is

the ratio of rates and the P value was calculated from a discrete log-rank

distribution. Event rates in the CLASS trial were expressed as percentages

of patients, with end points. Frequency of MIs across the trials was

compared using the Fisher exact test. Statistical analysis was performed

using Statistica version 5.5 (StatSoft Inc, Tulsa, Okla).

RESULTS

VIGOR Trial

 

The VIGOR trial18 was a double-blind, randomized, stratified, parallel group

trial of 8076 patients comparing the occurrence of gastrointestinal toxicity

with rofecoxib (50 mg/d) or naproxen (1000 mg/d) during long-term treatment

for patients with rheumatoid arthritis. Aspirin use was not permitted in the

study. Although not fully published, cardiovascular event data from the

VIGOR trial sponsor was recently submitted to the FDA.22 The baseline

characteristics between the treatment groups in the VIGOR trial demonstrated

no meaningful or significant differences. Patients requiring aspirin for

cardiac reasons were excluded from this trial.

Based on excessive cardiovascular adverse effects in one group in an interim

analysis, the data and safety monitoring board recommended blinded

adjudication of cardiovascular events.22 Ninety-eight cases (65/4047 from

the rofecoxib group, 33/4029 from the naproxen group) were sent for

adjudication of vascular events. Of these, 45 patients (46 events) in the

rofecoxib group and 20 patients (20 events) in the naproxen group were

adjudicated to have serious thrombotic cardiovascular adverse events (MI,

unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or

unexplained death, ischemic stroke, and transient ischemic attacks).

Event-free survival analysis of these 66 patients showed that the RR (95%

confidence interval [CI]) of developing a cardiovascular event in the

rofecoxib treatment group was 2.38 (1.39-4.00), P<.00122 (Figure 1).

A subgroup analysis was performed for patients classified as either " aspirin

indicated " or " aspirin not indicated. " In the VIGOR trial, aspirin-indicated

patients were defined as those with past medical history of stroke,

transient ischemic attack, MI, unstable angina, angina pectoris, coronary

artery bypass graft surgery, or percutaneous coronary interventions. Only

321 (3.9%) patients were aspirin-indicated patients (170 in the rofecoxib

group; 151 in the naproxen group), because the need for aspirin was an

exclusion criterion. The RR of developing serious cardiovascular events

among aspirin-indicated patients between the rofecoxib group and the

naproxen group was 4.89 (95% CI, 1.41-16.88), P = .01, and the RR for

aspirin not indicated patients was 1.89 (95% CI, 1.03-3.45), P = .04.22 Of

note, no patient in the aspirin indicated group sustained an MI.

If all cardiovascular events from the adverse event data sets that were

termed " serious " in the FDA medical reviewer's opinion were compared, there

were 111 patients in the rofecoxib group and 50 patients in the naproxen

group with serious cardiovascular events. Event-free survival analysis

showed the risk of serious cardiovascular events in the rofecoxib group was

2.2 times higher (95% CI, 1.62-3.21; P<.001) than in the naproxen group.22

CLASS Trial

 

CLASS was a double-blind, randomized controlled trial in which 8059 patients

were randomized to receive 400 mg of celecoxib twice per day, 800 mg of

ibuprofen 3 times per day, or 75 mg of diclofenac twice per day.19 Aspirin

use (<325 mg/d) was permitted in this study. Although not published,

cardiovascular event data from the CLASS study submitted to the FDA were

included in our review.23 The CLASS trial with celecoxib demonstrated no

significant difference in cardiovascular events compared with the NSAIDs.

Figure 2 shows the thrombotic event rates in the CLASS trial. The event

rates are stratified by patients receiving aspirin and those not receiving

aspirin.

Study 085 and Study 090

 

Study 085 (N = 1042) was a randomized, double-blind, parallel-group,

placebo-controlled trial of the efficacy and safety of rofecoxib (12.5 mg/d)

vs nabumetone (1000 mg/d) vs placebo after 6 weeks of treatment for

osteoarthritis of the knee. Patients were allowed to take low-dose aspirin

for cardioprotection.20 There were 3 total cardiovascular events in this

trial: 1 event (0.2%) in the rofecoxib group, 2 events (0.4%) in the

nabumetone group, and no events in the placebo group.

Study 090 (N = 978) was a randomized, placebo-controlled, parallel-group,

double-blind trial of the efficacy and safety of rofecoxib (12.5 mg/d) vs

nabumetone (1000 mg/d) vs placebo in patients with osteoarthritis of the

knee. Low-dose aspirin for cardioprotection was also allowed in this study.

Study 090 reported a total of 9 serious cardiovascular events: 6 (1.5%)

events in the rofecoxib group, 2 (0.5 %) in the nabumetone group, and 1

(0.5%) in the placebo group.

Adverse Event Reporting System

 

An Adverse Event Reporting System search revealed 144 unduplicated

thrombotic or embolic cases for celecoxib and 159 cases for rofecoxib.21

Forty-two celecoxib cases and 60 rofecoxib cases were excluded for a lack of

documented event or for hemorrhagic stroke in which the prothrombin time,

partial thromboplastin time, or international normalized ratio was above the

normal range; also excluded were secondhand reports with no confirmed

diagnosis. Ninety-nine thrombotic or embolic events were attributed to

rofecoxib and 102 cases to celecoxib. Table 2 summarizes the thrombotic

events reported with each agent.

Comparison With Contemporary Meta-analysis

 

The meta-analysis of the US Physicians' Health Study, the UK Doctors Study,

the Thrombosis Prevention Trial, and the Hypertension Optimal Treatment

trials included 48 540 patients, of whom 25 133 were treated with aspirin

and 23 407 were given placebo.24 The annualized MI rate in the placebo group

in this meta-analysis was 0.52%. The annualized MI rates for both the VIGOR

and the CLASS trials were higher: 0.74% with rofecoxib (P = .04, compared

with the placebo group of the meta-analysis) and 0.80% with celecoxib (P =

..02, compared with the placebo group of the meta-analysis) (Figure 3).

COMMENT

Aspirin and NSAIDs inhibit prostaglandin synthesis via a cyclooxygenase

enzyme. This action is the key to both their therapeutic and toxic effects.

The COX-1 isoform is constitutively expressed in most cells, which results

in the production of homeostatic prostaglandins that maintain

gastrointestinal mucosal integrity and renal blood flow. The COX-1 isoform

is also expressed in platelets and mediates production of thromboxane A2, a

potent platelet activator and aggregator. The COX-2 isoform produces

prostaglandins at inflammatory sites as well as PGI2, which is a vasodilator

and inhibitor of platelet aggregation. Nonselective NSAIDs inhibit the

production of both thromboxane and PGI2. Selective COX-2 inhibitors have no

effect on thromboxane A2 production, but by decreasing PGI2 production may

tip the natural balance between prothrombotic thromboxane A2 and

antithrombotic PGI2, potentially leading to an increase in thrombotic

cardiovascular events.25, 26

We reviewed the cardiovascular event rates in the 2 major trials with

selective COX-2 inhibitors and in 2 smaller trials. The VIGOR trial

demonstrated significantly increased risk of cardiovascular event rates with

use of rofecoxib although the study enrolled patients who did not require

aspirin for protection from ischemic events. Patients with angina,

congestive heart failure, MI, coronary artery bypass graft surgery within 1

year, stroke or transient ischemic attacks within 2 years, and uncontrolled

hypertension were excluded from this trial. However, these criteria can be

viewed as too stringent, given data from trials that support more liberal

use of aspirin for primary prevention.

The results of the VIGOR study can be explained by either a significant

prothrombotic effect from rofecoxib or an antithrombotic effect from

naproxen (or conceivably both). There are differential effects of NSAIDs and

COX-2 inhibitors on ex vivo platelet aggregation to 1 mM arachidonic acid.

Naproxen has significant antiplatelet effects, with mean platelet

aggregation inhibition of 93% compared with platelet aggregation inhibition

of 92% for those taking aspirin (81 mg).22 Thus naproxen, but not ibuprofen

(platelet aggregation of approximately 80%) or diclofenac (platelet

aggregation of approximately 40%), resulted in a high level of platelet

aggregation inhibition similar to that achieved with aspirin.22 There is

clinical evidence that flurbiprofen, 50 mg twice daily for 6 months, reduced

the incidence of MI by 70% compared with placebo.27 Indobufen, another

NSAID, was as effective as aspirin in preventing saphenous vein graft

occlusion after coronary artery bypass graft surgery.28

Because of the evidence for an antiplatelet effect of naproxen, it is

difficult to assess whether the difference in cardiovascular event rates in

VIGOR was due to a benefit from naproxen or to a prothrombotic effect from

rofecoxib. Therefore, we examined results from a meta-analysis of 4 aspirin

primary prevention trials24 to evaluate whether the cardiovascular event

rates observed with rofecoxib were similar in VIGOR to a placebo-treated

population with similar cardiac risk factors. While acknowledging that

comparison of patient populations in 2 different trials is always

problematic, the results of this meta-analysis may further demonstrate the

prothrombotic potential of rofecoxib and celecoxib and suggest that

increased event rates with COX-2 inhibitors are possibly due to a

prothrombotic effect, not merely a failure to offer the protection of

aspirin-like NSAIDs. However, it is important to point out that rheumatoid

arthritis increases risk of MI, making intertrial comparisons difficult.29

In contrast to the VIGOR study, the CLASS study with celecoxib did not show

a significant increase in cardiovascular event rates compared with NSAIDs,

possibly due to the use of low-dose aspirin in the CLASS trial or to

pharmacological differences in the NSAID agents used as controls in the 2

studies. Diclofenac and ibuprofen have significantly less antiplatelet

effects compared with naproxen.22 To have a vascular protective effect,

near-complete inhibition of thromboxane over time is needed30 and the degree

of thromboxane inhibition with diclofenac and ibuprofen may not afford

cardioprotection. Furthermore, diclofenac exhibits more effect on PGI2

inhibition than does naproxen. Van Hecken et al31 demonstrated that

diclofenac causes 94% inhibition of COX-2 compared with 71% inhibition of

COX-2 for naproxen. Thus, diclofenac not only has less antiplatelet effect,

but may have some intrinsic prothrombotic effect among NSAIDs due to

inhibition of vasodilatory PGI2 and this may have masked the increase in

event rates with celecoxib. Furthermore, the MI rate with celecoxib (0.80%)

was similar to that reported with rofecoxib (0.74%) when rates were

recalculated as an annualized percentage rate to enable direct comparison.

Shinmura et al32 recently demonstrated that up-regulation of COX-2 plays an

essential role in the cardioprotection afforded by the late phase of

ischemic preconditioning. Administration of selective COX-2 inhibitors 24

hours after ischemic preconditioning abolished the cardioprotective effect

of late ischemic preconditioning against myocardial stunning and MI.32 These

data would further suggest potential deleterious cardiac effects of COX-2

inhibitors.

The availability of selective COX-2 inhibitors has raised several important

clinical questions. These concern the prothrombotic potential of COX-2

inhibitors, differences in the antithrombotic effect of various NSAIDs, the

mandatory use of aspirin with selective COX-2 inhibitors, and whether

simultaneous use of aspirin negates the gastrointestinal protective effect

of selective COX-2 inhibitors.

Current data would suggest that use of selective COX-2 inhibitors might lead

to increased cardiovascular events. Two smaller studies (Study 085 and Study

090) of rofecoxib that both allowed the use of low-dose aspirin did not

demonstrate the significant increase in cardiovascular event rate noted in

VIGOR. However, these studies had smaller sample sizes, used only 25% of the

dose of rofecoxib used in VIGOR, and had few events for meaningful

comparison. Thus the prothrombotic effect seen with rofecoxib may

potentially be dose dependent. Also, the use of low-dose aspirin in these

protocols may negate some of the gastrointestinal benefits of selective

COX-2 inhibition. There is evidence that gastrointestinal bleeding from

aspirin is not dose related.33

COX-2 inhibitors also have been shown to increase blood pressure,34 and more

patients in the VIGOR trial developed hypertension in the rofecoxib group

compared with the naproxen group. For rofecoxib, the mean increase in

systolic blood pressure in the VIGOR trial was 4.6 mm Hg and the mean

increase in diastolic blood pressure was 1.7 mm Hg, compared with a 1.0-mm

Hg increase in systolic blood pressure and a 0.1-mm Hg increase in diastolic

blood pressure with naproxen. Changes in blood pressure in the CLASS trial

were not reported. Previous work has shown that a 2-mm Hg reduction in

diastolic blood pressure results in about a 40% reduction in the rate of

stroke and a 25% reduction in the rate of MI.35 The Heart Outcomes

Prevention Evaluation study demonstrated significant reduction in

cardiovascular events with a 3- 4-mm Hg reduction in blood pressure.36

Moreover, a recent reanalysis of 20 years of blood pressure data from the

Framingham Heart Study37 suggests that the degree of benefit expected from a

decrease in blood pressure may have been underestimated. Thus, the elevation

in blood pressure reported with use of COX-2 inhibitors may also play an

important role in adverse cardiovascular outcomes.

Based on this review, it is useful to consider nonselective and selective

COX inhibitors as possessing a spectrum of biological effects, both

favorable and unfavorable. At one end of the spectrum, COX-2 inhibitors show

less propensity for gastrointestinal toxicity but greater prothrombotic

potential. At the other end of the spectrum, aspirin and naproxen show

greater potential for gastrointestinal toxicity but have a cardioprotective

effect. Other agents fall along intermediate points in this spectrum.

Clinicians may want to consider these patterns of risk and benefit in

selecting the most appropriate agent for individual patients.

Our analysis has several significant limitations. The increase in

cardiovascular events in these trials was unexpected and evaluation of these

end points was not prespecified. There remains considerable uncertainty in

any post hoc analysis. The patient populations in these trials were

heterogeneous, and it has been established that patients with rheumatoid

arthritis have a higher risk of MI.29 This leads to difficulty in assessing

risk in a more representative sampling of patients. Also, the trials we

examined only addressed continuous use of COX-2 inhibitors. Currently, no

data exist on cardiovascular safety for the sporadic, intermittent use of

these agents by individuals for musculoskeletal pain, which appears to be

the most frequent pattern of use.

Our findings suggest a potential increase in cardiovascular event rates for

the presently available COX-2 inhibitors. It is possible that concomitant

use of aspirin may not fully offset the risk of selective COX-2 inhibitors.

However, definitive evidence of such an adverse effect will require a

prospective randomized clinical trial. On the other hand, the inflammatory

component of atherosclerosis has recently been emphasized7, 38, 39 and may

be suppressible by COX-2 inhibitors. Given the remarkable exposure and

popularity of this new class of medications, we believe that it is mandatory

to conduct a trial specifically assessing cardiovascular risk and benefit of

these agents. Until then, we urge caution in prescribing these agents to

patients at risk for cardiovascular morbidity.

Author/Article Information

Author Affiliations: Department of Cardiovascular Medicine, The Cleveland

Clinic Foundation, Cleveland, Ohio.

 

Corresponding Author and Reprints: J. Topol, MD, Department of

Cardiovascular Medicine, The Cleveland Clinic Foundation, F 25, 9500 Euclid

Ave, Cleveland, OH 44195 (e-mail: topole@...).

Author Contributions: Study concept and design, acquisition of data,

analysis and interpretation of data, and drafting of the manuscript:

Mukherjee, Nissen, Topol.

Critical revision of the manuscript for important intellectual content,

study supervision: Nissen, Topol.

Statistical expertise: Mukherjee, Topol.

Acknowledgment: We gratefully acknowledge the expert editorial assistance of

Donna Bressan, BA.

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