Drug Crieteria & Outcomes: Cardiovascular risk assessment: COX-2
By Calah Davis Merritt, PharmD
Written as a PharmD candidate at McWhorter School of Pharmacy, Samford University, Birmingham, AL
Introduction
Traditional nonsteroidal anti-inflammatory drugs (NSAIDS) act by blocking both of the cyclooxygenase enzyme isoforms, COX-1 and COX-2. Research has revealed that the therapeutic benefits result secondary to inhibition of COX-2, the isoform believed to be involved in mediation of the inflammatory process.
Conversely, adverse gastrointestinal effects and the changes in platelet aggregation are a result of the COX-1 blockade. Like traditional agents, the newer COX-2 specific antagonists are effective anti-inflammatory agents. At recommended doses, however, they are more selective for COX-2 and therefore have considerably less adverse gastrointestinal effects. Although specific COX-2 inhibitors may be better tolerated overall, it is important to remember that these drugs are not benign. Recent research has suggested that the trade-off for gastrointestinal protection may be an increased risk of adverse cardiovascular events.
Mechanism of cardiovascular risk
The proposed mechanism for increased cardiovascular risk associated with COX-2 selective inhibitors involves a proposed imbalance of prothrombotic and antithrombotic eicosanoids. COX-2 inhibitors decrease the production of PGI2, a vascular prostacyclin that promotes vasodilation and decreases platelet aggregation. Traditional NSAIDs have the same effect on PGI2; however, they also inhibit COX-1. This inhibition leads to a decrease in the production of thromboxane A2, a potent platelet aggregator. This will decrease platelet aggregation and maintain a healthy balance that does not promote thrombotic events. COX-2 inhibitors do not share this protective platelet inhibition property.
The result is an increase in prothrombotic factors without a subsequent increase in antithrombotic factors. It is proposed that this may tip the natural balance in favor of prothrombotic eicosanoids such as thromboxane A2, which may increase a patient’s risk for thrombotic events.
Where is the evidence?
There is little evidence to support the theory that selective COX-2 inhibitors actually increase the occurrence of cardiovascular thrombotic events. The primary piece of literature that implicates this class of drugs is a retrospective analysis published in the August 2001 edition of the Journal of the American Medical Association (JAMA). In this article, researchers retrospectively reviewed four clinical trials involving the two major COX-2 inhibitors, celecoxib and rofecoxib. It is important to note that when the trials were originally conducted, the endpoints were related to gastrointestinal safety, not relative cardiovascular risk.
Researchers analyzed the data presented in these trials to determine the following:
- Relative risk of cardiovascular events between the COX-2 inhibitor and traditional NSAID;
- Cardiovascular event rates (as percentages) among different NSAIDs; and
- Frequency of myocardial infarctions across trials.
Upon completion of the retrospective review, study analysts made the following conclusions:
VIGOR
Study description
- The double-blind, randomized, stratified, parallel group trial of 8,076 patients compared rofecoxib 50 mg/d to naproxen 1,000 mg/d.
- Only rheumatoid arthritis patients were allowed to participate.
- Low-dose aspirin was not allowed during the study, even when indicated.
Cardiovascular findings in retrospective review
- The relative risk of developing a cardiovascular event in the rofecoxib group vs. naproxen group was 2.38 (P < 0.001).
- The risk of serious cardiovascular events in the rofecoxib group was 2.2 times higher (95% confidence interval 1.62-3.21; P < 0.001) than in the naproxen group.
- One hundred and eleven patients in the rofecoxib group experienced serious cardiovascular events (i.e., myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attack). Fifty patients in the naproxen group experienced serious cardiovascular events.
CLASS
Study description
- The 8,053 patients in this randomized, double-blind, controlled trial received either celexocib 400 mg bid, ibuprofen 800 mg tid, or diclofenac 75 mg bid.
- Aspirin use was permitted in the study.
- Patients with osteoarthritis and rheumatoid arthritis were included in the study.
Cardiovascular findings in retrospective review
- There was no significant difference in the rates of cardiovascular events when celecoxib was compared to the traditional NSAIDS, ibuprofen and diclofenac.
Studies 085 and 090
- In study 085, there were three adverse cardiovascular events: one event in the rofecoxib groups (0.2%), two events in the nabumetone group (0.4%), and no events in the placebo group.
- In study 090, there were nine serious cardiovascular events: six in the rofecoxib group (1.5%), two in the nabumetone group (0.5%), and one in the placebo group (0.5%).
The authors of this analysis concluded that there was a potential increase in cardiovascular event rates for the presently available COX-2 inhibitors. It also was suggested that the risk might be higher with the use of rofecoxib as compared to celecoxib. The final recommendation was for additional studies to be conducted and for prescribers to use caution when using these agents in patients at high risk for cardiovascular morbidity.
Limitations/caution
There are several limitations to drawing these conclusions based on a retrospective review of this type of information. First, it is important to note that cardiovascular events were not assessed as endpoints in the original trials. This is significant in that a retrospective analysis has no defined controls. Researchers do not know the comorbid conditions that were specific to each patient.
Another limitation is that each trial compared rofecoxib and celecoxib to different traditional NSAIDs. The VIGOR trial showed rofecoxib patients to have an increased risk of cardiovascular (CV) events when compared to naproxen while the CLASS trial did not show a difference between celecoxib, nabumetone, and diclofenac. It is important to remember that naproxen has platelet inhibition properties similar to those of aspirin (93%), whereas ibuprofen and diclofenac have fewer effects (80% and 40%, respectively). One would expect naproxen to provide better protection against cardiovascular events than rofecoxib, ibuprofen, or diclofenac. In addition, the VIGOR trial did not allow the use of daily low-dose aspirin, even when indicated. The CLASS trial, however, did allow patients to continue aspirin therapy. This fact alone may partially explain why celecoxib appeared less likely than rofecoxib to cause adverse cardiovascular events.
The reporting of results also was a limitation to the use of these data. Adverse events were reported as relative risks and raw data numbers rather than as percentages. Additionally, P values were not disclosed for a number of the data sets. This makes it difficult to determine the actual clinical significance of the adverse events and ultimately limits the impact of the author’s conclusions.
The Whelton et al trial was conducted on a select group of hypertensive patients with concurrent osteoarthritis. A comparison was made between the adverse cardiorenal effects of celecoxib and rofecoxib. This trial is not particularly helpful in determining the relative risk of cardiothrombotic events because it looks primarily at the adverse renal effects of the COX-2 inhibitors. However, it does evaluate the risk of increased systolic and diastolic blood pressures, which may be helpful in determining a difference between the two drugs.
The study included 811 patients age 65 years or older, randomly assigned to either the rofecoxib 25 mg QD or celecoxib 200 mg QD study group. The doses of each medication are considered to be similar with pain control outcomes. Demographics and baseline patient characteristics were consistent between groups. Patients included were on at least one antihypertensive medication and remained on it throughout the study.
Results from the study revealed the following:
- Sixty-six rofecoxib patients vs. 45 celecoxib patients had a systolic blood pressure increase of > 20 mmHg (absolute value > 140); and
- Nine rofecoxib patients vs. six celecoxib patients had a diastolic blood pressure increase of > 15 mmHg (absolute value > 90).
Researchers concluded that rofecoxib was more likely to be associated with an increase in blood pressure than was celecoxib. There are several limitations to this study that bring into question this absolute conclusion. First, the dose of rofecoxib used in the study (25 mg QD) is twice the recommended dose for elderly hypertensive patients. The difference in blood pressure elevations may not be significant with the appropriate dose of rofecoxib. Additionally, the study did not examine the cardiorenal effects of these medications in patients without hypertension. The mechanisms of action for celecoxib and rofecoxib are similar and would suggest that their effects on the cardiovascular and renal systems also would be similar. The differences proposed in this study may be due to the higher dose of rofecoxib (25 mg vs. recommended 12.5 mg) coupled with the lower dose of celecoxib (200 QD vs. recommended bid dosing) and may not be clinically significant if adjusted.
Conclusion
There is a rational hypothesis for how selective COX-2 inhibitors have the potential to increase the risk of adverse cardiovascular events. The mechanism of action resulting in selective prostaglandin inhibition may well allow prothrombotic molecules to dominate. However, data must back up such a theory. Prospective research with adequate controls is needed to determine how much of a risk actually exists. Additionally, if any comparison between the relative risk of celecoxib and rofecoxib is to be made, a more reliable direct comparison trial must be completed. The current research, discussed in this report, is not reliable enough to support a clinical decision. Based on the available data, a clear decision cannot be made on the difference in risk of adverse cardiovascular events between celecoxib and rofecoxib.
Resources
1. Boers M. NSAIDS and selective COX-2 inhibitors: Competition between gastroprotection and cardioprotection. Lancet 2001; 357:1222-1223.
2. Emery P. Cyclooxygenase-2: A major therapeutic advance? Am J Med 2001;110:42S-45S.
3. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345:433-440.
4. Mukherjee D, et al. Risk of cardiovascular event associated with selective COX-2 inhibitors. JAMA 2001;286:954-958.
5. Perazella MA, Tray K. Selective cyclooxygenase inhibitors: A pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs. Am J Med 2001; 111:64-67.
6. Rofecoxib. McEvoy GK, ed. AHFS: Drug information. Bethesda, MD: American Society of Health-System Pharmacists; 2000:1983.
7. Villalba ML, et al. FDA Advisory Committee Briefing Document. NDA 21-042, s007: VIOXX Gastrointestinal Safety. 2001 Feb 8. Available at: www.fda.gov.
8. Whelton A, et al, for the SUCCESS VI Study group. Cyclooxygenase-2-specific inhibitors and cardiorenal function: A randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther 2001; 8:86-95.
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