This report was reviewed for medical and scientific accuracy by Ronald S. Freudenberger, MD, Director, Heart Failure and Transplant Cardiology, Associate Professor of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

According to the results of studies presented at the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 67th Annual Scientific Meeting in Orlando, Florida, the use of a cyclooxygenase (COX)-2 selective inhibitor in elderly patients (≥65 years of age) results in an increased risk of cardiovascular complications. In an observational study of 54,475 Medicare beneficiaries,¹ the use of rofecoxib (Vioxx) was associated with an increased adjusted relative risk of acute myocardial infarction compared with celecoxib (Celebrex) and with no nonsteroidal anti-inflammatory drug (NSAID) use. Dosages of rofecoxib greater than 25 mg were associated with the highest risk. Utilizing a subset of the same patient database, investigators assessed the relative risk of new-onset hypertension in 17,844 patients who had used rofecoxib or celecoxib compared to patients taking either the other COX-2 selective inhibitor, a nonselective NSAID, or no NSAID.² Patients who had taken rofecoxib were at a significantly increased relative risk for new-onset hypertension compared with patients taking celecoxib, taking a nonselective NSAID, or taking no NSAID. In patients with a history of chronic renal disease, liver disease, or congestive heart failure, the relative risk of new-onset hypertension associated with rofecoxib use was twice as high as compared with celecoxib.

Perspective
An association between COX-2 selective inhibitor and cardiovascular complications was first suggested in the Vioxx Gastrointestinal Outcomes Research (VIGOR) Study.³ The results of 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 (CI), 1.39-4.00; P<.001).⁴ The concern for cardiovascular complications is not limited to rofecoxib. The annualized myocardial infarction rates for both the VIGOR³ and the Celecoxib Long-term Arthritis Safety Study (CLASS) trial⁵ were significantly higher (0.74% with rofecoxib, P = .04; 0.80% with celecoxib, P = .02) compared with the annualized myocardial infarction rate for placebo-treated patients (0.52%) in a recent meta-analysis of 4 primary prevention aspirin trials.⁶

Rofecoxib and celecoxib have been known to increase systolic blood pressure,^7,8 and exacerbate existing hypertension.^9,10 In one study, systolic blood pressure increased significantly in 17% of rofecoxib-treated patients compared with 11% of celecoxib-treated patients (P = .032).⁷ Moreover, nearly twice as many rofecoxib-treated patients compared with celecoxib-treated patients experienced edema (9.5% vs 4.9%, respectively; P = .014). Although in some cases, the average increases in systolic blood pressure may be considered small (a few mm Hg), evidence indicates that mean increases of systolic blood pressure of 1 to 5 mm Hg are associated with 7,100 to 35,700 additional ischemic heart disease and stroke events over one year, with corresponding medical and economic costs of $114 to $569 million.¹¹

Respectively, clinically important differences between rofecoxib and celecoxib are related to oral bioavailability (92-93% vs 22-40%), half-life (10-17 hours vs 11), extent of plasma protein binding (86% vs >97%), and main pathways of hepatic metabolism (cytosolic reduction vs oxidation by cytochrome P-450).¹² Perhaps, the different pharmacologic profiles of rofecoxib and celecoxib may explain the observed differences from these data with respect to their adverse event profiles.

For those patients with cardiovascular comorbidities that require the use of an analgesic, acetaminophen (Tylenol®) may be the preferred treatment option on the basis of its long-established efficacy and safety profile.¹³ Unlike nonselective NSAIDs and COX-2 selective inhibitors, the pharmacology of acetaminophen offers no suggestion for increased risks of cardiovascular complications.

Acute Myocardial Infarction and COX-2 Selective Inhibitor Use

Looking to examine the relative risk of acute myocardial infarction of rofecoxib and celecoxib, investigators conducted a matched case-control study of 54,475 Medicare patients (≥65 years of age) to identify hospitalizations for acute myocardial infarction.¹ Medical records of a subset of identified hospitalizations due to acute myocardial infarction were reviewed. Conditional logistic regression models with indicators for patient demographics, health care utilization, medication use, and cardiovascular risk factors were constructed to assess the relative risk of acute myocardial infarction in individuals who took rofecoxib compared with individuals taking celecoxib, a nonselective NSAID, or no NSAID.

The current use of rofecoxib was associated with an increased adjusted relative risk of acute myocardial infarction compared with celecoxib (odds ratio (OR) 1.24, 95% CI, 1.05-1.46) and with no NSAID (OR 1.14, 95% CI, 1.00-1.31) (Table 1).

The adjusted relative risk of acute myocardial infarction was higher in dose-specific comparisons. The OR for doses of rofecoxib >25 mg was 1.70 when compared to >200mg of celecoxib (95% CI, 1.07-2.71). In contrast, the OR for doses of rofecoxib ≤25 mg was 1.21 when compared to <200 mg of celecoxib (95% CI, 1.01-1.44). A similar trend was observed when rofecoxib was compared to no NSAID treatment. For doses of rofecoxib >25 mg, the OR was 1.58 (95% CI, 1.04-2.40) and for doses ≤25 mg, the OR was 1.11 (95% CI, 0.96-1.28) when compared to no NSAID treatment.

In an analysis of new users of COX-2 specific inhibitors, the adjusted relative risk of acute myocardial infarction associated with use of rofecoxib compared to celecoxib for Days 1 to 30 (OR 1.39, 95% CI, 1.10-1.74) and Days 31 to 90 (OR 1.37, 95% CI, 1.09-1.71) were higher than >90 days (OR 0.96, 95% CI, 0.73-1.26). This elevation in risk was observed with both dosage levels of rofecoxib.

Investigators concluded that current use of rofecoxib was associated with an increased adjusted relative risk of acute myocardial infarction compared with celecoxib use and no NSAID treatment. Dosages >25 mg of rofecoxib were associated with the highest risk and the risk may be highest during the first 90 days of use.

Assessment of Confounding Bias
In assessing the potential association of COX-2 selective inhibitors and the incidence of acute myocardial infarction, the same group sought to assess the impact of confounding bias by factors not measured in the Medicare patient database.¹⁴ For 8,785 community-dwelling patients (≥65 years of age), the prevalence of COX-2 selective inhibitor exposure was estimated in addition to a set of 5 potential confounders (body-mass index, over-the-counter aspirin use, smoking, income status, educational attainment), as well as the association between drug exposure and confounders. Estimates of the confounder-disease associations were derived from the medical literature to calculate the extent of residual confounding bias for each of the 5 potential confounders.

Results of the study indicated there was no difference in the prevalence of obesity between COX-2 selective inhibitors users and nonselective NSAID users (23.6% vs 24.2%; P =.45), while COX-2 selective inhibitor users were less likely to be smokers (8.1% vs 9.8%; P<.005) and have income above $20,000 (52.4% vs 43.9%; P = .0001) than NSAID users. The prevalence of aspirin use was the same among all patients using COX-2 selective inhibitors and nonselective NSAIDs (P = .56). Estimates indicated that failure to adjust for the 5 potential confounders would lead to a small underestimation of the underlying relative risk. Comparing patients taking rofecoxib to patients taking naproxen, investigators calculated a net bias of -3.2% of the true effect size (maximum range -9% to 0%) explaining some, but not all of the differences in relative risks between observational studies and the VIGOR trial.

Investigators concluded that uncontrolled confounding by body-mass index, over-the-counter aspirin use, smoking, income status, and educational attainment was unlikely to cause important bias in assessing the association between patients taking COX-2 selective inhibitors or NSAIDs and acute myocardial infarction in the elderly.

Hypertension and COX-2 Selective Inhibitor Use

Utilizing a subset of the same patient database, the same group conducted a retrospective, case-control study of 17,844 patients (≥65 years of age) to examine the risk of developing new-onset hypertension taking COX-2 selective inhibitors.² Multivariable logistic models were constructed to assess the relative risk of new-onset hypertension in patients who used celecoxib or rofecoxib compared to patients taking either the other COX-2 selective inhibitor, a nonselective NSAID, or no NSAID. In patients taking celecoxib and rofecoxib, patient characteristics were similar with respect to age, gender, race, and comorbidities. However, patients taking rofecoxib were more likely to have had a history of coronary artery disease than those patients taking celecoxib (11% vs 6%).

The use of rofecoxib was associated with a significantly increased relative risk of new-onset hypertension compared with patients taking celecoxib (OR 1.6, 95% CI, 1.2-2.1), taking a nonselective NSAID (OR 1.4, 95% CI, 1.1-1.9), or taking no NSAID (OR 1.6, 95% CI, 1.3-2.0). There were no clear dosage or duration effects. In patients with a history of chronic renal disease, liver disease, or congestive heart failure, the relative risk of new-onset hypertension was twice as high in those taking rofecoxib compared with celecoxib (OR 2.1, 95% CI, 1.0-4.3).

In this retrospective case-control study, investigators concluded that the use of rofecoxib was associated with an increased relative risk of new-onset hypertension; whereas the use of celecoxib was not.

Conclusion

New data demonstrate that the use of rofecoxib may be associated with an increased relative risk of acute myocardial infarction and new-onset hypertension in elderly patients. Moreover, since both rofecoxib and celecoxib have been shown to be associated with an increased risk of myocardial infarction and exacerbation of hypertension, it is important for clinicians to be vigilant for these complications when initiating COX-2 selective inhibitor therapy. In cardiovascular patients requiring analgesic therapy, the use of an alternative agent such as acetaminophen, may be considered.

References

1. Solomon DH, Schneeweiss S, Glynn RJ, et al. The relationship between selective COX-2 inhibitors and acute myocardial infarction. American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 67th Annual Scientific Meeting, October 23-28, 2003, Orlando, Florida. Presentation Number 1823.
2. Solomon DH, Schneeweiss S, Levin R, Avorn J. The relationship between COX-2 specific inhibitors and hypertension. American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 67th Annual Scientific Meeting, October 23-28, 2003, Orlando, Florida. Presentation Number 65.
3. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:1520-1528.
4. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-959.
5. Silverstein FE, Faich G, Goldstein JL, et al for the Celecoxib Long-term Arthritis Safety Study. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA. 2000;284:1247-1255.
6. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomized trials. Heart. 2001;85:265-271.
7. Whelton A, Fort JG, Puma JA, Normandin D, Bello AE, Verburg KM; 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;8:85-95.
8. Whelton A, White WB, Bello AE, Puma JA, Fort JG; SUCCESS-VII Investigators. Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol. 2002;90:959-963.
9. Vioxx prescribing information [package insert]. Merck & Co. Inc. Available at http://www.vioxx.com. Accessed November 5, 2003.
10. Celebrex prescribing information [package insert]. Pfizer Inc. Available at http://www.celebrex.com. Accessed November 5, 2003.
11. Singh G, Miller JD, Huse DM, Pettit D, D'Agostino RB, Russell MW. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol. 2003; 30:714-719.
12. Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:433-442.
13. Prescott LF. Paracetamol: past, present, and future. Am J Ther. 2000;7:143-147.
14. Schneeweiss S, Tsai EH, Glynn RJ, Avorn J, Solomon DH. Selective COX-2 inhibitor use and myocardial infarction: assessment of potential confounding bias. American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) 67th Annual Scientific Meeting, October 23-28, 2003, Orlando, Florida. Presentation Number 980.

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Disclosure

Ronald S. Freudenberger, MD
No significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Cardiology Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Cardiology Express Report™ was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

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