Louis L. Battey, MD, SACC, Cardiology of Georgia, Atlanta, Georgia

Osteoarthritis (OA) and cardiovascular disease are very common medical problems in the United States, especially among the elderly. Patients with hypertension, congestive heart failure, coronary artery disease, and cerebrovascular disease are often taking medications for both OA and cardiovascular disease. Therefore, drug interactions and the resultant effects on comorbid conditions are very important in terms of patient safety. Cost and efficacy remain key issues as well.

Drug therapy for OA is indicated for symptoms. The foundation of drug therapy for OA is acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). As emphasized in the following report, the American Academy of Rheumatology has recommended acetaminophen as the drug of first choice in OA treatment. NSAIDs are considered for those patients who do not obtain adequate symptomatic relief. The potential gastrointestinal (GI) and renal side effects of NSAIDs are well known and limit their safety and efficacy in many patients.

Recently, a new class of NSAIDs was developed whose anti-inflammatory properties are thought to be due to inhibition of prostaglandin synthesis via inhibition of cyclooxygenase-2 (COX-2). The COX-2 inhibitors are touted as having a significantly lower incidence of GI side effects compared with more traditional NSAIDs while demonstrating comparable efficacy in the treatment of OA. The US Food and Drug Administration (FDA) has approved two COX-2 inhibitors for the treatment of OA: celecoxib (Celebrex, Pharmacia/Pfizer) and rofecoxib (Vioxx, Merck).

A number of recent reports have described a worrisome possible association between the use of COX-2 inhibitors and the occurrence of adverse cardiovascular events. These adverse cardiovascular events include acute myocardial infarction, congestive heart failure, pulmonary embolus, deep venous thrombosis, and cerebrovascular accidents. Although no definite causal relationship between the use of COX-2 inhibitors and adverse cardiovascular events has clearly been established, the FDA has decided to reexamine the safety data of the COX-2 inhibitors.

The following report traces the evolution of the concerns about the association of adverse cardiovascular events and the use of COX-2 inhibitors and presents the data on which these concerns rest. The report also discusses potentially adverse interactions between COX-2 inhibitors and commonly used cardiovascular drugs such as angiotensin-converting enzyme (ACE) inhibitors, diuretics, and warfarin. A thorough bibliography may be found at the end of the report.

When new drugs appear with great fanfare, it is easy for physicians and patients to forget that older, less expensive medications may offer advantages in terms of cost, efficacy, and toxicity. The COX-2 inhibitors represent an advance in the treatment of OA, especially in patients who do not respond to first-line therapy. However, while we await further scientific information regarding the possible association between COX-2 inhibitors and adverse cardiovascular events, these agents should be used cautiously in patients with significant cardiovascular disease.

Osteoarthritis

Osteoarthritis is the most common form of arthritis in the United States and the second most common cause of long-term disability,1-4 affecting an estimated 20.7 million adults. Radiographic evidence of OA is present in the majority of people by 65 years of age and in about 80% of those older than 75 years.5 As the elderly population in the United States grows, osteoarthritis is an increasingly important medical and financial concern. The goals of the contemporary management of the patient with OA, as advocated by the American College of Rheumatology (ACR),6 include control of pain and improvement in function and health-related quality of life. However, the toxic effects of therapy should be avoided through the use of nonpharmacologic modalities and drug therapy. Recent revelations in the mainstream media7,8 concerning adverse cardiovascular events associated with a therapeutic class of drug (COX-2 inhibitors) used in the management of osteoarthritis have provided an impetus for the medical community to reexamine the pharmacologic treatment of OA, particularly as it relates to the cardiac patient.

Pharmacologic Treatment of Osteoarthritis

Because OA patients are generally elderly and often have comorbid conditions (e.g., cardiac disease, hypertension, peptic ulcer disease, renal disease), it is essential to use the safest possible treatments. Pain is the main symptom that limits function and quality of life for OA patients. The ACR guidelines6 emphasize that acetaminophen (Tylenol, McNeil Consumer Health; generic form available) is the drug of first choice in OA based on its overall cost, efficacy, and toxicity profile.9,10 For those patients who fail to obtain adequate symptomatic relief with acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) may be considered. There are many NSAIDs to choose from, and no evidence indicates that one is more effective than another in OA.11 The choice should be made after clinical evaluation of risk factors for serious GI and renal toxicity. Long-term studies have shown that 10% to 30% of patients receiving NSAIDs have ulcers and 30% to 50% have erosions or histological evidence of gastritis.12 Interestingly, the ACR provides no specific guidelines for the prevention and treatment of active ulcer disease and its complications in patients with OA who are taking NSAIDs.2

The need for safer medications in OA, as well as advances in the understanding of prostaglandin synthesis as it relates to metabolic effects, led to the development of the selective COX-2 inhibitors. They were specifically designed to exploit chemical differences between the COX-2 and COX-1 isoforms (COX-1 is associated with nonselective inhibition by NSAIDs). It was hoped that the selective inhibition of COX-2 would lead to reductions in the adverse GI and bleeding side effects compared with the traditional, nonselective NSAIDs. The warnings and contraindications for COX-2 inhibitors are similar to those for the older NSAIDs, however.13,14 Two COX-2 inhibitors have been approved by the FDA for use in OA: celecoxib (Celebrex, Pharmacia/Pfizer) and rofecoxib (Vioxx, Merck).

The initial promise of COX-2 inhibitors remains strong, but emerging adverse cardiovascular events are raising safety concerns. A recent clinical study revealed a 4-fold increase in the incidence of myocardial infarction (MI) associated with rofecoxib (0.1% vs. 0.4%; relative risk [RR], 0.2; 95% confidence interval [CI], 0.1-0.7) compared with naproxen sodium (an NSAID).15 The FDA is reexamining these and other cardiovascular adverse events associated with the use of COX-2 inhibitors. The purpose of this report is to educate the clinician about the cardiovascular implications of pharmacologic therapy for OA.

Cardiovascular Implications

In September 2000, the U.K.'s Medicines Control Agency (MCA) and the Committee on Safety of Medicines (CSM) reported the deaths of 11 patients who had been taking rofecoxib.16 Five patients died after GI reactions, three after cardiac failure, and three after MI. In fact, the CSM had discussed rofecoxib and thromboembolic events documented in the Vioxx Gastrointestinal Outcomes Research (VIGOR) Study in a meeting on July 12, 2000. In its September publication, MCA/CSM cited a total of 177 reports of suspected cardiovascular reactions to rofecoxib. The majority of these reports were of edema (101, 57%), hypertension (31, 17.5%), and palpitations (19, 10.7%). There were 15 reports of cardiac failure (8.47%) or "cardiac failure aggravated," three of which (1.69%) had a fatal outcome. There were also nine reports of MI (5.08%), of which three (1.69%) were fatal. In most cases, the patient had risk factors for cardiovascular disease. The publication went on to remind prescribers that rofecoxib was contraindicated in patients with severe congestive heart failure,17 a contraindication absent in the US (FDA-approved) labeling text.14

The findings of the VIGOR Study did not escape the attention of the FDA. In a memorandum dated February 1, 2001,18 it was recommended that the celecoxib data be examined to evaluate evidence of a class effect of cardiovascular adverse events. A division of the FDA (Division of Drug Risk Evaluation I, HFD-430) had conducted such an evaluation,8 which revealed 223 US cases of thrombotic or embolic events possibly associated with rofecoxib (n = 99) and celecoxib (n = 102). Of the 99 cases possibly associated with rofecoxib, 26 were MI, 19 pulmonary embolism (PE) or deep venous thrombosis (DVT), 43 cerebrovascular events, and 14 miscellaneous thrombotic vascular events. Seven of the 26 patients who experienced an MI did not have apparent precipitating factors or cardiovascular risk factors. Of the 102 cases possibly associated with celecoxib, 37 were MI, 27 PE or DVT, 31 cerebrovascular events, and 10 miscellaneous thrombotic vascular events. Six of the 37 patients who experienced an MI did not appear to have precipitating factors or cardiovascular risk factors for MI.

These results may speak to the role of appropriate patient selection for COX-2 pharmacologic therapy, as suggested by the FDA's conclusion: "Although certain thrombotic events such as [cardiovascular accident], MI, PE, venous thrombosis, and [transient ischemic attack] are mentioned in the product labeling, the continued existence of thrombotic events in high-risk population in post-marketing phase is an important finding." Perhaps even more disconcerting is the FDA's admonishment that "the actual number of thrombotic adverse events may in fact be higher due to the underreporting of adverse events in passive surveillance systems."18

Conversely, non-NSAID analgesics (such as acetaminophen) have essentially no renal or related cardiovascular side effects at recommended dosing schedules.19 Moreover, the Scientific Advisory Committee of the National Kidney Foundation recommends acetaminophen as the drug of choice for analgesia in patients with impaired renal function.20

Drug Interactions Complicating Cardiovascular Conditions

The two most prevalent comorbidities among OA patients are hypertension and congestive heart failure (CHF). CHF is the most frequent cause of hospitalizations in the elderly and is responsible for 5% to 10% of all hospital admissions.21 Heart failure causes or contributes to approximately 250,000 deaths every year.22 Coronary heart disease is the major cause of death in the elderly, and hypertension is considered a major risk factor for coronary heart disease. Clearly, the pharmacologic treatment associated with these conditions is critical. Any interference or attenuation of the pharmacologic drug effect would result in less-than-optimal clinical response. As such, the clinician must be acutely aware of possible drug interactions in the OA patient.

Angiotensin-converting enzyme inhibitors and diuretics are two classes of drug used in the treatment of congestive heart failure and hypertension. Traditional NSAIDs and COX-2 inhibitors may diminish the antihypertensive effect of ACE inhibitors, according to the "precautions" sections of their package inserts. Moreover, in patients with mild to moderate hypertension, administration of rofecoxib 25 mg/day with the ACE inhibitor benazepril 10-40 mg for 4 weeks was associated with an average increase in mean arterial pressure of about 3 mmHg compared with the ACE inhibitor alone.14 Not only can COX-2 inhibitors attenuate ACE inhibitor antihypertensive effects, they are also capable of inducing elevations in blood pressure by themselves. In studies presented at the 2001 Congress of the European League Against Rheumatism (EULAR),23 the percentages of patients with predefined changes in systolic blood pressure (SBP) (increase >20 mmHg and SBP >140 mmHg) and diastolic blood pressure (DBP) (increase >15 mmHg and DBP >90 mmHg) were 9.6% and 2.8% for rofecoxib and 9.4% and 2.0% for celecoxib, respectively. Similar increases in baseline blood pressure were seen by Schwartz et al. (rofecoxib, SBP +3.4 mmHg and DBP +0.3 mmHg; celecoxib, SBP +4.3 mmHg and DBP + 0.8 mmHg).24

NSAIDs and COX-2 inhibitors have the potential to interfere with diuretic therapy. Clinical studies and postmarketing observations have demonstrated that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis.13,14 The package insert for ibuprofen (Motrin, Pharmacia; generic form available) contains a similar warning.25 Overviews of clinical trial data indicate that elevations in blood pressure associated with concomitant use of NSAIDs can produce a significant increase in subsequent incidence of stroke, end-stage renal disease, or congestive heart failure.26 Furthermore, the clinician should consider alternative analgesics, such as acetaminophen, that do not affect prostaglandin synthesis.26,27 Additionally, ACE inhibitor pharmacokinetics have been shown to be unaffected by concurrent acetaminophen administration.28

Clinicians will often prescribe prophylactic low-dose aspirin or warfarin to patients who have experienced MIs. The concomitant use of NSAIDs or COX-2 inhibitors with low-dose aspirin continues to be researched. Low-dose aspirin may be used concurrently with COX-2 inhibitors, which have no antiplatelet effect. However, the GI safety advantages of the COX-2 inhibitors are significantly diminished by use of low-dose aspirin,29 and the combination potentially increases the risk of GI bleeding.13,14 Rofecoxib and celecoxib have been shown to cause a slight elevation of prothrombin time (8%-11% with rofecoxib14) in patients who are taking warfarin. Thus, the international normalized ratio (INR) should be carefully monitored during concomitant use. Although both have been found to cause fewer GI ulcers than traditional NSAIDs,30 the combination of COX-2 inhibitors with warfarin requires judicious monitoring by the clinician because of the incidence of GI perforations, ulcerations, and bleeding. Acetaminophen does not significantly alter warfarin disposition as assessed by prothrombin time31 and should be the analgesic and antipyretic of choice in patients taking warfarin.32

Conclusions

Clinicians must consider the cardiovascular implications of pharmacologic therapy for OA patients. The American College of Rheumatology guidelines6 emphasize that acetaminophen is the drug of first choice in OA because of its efficacy, safety, cost, and availability.33 Acetaminophen may be routinely used in patients with congestive heart failure, hypertension, anticoagulant therapy, and a history of GI-tract complications. For those patients not responding to acetaminophen, progression to NSAIDs and COX-2 inhibitors may be considered. However, the clinician must remain ever vigilant to GI bleeding complications, drug interactions, and increasing evidence of adverse cardiovascular events associated with pharmacologic therapy with NSAIDs, particularly the COX-2 inhibitors.

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