Overview of the Vioxx (Rofecoxib) Cardio-Renal Related Adverse Medical Events

Vioxx Background
Vioxx was approved by the U.S. Food and Drug Administration in May 1999. It is marketed as 12.5 mg, 25 mg and 50 mg tablets and as an oral suspension. It is also available in 73 other countries. Merck estimates that 13 and 24 million patients have been prescribed the drug in the U.S. and worldwide, respectively. U.S. Vioxx sales exceeded $2.5 billion in 2001. Vioxx is classified as a nonsteroidal anti-inflammatory drug (NSAID or NANSAID) with anti-inflammatory, analgesic and antipyretic properties. As such, it is indicated for pain, dysmenorrhea, osteoarthritis and rheumatoid arthritis. The earlier marketed NSAID products (i.e., ibuprofen, naproxen, etc.) are approved for similar indications, but are associated with greater (in frequency and severity) gastrointestinal-related adverse medical events.

Vioxx Overview: The Cyclooxygenase Enzymes
Vioxx belongs to a category of new drugs known as the selective COX (cyclooxygenase) 2 enzyme inhibitors. [The cyclooxygenase enzymes are involved in the metabolic conversion of arachidonic acid to protaglandins, thromboxanes and prostacyclin.] The cyclooxygenase enzymes exist in two forms, Cox-1 and Cox-2. The Cox-1 enzyme form is found in most healthy tissues, platelets, the gastrointestinal tract, heart, etc. The Cox-2 enzyme form is located in areas of inflammation, the kidney and in the vascular endothelium. The Cox-2 enzyme is believed to produce prostaglandins which moderate erythema, swelling and pain in inflamed tissues. The early NSAIDs inhibit both the Cox-1 and Cox-2 enzyme forms. It is their inhibition of the Cox-1 enzyme in the gastrointestinal tract that is responsible for their exacerbation of ulcer formation, gastric irritation, inflammatory disease processes, etc. Like the older NSAIDs, Vioxx will lead to relief from Cox-2 mediated inflammatory signs and symptoms. However, the attendant increase in gastrointestinal-related disorders is not seen with Vioxx.

Vioxx Overview: Disturbances in Blood Clotting Properties
The cyclooxygenase enzyme system mediates the body's normal blood clotting pathways. Specifically, the body produces two chemicals which are critical determinants for the clotting process. These are thromboxane A and prostacyclin. Prostacyclin is formed in the vascular endothelium by the Cox-1 enzyme. Prostacyclin has important properties designed to confer vasoprotective properties by inhibiting the clotting process. These include increasing blood flow to injured tissues, decreasing cholesterol accumulation in vessels, reducing leukocyte adherence and inhibiting platelet aggregation. Thromboxane is produced by Cox-1 activity in the platelets and is responsible for vessel constriction, platelet aggregation and platelet adhesivity. These events precipitate clot (thrombus) formations. In the physiologic setting, thromboxane and prostaglandin function in tandem to effect and maintain normal blood clotting activities. However, normal blood clotting activities may be disturbed by a variety of factors. These include trauma, diseases, drugs, injury, surgery, etc. As examples of disease-related disturbances, individuals with congestive heart failure and atherosclerotic vascular disease are particularly prone to a thrombic state in which there is an increased propensity for clot formation. Drugs influencing the normal clotting activities include both nonselective and selective COX inhibitors. Patients receiving the selective Cox-2 inhibitors will experience a decreased formation of prostacyclin rendering them more prone to thrombus formation secondary to unopposed thromboxane activity. The nonselective Cox inhibitors are associated with decreases in both thromboixane and prostacyclin. The reductions in thromboxane are significant (95%), leading to 88% reductions in platelet aggregation.

Vioxx Overview: Renal Toxicities
NSAID therapy can precipitate changes in renal function, particularly with respect to solute homeostasis and maintenance of renal perfusion. Perturbation in these events significantly increases cardiorenal related adverse medical events. Sodium retention has been reported in up to one quarter of all NSAID users. Decreased sodium excretion leads to weight gain, peripheral edema and elevated blood pressures. Renal prostaglandins have been shown to maintain renal perfusion. NSAID use is associated with a dose-dependent reduction in prostaglandin formation leading to reductions in renal blood flow, renal decompensation and renal failure. Deleterious changes in renal function are observed more frequently in patients with concurrent diseases and medications. Patients receiving Vioxx tablets have experienced multiple events associated with its direct renal toxicities. These include weight gain, edema, congestive heart failure increased systololic blood pressure, increased diastolic blood pressure and renal failure.

Vioxx Overview: Implications for Patient Groups
The selective Cox-2 inhibitors are associated with actions known to precipitate cardiorenal-related adverse medical events including myocardial infarction, stroke, pulmonary emboli,hypertension, congestive heart failure and renal failure. Their actions include a reduction in the effective prostacyclin antagonism of thromboxane activity leading to the creation of prothrombotic states and blood clot formation. Another action is a direct effect on renal function leading to edema, weight gain and increased blood pressure. Unfortunately, the patient populations indicated for Cox-2 inhibitors are the very ones most vulnerable to these cardiorenal actions and at most risk for myocardial infarction, stroke, kidney failure and other life threatening events. Older patients are afflicted with rheumatoid arthritis and osteoarthritis and are therefore, the most likely candidates for Vioxx. Many of these patients are also taking other medications, especially for age-related cardiovascular condition, including hypertension, congestive heart failure, angina, ischemic heart disease, reduced renal function, etc. The pharmacologic consequences of Cox-2
inhibition create an environment of increased risk for these older patients who are already predisposed to cardiac events and requiring polypharmacy. Patients with hypertension, congestive heart failure or compromised renal function experience decreased renal perfusion, edema and increased blood pressures when Cox-2 inhibitors are added to their armamentatium. The C0x-2-related risks are also magnified in those patients with underlying inflammatory disorders, including coronary artery disease, because they are even more predisposed to thrombosis resulting in myocardial infarctions, strokes and pulmonary emboli.

Vioxx Overview: The V.I.G.O.R. Study
Merck conducted a prospective, randomized, double blind, positive-control, comparison of rofecoxib with naproxen in 8000 patients with rheumatoid arthritis, using 301 testing centers in 22 countries. Following stratification for gastrointestinal-related disorders patients were randomized to one of the two medications for 12 months (median follow up was 9 months). Patients were assessed at 6 weeks, four months and thereafter at four-month intervals for safety and efficacy assessments.The two agents were associated with similar efficacy. Rofecoxib was associated with significantly fewer upper gastrointestinal events. This was not unexpected since only the Cox-1 enzyme is involved with maintenance of the gastrointestinal mucosa. It appears that the Vioxx induced inhibition of the vasodilatory and antiaggregatory properties of prostacyclin (through its decreased production) may have led to amplified prothrombotic activity. There were significant differences between the rofecoxib and naproxen treated patients in thrombotic-related cardiovascular events including sudden death, myocardial infarction, unstable angina stroke and venous and arterial thromboses. Based on these data, FDA required Merck to effect the labeling changes noted in Section 2.

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