Linking COX-2 Inhibitors and Cardiovascular Event Risk

Pharmacology Watch

A new, and as of yet unpublished study, has raised increased concern about the relationship between rofecoxib (Vioxx), Merck’s blockbuster COX-2 inhibitor, and cardiovascular events. The study, which was presented at a meeting in Bordeaux France, was financed by the FDA in collaboration with California’s HMO giant Kaiser Permanente. The study was designed to determine if celecoxib, rofecoxib, ibuprofen, naproxen, or other NSAIDs increase the risk of acute myocardial infarction (AMI) or sudden cardiac death (SCD). Utilizing the 6-million member California database for Kaiser Permanente, all patients ages 18-84 who had taken a COX-2 inhibitor or nonselective NSAIDs between January 1999 and December 2001 were entered into the cohort. Controls were a risk-set match 4:1 on event date, birth year, gender, and health plan region. There were 8199 acute cardiac events within the study cohort (6675 AMI, 1524 SCD). The data revealed that rofecoxib use at > 25 mg per day increased the risk of acute cardiac events 3.15 fold (OR, 3.15 [1.14-8.75]). Rofecoxib at a dose < 25 mg resulted in an odds ratio of 1.29 (0.93-1.79), which was not statistically significant. When comparing low-dose rofecoxib to celecoxib (Celebrex), the risk of AMI and SCD was higher with rofecoxib (P= 0.04). Other NSAIDs, including naproxen, indomethacin, and possibly diclofenac, also increased the risk of AMI and SCD. These data will be presented in this country in October at the American College of Rheumatology. Concern about the relationship between rofecoxib and cardiac events was first raised with the publication of the VIGOR trial (N Engl J Med. 2000;343:1520-1528) which showed a relative risk of cardiac events associated with rofecoxib of 2.38 (95% CI, 1.39-4.00; P= .002). Dr. Eric Topol and colleagues from the Cleveland clinic subsequently reevaluated these data along with data from other studies and raised the concern of prothrombotic potential of COX-2 inhibitors, especially rofecoxib (JAMA. 2001;286:954-959). Their concern centered on the tendency for COX-2 inhibitors to block production of prostacyclin—thus blocking antiaggregatory and vasodilatory effects, while having no effect on thromboxane, which is responsible for platelet aggregation. Blockage of thomboxane is a COX-1 effect and accounts for the majority of the cardioprotective effects of aspirin and other NSAIDs. Rofecoxib, the most COX-2 specific of the drugs tested, may unbalance thromboxane and prostacycline accounting for the cardiovascular risk.

Some have considered a strategy of adding aspirin to a COX-2 inhibitor, but a new study suggests that aspirin negates the GI benefits of the COX-2 inhibitor, the primary benefit of COX-2 inhibitors over nonselective NSAIDs.

Researchers from USC performed a double-blind trial of rofecoxib, rofecoxib plus low-dose aspirin, ibuprofen, or placebo in patients without ulcers or erosive esophagitis. Endoscopies were performed at baseline, 6 weeks, and 12 weeks. At 12 weeks, the cumulative index of ulcers was placebo 5.8%, aspirin 7.3%, rofecoxib plus aspirin 16.1%, and ibuprofen 17.1% (P < 0.001 for rofecoxib plus aspirin and for ibuprofen vs each of placebo and aspirin). Over the same time, rofecoxib plus aspirin and ibuprofen both significantly increased the number of erosions (both P < 0.001 vs aspirin and placebo). The authors conclude that low-dose aspirin does not significantly increase ulcer recurrence, but that the addition of a COX-2 inhibitor with aspirin increases the rate of ulceration to a rate that is similar to a nonselective NSAIDs (Gastroenterology. 2004;127:395-402).

Viagra: Maximum Capacity at High-Altitudes?

High-altitude hikers may soon be requesting sildenafil (Viagra) prescriptions based on the results of a new study. The drug, which is a phosphodiesterase-5 inhibitor, is known to cause pulmonary vasodilation. German researchers postulated that such an effect may increase exercise capacity during induced hypoxemia at low altitudes and at Mount Everest base camp. Fourteen healthy mountaineers and trekkers were assessed with measurements of systolic pulmonary artery pressure, cardiac output, and peripheral arterial oxygen saturation at rest and during assessment of maximal exercise capacity on cycle ergometry while breathing a hypoxic gas mixture at low altitude, and retested at high-altitude at the Mount Everest base camp. Sildenafil 50 mg significantly increased arterial oxygen saturation during exercise (P = 0.005), reduced systolic pulmonary artery pressure at rest (P < 0.001), and during exercise (P = 0.031). Sildenafil also increased maximum workload and maximum cardiac output compared with placebo. At high-altitude, the drug had no effect on arterial oxygen saturation at rest nor during exercise compared with placebo, however, the sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003), during exercise (P = 0.021), increased maximum workload (P = 0.002), and cardiac output (P= 0.015). Two patients noted worsening headache at high-altitude with the drug. The authors conclude that sildenafil is the first drug to increase exercise capacity during severe hypoxia both at sea level and at high-altitude (Ann Intern Med. 2004;141:169-177). An accompanying editorial suggests that sildenafil is not a substitute for acclimatization to high-altitude and suggests that the findings of the study are compelling and that further research into a phosphodiesterase inhibitors in the treatment of pulmonary vascular disease is needed (Ann Intern Med. 2004;141:233-235).

FDA Actions

Eli Lilly has received FDA approval to market duloxetine (Cymbalta) for the treatment of major depression. The drug is a serotonin and norepinephrine reuptake inhibitor (SNRI), similar to venlafaxine (Effexor-Wyeth). The drug is also being studied for the treatment of stress urinary incontinence and diabetic neuropathic pain. Lilly, and the drug approval process for duloxetine, came under scrutiny earlier this year when a 19-year-old female volunteer committed suicide after discontinuing the drug during clinical trials. The patient had no history of depression prior to the study.

Shire Pharmaceuticals has received expanded indication for its mixed amphetamine product Adderall XR for the treatment of adults with attention deficit hyperactivity disorder (ADHD). The drug is a one-a-day preparation that has been widely used in children since 2001.

The FDA and Genentech have issued a warning to physicians regarding the risk of serious arterial thromboembolic events associated with bevacizumab (Avastin). The drug is an angiogenesis inhibitor, a novel antineoplastic used to treat metastatic colon cancer and other solid tumors. Reports of cerebral infarctions, myocardial infarctions, transient ischemic attacks, and angina have all been associated with use of the drug.

The FDA has approved an orally disintegrating form of carbidopa/levodopa for the treatment of Parkinson’s disease. The preparation dissolves rapidly in the mouth without the need for water, allowing for dosing even when patients are rigid or suffering from "off periods," when producing can be problematic. It will be marketed under the trade name Parcopa and will be available in 10/100 tabs, 25/100 tabs, and 25/250 tabs, similar to brand name Sinemet levodopa/carbadopa.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Telephone: (404) 262-5416. E-mail: In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.