Drug Recalls

Risk of Acute Myocardial Infarction and Sudden Cardiac Death in Patients Treated with COX-2 Selective and Non-Selective NSAIDs

Memorandum

By: David J. Graham

Date: September 30, 2004

Source: David J. Graham. "Risk of Myocardial Infarction and Sudden Cardiac Death in Patients Treated with COX-2 Selective and Non-Selective NSAIDs" (memorandum) U.S. Food and Drug Administration. September 30, 2004. Available online at 〈http://www.fda.gov/cder/drug/infopage/vioxx/vioxxgraham.pdf〉 (accessed October 1, 2005).

About the Author: David J. Graham is Associate Director for Science and Medicine at the Unted States Food and Drug Administration (FDA) Office of Drug Safety. As both a physician and public health expert, Graham has participated in research that has led to the removal of ten drugs from the pharmaceutical market that were deemed unsafe.

INTRODUCTION

The U.S. Food and Drug Administration (FDA) is an agency within the Department of Health and Human Services and consists of eight divisions, including the Center for Drug Evaluation and Research (CDER). The CDER promotes and protects the health of Americans by assuring that all prescription and over-the-counter drugs are safe and effective. Its jurisdiction encompasses most food products other than meat and poultry, human and animal drugs, therapeutic agents of biological origin, medical devices, radiation-emitting products for consumer, medical, and occupational use, cosmetics, and animal feed. Agency scientists evaluate applications for new human drugs and biologics, complex medical devices, food and color additives, infant formulas, and animal drugs.

Produced by Merck & Co., Vioxx belongs to a class of selective nonsteroidal anti-inflammatory drugs, or NSAIDs, called COX-2 inhibitors. Cycloogygenase is an enzyme that produces mediators that cause pain and inflammation in the body, and exists in two forms, known as COX1 and COX2. COX-2 inhibitors reduce inflammation and pain, while minimizing undesired gastrointestinal adverse effects, such as stomach ulcers, that are sometimes associated with other anti-inflammatory drugs.

In the clinical trials conducted before approval of Vioxx, the drug showed a significant therapeutic advantage over existing approved drugs due to fewer gastrointestinal side effects, including bleeding. Because of its advantages and wide potential, the review and approval of Vioxx was made a fast-track priority. Vioxx was approved by the FDA in 1999, and COX-2 inhibitors soon dominated the prescription-drug market for NSAIDs. The drug was marketed in more than eighty countries and its sales had reached $2.5 billion in 2003.

Several studies published after the approval of Vioxx, however, showed that the drug could cause increased blood pressure, a known risk factor for cardiovascular disease, and also increased blood clotting in some people taking the drug. A long-term clinical study conducted by David J. Graham at the FDA showed that people taking the medicine for more than eighteen months exhibited an increased risk for development of serious cardiovascular problems, including heart attacks and blood clots. This study also found that patients taking the highest recommended daily dosage of Vioxx had three times the risk of heart attack and sudden cardiac death compared to those not taking it. Graham summarized his findings in the following memo to Paul Seligman, the FDA's Director of Drug Safety.

PRIMARY SOURCE

MEMORANDUM

DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH

DATE: September 30, 2004

FROM: David J. Graham, MD, MPH
Associate Director for Science, Office of Drug Safety

TO: Paul Seligman, MD, MPH
Acting Director, Office of Drug Safety

SUBJECT: Risk of acute myocardial infarction and sudden cardiac death in patients treated with COX-2 selective and non-selective NSAIDs

The following report describes the study we performed to investigate the cardiovascular risk of the COX-2 selective NSAIDs rofecoxib and celecoxib, and a variety of non-selective, traditional NSAIDs….

BACKGROUND

Cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed for the treatment of arthritis and other musculoskeletal complaints because of their reduced gastrointestinal toxicity compared with traditional, non-selective NSAIDs. Questions about cardiovascular risk with these newer agents were raised by the finding of a 4-fold difference in incidence of acute myocardial infarction (AMI) between patients treated with rofecoxib (Vioxx) 50 mg/day compared to naproxen 1000 mg/day in a large randomized clinical trial. Given the high utilization of COX-2 agents in the US, even a small difference in cardiovascular risk between members of this class would have substantial public health impact.

A series of observational studies have examined the questions of cardiovascular risk with rofecoxib. A cohort study found nearly a 2-fold increased risk of serious coronary heart disease (AMI [acute myocardial infarction, or heart attack] and sudden cardiac death, SCD) among users of high-dose rofecoxib (>25 mg/day) compared to non-users. Another cohort study found no increase in risk but did not look at high-dose rofecoxib separately. A case-control study found an increased risk of hospitalized AMI in patients treated with rofecoxib compared with celecoxib use or no current use of other NSAIDs at both high- and standard-doses of rofecoxib….

METHODS

Study setting. Kaiser Permanente is an integrated managed care organization providing comprehensive health care to over 6 million residents in the state of California….

Base cohort. From January 1, 1999 through December 31, 2001, all patients from age 18 to 84 years who filled at least one prescription for a COX-2 selective or non-selective NSAID were identified. Patients with at least 365 days of health plan coverage prior to the date of that first NSAID prescription were entered into the study cohort if they had no diagnoses of cancer, renal failure, liver failure, severe respiratory disease, organ transplantation, or HIV/AIDS during the screening interval. Cohort members were followed from this entry date until the end of the study period, occurrence of an AMI or death, whichever came first.

Study design. Within this NSAID-treated cohort, a nested case-control study was performed. The primary study question was: is the risk of AMI and SCD increased in patients taking rofecoxib at standard (=25 mg/day) or high (>25 mg/day) doses compared with a) remote use of any NSAID or b) current use of celecoxib.

Study outcome. The study outcome of interest was a serious cardiac event, defined as hospitalized AMI or out-of-hospital SCD…. Outpatient deaths were classified as SCD if the underlying cause of death listed conditions previously associated with this outcome including hypertensive heart disease, ischemic heart disease, conduction disorders, dysrhythmias, heart failure, atherosclerotic heart disease, sudden death, or death from an unknown cause….

DISCUSSION

Our data suggest that risk of serious coronary heart disease is increased in patients treated with rofecoxib compared with celecoxib use. High-dose rofecoxib conferred a 3.7-fold increase in risk and standard-dose a 1.5-fold increase compared with celecoxib, the most frequently prescribed COX-2 selective agent….

CONCLUSIONS

Rofecoxib increases the risk of serious coronary heart disease defined as acute myocardial infarction and sudden cardiac death. High-dose rofecoxib increased risk by 3.7-fold and standard-dose rofecoxib increased risk by 1.5-fold compared to celecoxib use….

The population impact of rofecoxib's increased risk is great because of the widespread exposure to the drug. This illustrates the effect that even a relatively small increase in risk can have if you're dealing with a serious outcome that is not rare in the general population, such as is the case with AMI and SCD….

Prior to today, my conclusions regarding rofecoxib were that high-dose use of the drug should be ended and that lower-dose rofecoxib should not be used by physicians or patients. If lower-dose rofecoxib remained on the market, physicians and patients needed to understand that risk of AMI and SCD was substantially increased and that there were safer alternatives.

SIGNIFICANCE

Also on September 30, 2004, Merck, the manufacturer of Vioxx, announced a voluntary worldwide withdrawal of the drug. In the days following the announcement, Merck's shares lost value and the Vioxx story was front-page news across the United States.

A recall is a voluntary withdrawal from the market of products that may cause health problems, usually done by the manufacturer or distributor with the intention to protect the public. Drug recalls are possible when serious adverse effects are identified after approval either in post-marketing long-term clinical trials or through spontaneous reporting of adverse events. In the case of Vioxx, however, some scientists criticized the FDA and Merck for rushing an unsafe drug to market and leaving it there too long.

Graham testified before Congress in November 2004 (six weeks after writing this memo) about the dangers of the drug Vioxx and the state of the FDA's drug approval process. The Vioxx case also led to a storm of criticism from members of Congress, medical journals, and even scientists from within the FDA, and fuelled fierce debate about how to reorganize the agency's system of monitoring approved drugs. As the dust from the withdrawal of Vioxx began to settle, one consideration became clear: the views of society regarding the balance between the risks and benefits of medicines has shifted, and pharmaceutical companies, regulators, and scientists are considering higher standards of safety that new products could be required to demonstrate before they are brought to market.

FURTHER RESOURCES

Books

Ng, Rick. Drugs From Discovery to Approval. Indianapolis: Wiley-Liss, 2003.

Periodicals

Oberholzer-Gee, F. Inamdar, SN. "Merck's Recall of Rofecoxib—a Strategic Perspective." New England Journal of Medicine. 18 (2004): 2147-2149.

Web sites

U.S. Food and Drug Administration. "Vioxx (Rofecoxib) Questions and Answers." 〈http://www.fda.gov/cder/drug/infopage/vioxx/vioxxQA.htm〉 (accessed September 13, 2005).