(Circulation. 2000;101:e9027.)
© 2000 American Heart Association, Inc.
Drugs and Disease
Two Drugs With Troubled Pasts Will No Longer Be Marketed in the United States
Two drugs that have required frequent changes in warning labels will not longer be sold, at least in the United States, according to their manufacturers. The manufacturers made their announcements in the same week in March.
On March 21, 2000, the US Food and Drug Administration (FDA) asked Parke-Davis/Warner-Lambert, the manufacturer of the type 2 diabetes drug Rezulin (troglitazone), to remove the drug from the market and the company agreed. After months of lobbying by various healthcare advocates such as Sidney Wolfe, MD, of the Health Research Group of the Public Citizen organization, the FDA took the action after comparing the safety data on Rezulin to those of 2 similar drugs, Avandia (rosglitazone) and Actos (pioglitazone), and finding that Rezulin was the most liver toxic. "When considered as a whole, the pre-marketing clinical data and post-marketing safety data from Rezulin as compared to similar, alternative diabetes drugs indicate that continued use of Rezulin now poses an unacceptable risk to patients," said Dr Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research. Now that patients have an alternative to Rezulin, she said the action to withdraw it was reasonable.
Parke-Davis had strengthened the warnings on the drug’s labeling several times since the drug was approved, and the company had recommended closely monitoring liver function in patients who take the drug. In March 1999, an FDA advisory committee reviewed the safety data and recommended that Rezulin remain available to patients whose diabetes was not well controlled by other diabetes drugs. Although the liver toxicity of the other 2 diabetes drugs is less than that of Rezulin, Dr Wolfe, in a March 7 letter to FDA Commissioner Jane Hennessey, asked that the labeling on these medications be strengthened as well.
The second drug removed from the US market was Propulsid (cisapride), a medication for severe nighttime heartburn in adults with gastroesophageal reflux disease. In this case, Janssen Pharmaceutica Inc, of Titusville, NJ, announced that it would stop marketing the drug in the United States as of July 14, 2000. The date of the voluntary action was set to give doctors and patients time to make alternative decisions about treatment.
As of December 31, 1999, the drug had been associated with 341 reports of heart rhythm abnormalities, including 80 reports of death, said FDA officials in a talk paper on the subject. In most cases, the adverse events occurred in patients taking other medications or those who had other conditions that were known to increase the risk of cardiac arrhythmia associated with Propulsid.
As in the case of Rezulin, the labeling of Propulsid had been revised several times to alert patients and physicians to its risk. Despite these attempts at warning the public, the firm, in consultation with the FDA, decided to withdraw the drug from the US market, citing unacceptable risks.
Inflammation Marker Proposed as a Predictor of Cardiovascular Disease in Women
Adding the measurement of C-reactive protein to standard screenings of lipid levels may improve methods of identifying women at risk for cardiovascular events, according to researchers from Harvard Medical School in Boston (N Engl J Med. 2000;342:836–843).
Paul M. Ridker, MD, and his colleagues at the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital conducted a prospective, nested, case-controlled study of 28 263 apparently healthy postmenopausal women over a period of 3 years to assess the risk of cardiovascular events associated with markers of inflammation. The women were all enrolled in the Women’s Health Study. Among the markers for which the researchers tested were high sensitivity C-reactive protein, serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 (sICAM-1). Evaluations of homocysteine and several lipid and lipoprotein measurements were also included in the study.
In the study, the high sensitivity C-reactive protein marker proved the strongest predictor of the risk of cardiovascular events such as death from coronary heart disease, nonfatal myocardial infarction, stroke, or the need for coronary revascularization procedures. The relative risk of events in women who had C-reactive protein marker levels in the top quartile of the group was 4.4 compared with women who had levels in the lowest quartiles. The relative risk for amyloid A was 3.0 for the highest quartile compared with the lowest; the relative risks for the other markers were as follows: sICAM-1, 2.6; interleukin-6, 2.2; homocysteine, 2.0; total cholesterol, 2.4; LDL cholesterol, 2.4, apolipoprotein B-100, 3.4; HDL cholesterol, 0.3; and the ratio of total cholesterol to HDL cholesterol, 3.4.
In an interview on The News Hour with Jim Lehr on PBS, Dr Ridker said, "While cholesterol is a very important risk factor for heart attack and for stroke, reality is that half of all those events which will occur, occur among individuals who actually have normal levels of cholesterol." His study was an attempt to find a measurement that does a better job of identifying those who are at the highest risk of events related to cardiovascular disease. Dr Ridker theorizes that those who have a high level of inflammatory response are more likely to have a cardiac event. Although cholesterol level shows how much fatty plaque buildup occurs in arteries, he thinks that the inflammatory marker identifies people at risk of having vulnerable plaque. "The rupturing of that plaque is what determines who actually has the event," he said.
"I think that the cholesterol levels remain very important. The key issue is that risk is a global marker, and individuals who have a cholesterol problem and have this inflammatory problem are at very high risk. But those individuals who just have the cholesterol or just have inflammation, they too are at substantial risk," he noted in the interview.
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