Research Replication
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《新英格兰医药杂志》
In January 2006, we published an article by Mangano and colleagues1 that reported the results of an observational study of antifibrinolytic agents to control bleeding in cardiac surgery. The data suggested that patients treated with aprotinin, as compared with no antifibrinolytic agent, aminocaproic acid, or tranexamic acid, had higher risks of a number of adverse events, including cardiovascular events (myocardial infarction, heart failure, and stroke) and renal failure requiring dialysis. The study data were from a prospective registry funded by the Ischemia Research and Education Foundation. As detailed by Hiatt in a Perspective article in this issue of the Journal, the Food and Drug Administration (FDA),2 on the basis of the Mangano article and other data, called a meeting of the Cardiovascular and Renal Drugs Advisory Committee in September to discuss the matter. Dr. Mangano was asked to provide his study data so that the FDA could conduct an independent analysis. In a letter to the editor in this issue of the Journal,3 Dr. Mangano reports that he initially placed restrictions on the FDA's access to his data. However, he reports that more than five months ago he offered the FDA unrestricted access to the data, but the offer was not accepted. As noted in a response from the FDA,4 the agency is now eager to move forward with replication of the Mangano analysis.
It is not clear why the matter of data reanalysis was not resolved before the advisory committee met in September. If the data reanalysis had been completed and had confirmed the risks associated with the use of aprotinin, the action of the committee, which concluded that no labeling change was necessary, might have been different. Regardless of the reasons for the delay, the Mangano data and data from a study commissioned by Bayer that were not provided to the advisory committee before its September meeting should be reviewed and the committee reconvened as soon as possible. The goal should be to get a clear picture of potential adverse drug events of aprotinin from the available data. With this information, a course that puts patient safety at the forefront can be charted. The sooner this happens, the better.
References
Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-365.
Hiatt WR. Observational studies of drug safety -- aprotinin and the absence of transparency. N Engl J Med 2006;355:2171-2173.
Mangano DT. Judging the safety of aprotinin. N Engl J Med 2006;355:2261-2262.
Rieves RD, Weiss KD. Judging the safety of aprotinin. N Engl J Med 2006;355:2262-2262.(Jeffrey M. Drazen, M.D.)
It is not clear why the matter of data reanalysis was not resolved before the advisory committee met in September. If the data reanalysis had been completed and had confirmed the risks associated with the use of aprotinin, the action of the committee, which concluded that no labeling change was necessary, might have been different. Regardless of the reasons for the delay, the Mangano data and data from a study commissioned by Bayer that were not provided to the advisory committee before its September meeting should be reviewed and the committee reconvened as soon as possible. The goal should be to get a clear picture of potential adverse drug events of aprotinin from the available data. With this information, a course that puts patient safety at the forefront can be charted. The sooner this happens, the better.
References
Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-365.
Hiatt WR. Observational studies of drug safety -- aprotinin and the absence of transparency. N Engl J Med 2006;355:2171-2173.
Mangano DT. Judging the safety of aprotinin. N Engl J Med 2006;355:2261-2262.
Rieves RD, Weiss KD. Judging the safety of aprotinin. N Engl J Med 2006;355:2262-2262.(Jeffrey M. Drazen, M.D.)