Black box restrictions imposed by the Food and Drug Administration on the use of ultrasound contrast agents have caused consternation among cardiologists and radiologists who fear that the agency's decision will have a chilling effect upon the use and further development of these “microbubble” agents.
Efforts at getting the FDA to reconsider the label change, which was issued in October (CARDIOLOGY NEWS, November 2008, p. 20), may have borne fruit in December, when a delegation of four cardiologists met with Dr. Rafel D. Rieves, acting director of the FDA's Division of Medical Imaging and Hematology Products, and his staff in Silver Spring, Md. The cardiologists were Dr. Steven B. Feinstein of the Rush Medical College, Chicago; Dr. Jonathan H. Goldman of the University of California, San Francisco; Dr. Paul A. Grayburn of the Baylor University Medical Center, Dallas; and Dr. Michael L. Main of the Mid-America Heart Institute, Kansas City, Missouri.
The emissaries represented an international group of 160 cardiologists, radiologists, and other medical imaging professionals who had earlier signed a letter to Dr. Rieves asking that the FDA division convene a panel of cardiologists to assess fully the adverse events that have been attributed to the contrast agents and determine the most appropriate corrective actions.
The letter, dated Nov. 10, 2007, said the black box warning ignores the proven efficacy and established safety of perflutren gas microspheres for use as echocardiographic contrast agents, as well as the potential risks of alternative procedures and the likely confounding effect of pseudocomplications that may be pertinent to some of the deaths associated with use of the ultrasound contrast agents.
“Our presentation to the division of medical imaging focused on the critical role that ultrasound contrast agents play in the diagnosis and management of patients with acute coronary syndromes, decompensated heart failure, and respiratory failure,” Dr. Main said in an interview.
“These are patient groups [that] must now undergo more invasive alternative testing when their baseline echocardiographic imaging is inadequate. We were encouraged that the FDA seemed receptive to the basic premise, which was that the risk-benefit ratio of ultrasound contrast is so favorable that the new contraindications will result in more harm than good,” said Dr. Main, medical director of the echocardiography laboratory at the Mid America Heart Institute of St. Luke's Health System.
Dr. Main has received research support from and has a consultant relationship with, POINT Biomedical Corp., Acusphere Inc., and Bristol-Myers Squibb Medical Imaging Inc. Dr. Goldman is a POINT Biomedical shareholder and has a consultant relationship with Bristol-Myers Squibb Medical Imaging. Dr. Grayburn has received grant support from Acusphere, POINT Biomedical, Medtronic Inc., and Guidant Corp.
Two ultrasound contrast agents, Definity (Bristol-Meyers Squibb) and Optison (GE Healthcare), are approved for use to improve suboptimal echocardiograms. Both consist of injectable, perflutren-filled lipid microspheres. Optison is back on the market following a 2-year hiatus attributed to a manufacturing recall.
In issuing the warning, the FDA said it had received reports of serious cardiopulmonary reactions following contrast injection, including 10 deaths following the administration of Definity and 1 death following an Optison injection. Of those 11 deaths, 4 were caused by cardiac arrest and occurred during or within 30 minutes of infusion; the remaining 7 deaths occurred within 12 hours of administration.
In addition, about 190 nonfatal serious reactions were reported in the United States following administration of Definity and Optison.
The boxed warning states that “serious cardiopulmonary reactions, including fatalities, have occurred during or within 30 minutes” after administration of Definity or Optison. Referring to contraindications described on the label, the warning requires that all patients be assessed for the presence of any condition that precludes administration of the contrast agent. In addition, patients are to be monitored during, and for 30 minutes following, contrast administration, including vital sign measurements and electrocardiography in all patients and cutaneous oxygen saturation in patients at risk for hypoxemia. Resuscitation equipment and trained personnel should be readily available.
Additional pressure on the FDA has come from the 12,000-member American Society of Echocardiography (ASE). In late November, ASE President Thomas Ryan wrote a letter to Dr. Andrew C. von Eschenbach, the FDA Commissioner, requesting an opportunity to engage in a dialogue with the agency regarding its decision to issue the black box warning.
“The risk of an adverse event resulting from the administration of a contrast agent must be weighed against the value of a correct diagnosis,” said Dr. Ryan, who noted that he has no conflicts of interest related to the topic. “Because contrast agents improve accuracy and reduce the need for additional downstream testing, we believe their continued use in appropriate cases is justified and consistent with the mission of both the FDA and the ASE,” wrote Dr. Ryan, who is the John G. & Jeanne Bonnet McCoy Chair in Cardiovascular Medicine and the director of the Ohio State University Heart Center in Columbus.