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Doctor Disputes FDA Black Box Warning on Ultrasound Contrast Agents

Apr 3, 2008 | Parker Waichman Alonso LLP

A controversy has erupted over the safety of ultrasound contrast agents used to diagnose heart defects and malfunctions.  Last year, the Food & Drug Administration (FDA) required the makers of ultrasound contrast agents - also known as micro-bubble contrast agents -  to include a black box warning on the products' labels about their association with serious cardiac injuries and deaths.  But one scientist who has researched the ultrasound contrast agents says they are safe, and that the FDA's actions may have actually endangered patients.

There are currently two micro-bubble contrast agents currently on the market - Definity, marketed by Bristol Myers Squibb, and Optison, distributed by General Electric.  Definity and Optison contrast agents are used in ultrasounds of the heart to enhance images during a procedure called echocardiography. During an echocardiography, the contrast agents are injected into a patient’s veins. The drugs consist of microscopic gas-filled spheres that sharpen the resulting ultrasound picture.  The use of Definity or Optison contrast agents allow doctors to better diagnose heart defects and malfunctions.

But in October 2007, the makers of Definity and Optison agreed to include a new black box warning on their package inserts after the FDA received hundreds of reports of serious cardiac reactions and deaths associated with the administration of these drugs.

A black box warning is given to drugs that carry significant risk of serious or even life-threatening adverse effects.   According to the FDA, there have been more than 200 reports of serious cardiac reactions involving the use of Definity and Optison.  In October 2007, the FDA said that it knew of at least 11 deaths associated with the administration of either Definity or Optison.  Four of those fatalities occurred either during infusion or within 30 minutes following the administration of the contrast agent.   The FDA said that most of the serious but non-fatal reactions also occurred in the same time frame.

But Dr. Melda Dolan, an associate professor of cardiology at the St. Louis University School of Medicine, says the black box warning was added to the ultrasound contrast agents without a formal examination of the risks and benefits of using them.  Dr. Dolan said his research, which was presented this week at the American College of Cardiology annual meeting in Chicago, raised questions about the FDA's decision.

The purpose of this study was to evaluate the overall risk and benefits of ultrasound contrast agents. Using results from two university hospitals, the researchers examined the clinical outcomes of nearly 24,000 patients who received ultrasound contrast agents during an echocardiogram and compared their results to those from a group of approximately 6,000 patients who did not need to receive contrast agents.

To test the safety of contrast agents, the researchers looked at the short-term (within 30 minutes of the infusion) and long-term (within 24 hours) outcomes and noted any serious adverse events or deaths. Of the nearly 24,000 individuals to receive the contrast agents, not one experienced an adverse event within 30 minutes. One death and three non-fatal heart attacks occurred within 24 hours; however these could not be attributed to the contrast agents.

"Based on the results of our study, we believe the FDA should reconsider its stance on contrast agents because the benefits outweigh the potential, although not established, risk," said Dolan.   Many doctors have limited their use of ultrasound contrast agents since the introduction of the black box warning.  Dolan said that withholding these agents would make diagnosis of life-threatening heart disease more difficult.