Shockwaves Subside from the FDAs Echo Contrast Warning

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  Views of the heart taken from the apex of the ventricles, to visualize parts of the left- and right-sided chambers. Top, without contrast, bottom, with contrast. Source: Lantheus Medical Imaging

Since the FDA placed a black-box warning on echocardiography contrast agents in October 2007, the market for the agents dropped tremendously. However, the subsequent movement to educate both regulators and providers led to a modification of the agency’s contraindications and may have generated a resurgence in their use, along with a better understanding of their clinical value.

Two products are available on the U.S. market: Definity from Lantheus Medical Imaging and Optison from GE Healthcare. In Europe, Definity and Optison are approved, but only SonoVue from Bracco Diagnostics is currently being marketed.

Regulatory action

In October of last year, the FDA changed the product labeling for perflutren cardiac ultrasound agents due to reports of about “200 serious adverse events shortly following administration of the products,” including seven deaths, which were mainly attributed to allergic reactions. The cardiac or pulmonary complications included cardiac arrest, heart rhythm problems, hypotension and hypoxemia.

“The approach that the FDA took in contraindicating contrast agents in various disease states was probably not the best approach. Since that time, we were able to demonstrate how patients with these disease states are the very patients who are most likely to benefit from the administration of contrast,” says Michael L. Main, MD, of the Mid-America Heart Institute in Kansas City, Mo.

Specifically, Main says, “patients with acute coronary syndrome [ACS], heart failure and respiratory failure are somewhat tenuous cases, but these are the patients in whom an accurate diagnostic study is most needed.”

The FDA labeling change also included a recommendation to monitor all patients for at least 30 minutes following administration of the agents. But when acute reactions occur—about one in every 10,000 cases—they generally happen within the first five to 10 minutes after injection. “As a result, monitoring patients for 30 minutes does not prevent or help us manage acute reactions,” Main says.

Researchers presented several studies at the American College of Cardiology (ACC) conference in March in support of the contrast agents’ clinical benefits. Melda Dolan, MD, from St. Louis University School of Medicine, presented findings based a dual-center assessment of nearly 8,000 patients, revealing no death or serious adverse events within 30 minutes of contrast use. At 24 hours, there were three nonfatal MIs and one death, none of which the researchers attributed to the ultrasound contrast agents.

“The warning placed on ultrasound contrast agents was issued without formal examination of the risks and benefits of using them,” Dolan says.

In May, the FDA revised several of its warnings and contraindications because the agency said it “determined that, in some patients, the benefits from the diagnostic information that could be obtained through the use of Definity or Optison may outweigh the risk for serious cardiopulmonary reactions, even among some patients at particularly high risk for the reactions.”

Many contraindications were removed, including worsening or clinically unstable congestive heart failure, acute MI, ACS, serious ventricular arrhythmias or high risk of arrhythmias. And several remained, including the monitoring of patients at high-risk of pulmonary hypertension or unstable cardiopulmonary conditions for at least 30 minutes post-administration of the agents.

Last October, the FDA did not have the proper data to correctly assess the safety-benefit ratio of the agents, particularly for the inpatient population, who benefit most from their diagnostic accuracy, according to the William A. Zoghbi, MD, president of the American Society of Echocardiography (ASE). Since that time, the ASE, along with other physicians and societies, have worked to educate the agency and the general cardiovascular community about contrast agent safety through a series of clinical studies published over the past year. Additionally, a new cross-disciplinary professional society, the International Contrast Ultrasound Society (ICUS), was formed in October 2008 to overcome challenges in the field of contrast ultrasound and increase contrast’s role in improving patient care worldwide.

Clinical proof  

Studies proving the efficacy of echo contrast