Update: Shockwaves Subside from the FDA's 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. But there is good news for the echo contrast agent market and patients as the pendulum is swinging back again. The subsequent movement to educate both regulators and providers has 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.

Regulatory action

In October 2007, 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”, says Michael L. Main, MD, of the Mid-America Heart Institute in Kansas City, Mo. “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.”

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.”

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

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. “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) annual meeting in March 2008 supporting the clinical benefits of the contrast agents. 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 myocardial infarctions 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.

Advocates of echocardiography gathered forces and worked to educate the FDA and the general cardiovascular community about contrast agent safety. Additionally, a new cross-disciplinary professional society—the International Contrast Ultrasound Society (ICUS)—was formed.

The efforts paid off. In May 2008, 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.

Safe and cost-effective

Studies proving the efficacy of echo contrast agents began appearing in 2001. They have demonstrated that up to a third of the images taken without contrast are often inadequate. They also have demonstrated that medical management of patients is significantly improved when contrast agents are used. When patients bypass contrast-enhanced echo, they invariably are referred to nuclear tests,