Washington, DC - The FDA is facing mounting pressure to rethink the black-box warning and contraindications it recently imposed on two ultrasound contrast agents. The product labels for perflutren liquid microspheres (Definity, Bristol-Myers Squibb) and perflutren protein-type A microspheres for injection (Optison, General Electric) now warn users about serious cardiopulmonary reactions occurring within 30 minutes of product administration and note that the products are contraindicated in patients with unstable cardiopulmonary status, including those with unstable angina, acute MI, respiratory failure, and recent worsening of congestive heart failure.

But according to an expedited Viewpoint article published in the Journal of the American College of Cardiology online today [1], the patients now excluded from undergoing echocardiograms with these contrast agents are precisely the patients in whom the agents are needed.

"I and others have used these contrast images for several years in many thousands of patients, and we know that these agents are both efficacious and safe," first author on the Viewpoint, Dr Michael Main (Mid America Heart Institute, Kansas City, MO), told heartwire. "We disagree very strongly with these new contraindications and boxed warnings."

As previously reported by heartwire, the FDA issued its warning on the contrast agents last month, following reports of 11 deaths and 199 serious cardiopulmonary reactions during or within 12 hours of administration of one of the contrast agents. Four deaths followed cardiac arrest and occurred during or within 30 minutes of Definity administration.

But Main et al argue in their Viewpoint that a "significant proportion" of the deaths cited could be attributable to progression of the underlying disease state in these patients and not the contrast agent. Indeed, echocardiography using one of these agents—the only two commercially available contrast agents for this test—is often the only available diagnostic test for critically ill patients, the very patients singled out for exclusion in the new label.

"For example, without contrast, we're often not able to exclude a left ventricular apical mural thrombus in acute MI," Main commented. "Contrast can play a pivotal role in excluding a pseudoaneurysm, and that can literally mean the difference between life and death."

In their Viewpoint, Main et al recommend that the FDA convene a panel of cardiologists with and without imaging experience to review the warning and determine a course of action and that future FDA warnings acknowledge the possible role of pseudocomplications. But Main's words were stronger in his interview with heartwire: "I can speak for myself and my coauthors when I say that what we recommend is that the contraindications be immediately lifted."

The boxed warning could be removed after the evidence has been more thoroughly reviewed, he added.

The FDA may already be listening: according to Main, he, his coauthors, and others are meeting with the FDA next month "to discuss these issues in more detail." But already, Main believes the new label is having an impact on patient care, amplified by attorney websites that sprang up following the FDA's announcement, seeking patients "injured" by contrast agents.

"The echocardiographers and other cardiologists that I've talked to have dramatically reduced their use of contrast. . . . Unfortunately, fear of potential litigation is also having a chilling effect on the use of these agents."

To put their concerns in perspective, Main et al point out in their Viewpoint that the risk of death purportedly associated with contrast-enhanced echocardiography (approximately 1:500 000) is far lower than the mortality risk associated with other imaging tests, including diagnostic coronary angiography (1:1000). Risk of MI or death following exercise treadmill testing is approximately 1:2500, while stress single-photon emission CT or a radionuclide ventriculogram exam, they estimate, carries a lifetime risk of fatal malignancy that ranges from 1:1000 to 1:10 000.

Optison, which had been withdrawn from the market in 2005 for manufacturing reasons, is now back on the US market, carrying the FDA's new warning.