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 agents began appearing in 2001. They have demonstrated that up to a third of the images taken without contrast are often inadequate. They have also 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, which are more costly.

Zoghbi says that the appropriate use of contrast is extremely cost-effective, since the improved accuracy of echocardiographic studies in difficult-to-image patients impacts patient management and decreases downstream utilization of more invasive—and more costly—procedures, such as nuclear scans, transesophageal echocardiography (TEE) or cardiac catheterization. In particular, he cites a study, conducted by Leslee J. Shaw, MD, et al which found that contrast agents were cost-efficient (Ultrasound Con Agents 2001).  

Yongqi Yong, MD, from Baylor College of Medicine in Houston, and colleagues found that contrast echo was cost-effective compared with TEE, in determining regional and global ventricular function, with a cost saving of 3 percent and 17 percent, respectively (Am J Cardiol 2002;89:711–718).

The consensus is, and the evidence suggests that, when the correct diagnosis is made the first time with the help of contrast agents, the hospital saves money, says Main. He also acknowledges serious adverse events with the contrast agents are quite rare in daily practice. Additionally, new data have emerged indicating that side effects occur at a very low level.

Main et al conducted a study seeking to assess any mortality difference in patients undergoing echocardiography while hospitalized, with (12,475 cases) and without (6,196 cases) contrast enhancement (Definity)  (JACC 2008;51:1704-1706). They found that 0.4 percent of hospitalized patients died within 24 hours of the echo, but found no increased mortality risk associated with Definity, “despite evidence for higher clinical acuity and more co-morbid conditions in patients undergoing contrast studies.”     

Main says that the 0.4 percent mortality rate is “due to the fact that this patient population is very sick. We suggest that the adverse events, previously attributed to the echo contrast agents, might be pseudo-complications, due to their underlying disease.”

Charles A. Herzog, MD, of the echocardiography laboratory at Hennepin County Medical Center in Minneapolis, found that from February 1998 to February 2002, 3,051 patients received Optison with no adverse events recorded. From February 2002 to October 2007, 12,974 received Definity and 20 events were recorded, four of which were serious (JAMA 2008;299(17):2023-2025). The adverse event rate overall was 0.12 percent.

In an analysis, Paul Grayburn, MD, from Cardiology Consultants of Texas, said that the four deaths cited by the FDA occurred over a six-year period, in which two million doses were administered, indicating that the fatal event rate was approximately one in 500,000. Grayburn wrote that the rate “is far less than the fatal event rate of a treadmill exercise test (one in 2,500) or a transesophageal echocardiogram (one in 10,000)” (Am J Cardiol 2008;101(6):892-893).

A larger multicenter clinical study evaluating more than 4.3 million patients—almost 60,000 of which had contrasts administered—found no difference in crude mortality. However, when the researchers examined the risk-adjusted mortality rates, there was an association between improved survival rates with contrast-enhanced echocardiography studies compared with non-contrast enhanced studies. The study is slated to be published in the December issue of the American Journal of Cardiology.

The market drop-off


Despite the recent studies and modification of the contraindications, the remaining black-box warning seems to have scared off providers from using the agents. In fact, the use of contrast for echocardiography declined 22 percent in the second quarter of 2008, compared to usage in the same quarter of 2006, according to research from Arlington Medical Resources (AMR), which provides market analysis for the pharmaceutical and diagnostic imaging industries. AMR collected data from a random sampling from several hundred facilities throughout the U.S. and Europe.

Analyst Anna Fisher says the role of ultrasound contrast agents continues to be important in the overall echocardiography market because it enhances imaging quality for interpretation. For fear of liabilities, however, many facilities, especially community hospitals, are performing more cases with saline. Experts say that saline is not as efficacious in imaging the heart as contrast agents. “The contrast agents allow us to look at the left side of the heart chambers to help us indentify the function of the left chamber of the heart. Agitated saline does not cross the lungs,” says Steven B. Feinstein, MD, director of echocardiography at Rush University Medical Center in Chicago.

AMR’s research also found that the first quarter of this year experienced a 26 percent drop-off rate, compared to the first quarter of 2006—indicating a 4 percent increase from quarter-to-quarter in 2008. The slight positive trend might be indicative of fears being assuaged and a continued increase in usage.

“Cardiologists continue to advocate for contrast agent usage, especially in certain at-need patient populations who require enhanced image accuracy,” Fischer says.   
 



The greatest percentage improvement in evaluability after contrast administration occurred in the mid anterolateral segment, followed by the basal anterolateral and apical lateral segments. (Pooled data on file at Lantheus Medical Imaging from 126 patients in two open-label multicenter trials with similar study design and patient populations.