Update: Shockwaves Subside from the FDA's Echo Contrast Warning
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, which are more costly.
William A. Zoghbi, MD, president of the American Society of Echocardiography (ASE), 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 also 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 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.”
Main et al published a seperate retrospective study in December 2008 in the American Journal of Cardiology that found the administration of a contrast agent (Definity) was associated with a 24 percent decreased risk of mortality. Researchers examined nearly 60,000 contrast-enhanced studies and more than 4 million unenhanced studies.
Mustafa Kurt, MD, and colleagues from the Methodist DeBakey Heart and Vascular Center Imaging Institute in Houston recently found that the utilization of contrast echo in technically difficult cases improves endocardial visualization and impacts cardiac diagnosis, resource utilization and patient management. The study was published online Feb. 11, 2009 in the Journal of the American College of Cardiology.
Kurt et al prospectively enrolled 632 consecutive patients with technically difficult echocardiographic studies, who received contrast (Definity). They found that the percent of uninterpretable studies decreased after contrast administration from 11.7 to 0.3 percent and technically difficult studies decreased from 86.7 to 9.8 percent. A significant impact of contrast echo on management was observed: additional diagnostic procedures were avoided in 32.8 percent of patients and drug management was altered in 10.4 percent, with a total impact (procedures avoided, change in drugs, or both) observed in 35.6 percent of patients, according to the investigators. The impact of contrast increased with worsening quality of nonenhanced study, the highest being in intensive care units.
A cost-benefit analysis showed that the use of contrast resulted in a $122 saving per patient. “In these technically difficult-to- image patients, a rapid, simple, inexpensive, and safe test that results in accurate information is desirable,” Kurt says.
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, indicated 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).
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 instead of contrast. 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.
It is hoped that supportive clinical studies, the International Contrast Ultrasound Society and other echo contrast proponents will continue to spread the word that these agents can increase the efficacy and cost-effectiveness of echocardiography.