Researchers challenge FDAs ultrasound contrast black-box warning
The FDA should reconsider a strong warning it issued on ultrasound contrast agents, according to study results presented by Melda Dolan, MD, at the 2008 American College of Cardiology (ACC) Scientific Sessions last week in Chicago.
Last October, the FDA placed a black box warning on ultrasound contrast agents used to improve the quality of echocardiograms. The warning was issued after reports of four deaths and serious reactions occurring shortly after or during the infusion.
A black box warning is given to drugs that carry significant risk of serious or even life-threatening adverse effects. The warning placed on ultrasound contrast agents was issued without a formal examination of the risks and benefits of using them, said Dolan.
Dolan, an associate professor of cardiology at St. Louis University School of Medicine, conducted a study to determine the risk/benefit ratio associated with ultrasound contrast agents in a multicenter setting. At two university hospitals, clinical outcomes of 7,961 patients undergoing stress echocardiogram (6,543 dobutamine stress, 1,418 exercise stress echo) for suspected coronary artery disease (CAD) were studied. All patients received ultrasound contrast agents (4,333 Optison, 3,628 Definity).
The researchers examined short- and long-term adverse events related to the ultrasound contrast agents. Test sensitivity and specificity for wall motion (WM) in patients with suboptimal windows for detecting angiographic CAD were compared to patients with optimal windows. The benefit of assessing myocardial perfusion (MP) and wall motion on long-term outcome was evaluated by event rates (non-fatal myocardial infarction (MI) and death).
According to the study results, no death or serious adverse events occurred within 30 minutes of ultrasound contrast agent use. At 24 hours, there was one death and three nonfatal MIs, none of which could be attributed to the ultrasound contrast agents.
Dolan said her research shows the contrast agents are safe and withholding their use — which has occurred since the FDA issued the warning — would make diagnosis of life-threatening heart disease more difficult.
Ultrasound contrast agents improved the detection of wall motion abnormalities in patients with suboptimal images, resulting in comparable sensitivity (81 percent vs. 73 percent) and diagnostic accuracy (82 percent vs. 77 percent) to patients with optimal images.
Among 6,075 patients with long-term follow up, non-fatal MI occurred in 237 (3.9 percent) and death in 273 (4.4 percent). Similarly, among 1,923 patients who had stress echo without ultrasound contrast agents, non-fatal MI occurred in 82 (4.3 percent) and death in 78 (4.1 percent). By sequential Cox regression, both wall motion and myocardial perfusion analysis independently increased predictive value of stress echo over clinical risk factors and resting ejection fraction. Patients with abnormal myocardial perfusion despite normal wall motion during dobutamine stress echo had a worse event-free survival than patients with normal wall motion and myocardial perfusion.
The findings indicate that withholding use of ultrasound contrast agents could lead to failure to detect life-threatening cardiac events and that the added benefits of ultrasound contrast agents are both improving LVO and detecting myocardial perfusion during dobutamine stress echo, according to Dolan.
"Based on the results of our study, we believe the FDA should reconsider its stance on contrast agents because the benefits outweigh the potential, although not established, risk," she added.
Last October, the FDA placed a black box warning on ultrasound contrast agents used to improve the quality of echocardiograms. The warning was issued after reports of four deaths and serious reactions occurring shortly after or during the infusion.
A black box warning is given to drugs that carry significant risk of serious or even life-threatening adverse effects. The warning placed on ultrasound contrast agents was issued without a formal examination of the risks and benefits of using them, said Dolan.
Dolan, an associate professor of cardiology at St. Louis University School of Medicine, conducted a study to determine the risk/benefit ratio associated with ultrasound contrast agents in a multicenter setting. At two university hospitals, clinical outcomes of 7,961 patients undergoing stress echocardiogram (6,543 dobutamine stress, 1,418 exercise stress echo) for suspected coronary artery disease (CAD) were studied. All patients received ultrasound contrast agents (4,333 Optison, 3,628 Definity).
The researchers examined short- and long-term adverse events related to the ultrasound contrast agents. Test sensitivity and specificity for wall motion (WM) in patients with suboptimal windows for detecting angiographic CAD were compared to patients with optimal windows. The benefit of assessing myocardial perfusion (MP) and wall motion on long-term outcome was evaluated by event rates (non-fatal myocardial infarction (MI) and death).
According to the study results, no death or serious adverse events occurred within 30 minutes of ultrasound contrast agent use. At 24 hours, there was one death and three nonfatal MIs, none of which could be attributed to the ultrasound contrast agents.
Dolan said her research shows the contrast agents are safe and withholding their use — which has occurred since the FDA issued the warning — would make diagnosis of life-threatening heart disease more difficult.
Ultrasound contrast agents improved the detection of wall motion abnormalities in patients with suboptimal images, resulting in comparable sensitivity (81 percent vs. 73 percent) and diagnostic accuracy (82 percent vs. 77 percent) to patients with optimal images.
Among 6,075 patients with long-term follow up, non-fatal MI occurred in 237 (3.9 percent) and death in 273 (4.4 percent). Similarly, among 1,923 patients who had stress echo without ultrasound contrast agents, non-fatal MI occurred in 82 (4.3 percent) and death in 78 (4.1 percent). By sequential Cox regression, both wall motion and myocardial perfusion analysis independently increased predictive value of stress echo over clinical risk factors and resting ejection fraction. Patients with abnormal myocardial perfusion despite normal wall motion during dobutamine stress echo had a worse event-free survival than patients with normal wall motion and myocardial perfusion.
The findings indicate that withholding use of ultrasound contrast agents could lead to failure to detect life-threatening cardiac events and that the added benefits of ultrasound contrast agents are both improving LVO and detecting myocardial perfusion during dobutamine stress echo, according to Dolan.
"Based on the results of our study, we believe the FDA should reconsider its stance on contrast agents because the benefits outweigh the potential, although not established, risk," she added.