FDA ultrasound contrast warning challenged
Last October, the FDA placed a black box warning on UCAs 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 UCAs was issued without a formal examination of the risks and benefits of using them, said Dolan.
Dolan, an associate professor of cardiology at the St. Louis University School of Medicine, conducted a study to determine the risk/benefit ratio associated with UCA in a multi-center setting. At two university hospitals, clinical outcomes of 7961 patients undergoing stress echocardiogram (SE) for suspected coronary artery disease (CAD) [6,543 dobutamine stress (DSE), 1,418 exercise stress echo] were studied. All patients received UCA (4,333 Optison, 3,628 Definity).
The researchers examined short- and long-term adverse events related to UCA. 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 WM 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 UCA use. At 24 hours, there was one death and three non fatal MIs, none of which could be attributed to UCA.
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.
UCA improved the detection of WM 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 SE without UCA, non-fatal MI occurred in 82 (4.3 percent) and death in 78 (4.1 percent). By sequential Cox regression, both WM and MP analysis independently increased predictive value of SE over clinical risk factors and resting ejection fraction. Patients with abnormal MP despite normal WM during DSE had a worse event free survival than patients with normal WM and MP.
The findings indicate that withholding use of UCA, which has occurred as a result of the FDA warning, could lead to failure to detect life-threatening cardiac events and that the added benefits of UCA are both improving LVO and detecting MP during DSE, 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.