Safety and Risk–Benefit Profile of Microbubble Contrast Agents in Echocardiography

Safety and Risk–Benefit Profile of Microbubble Contrast Agents in Echocardiography

Khumri Taiyeb M, Main Michael L
Asia-Pacific Cardiology - Volume 2 Issue 1
US Cardiology - Volume 6 - Issue I
Published: March 2009
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Abstract
In October 2007, the US Food and Drug Administration (FDA) imposed a ‘black box’ warning, new disease state contraindications, and a mandatory 30-minute monitoring period on the ultrasound contrast agents Definity® (perflutren lipid microspheres, Lantheus Medical Imaging, North Billerica, MA) and Optison™ (perflutren protein-type A microspheres, GE Healthcare, Buckinghamshire, UK), effectively restricting their use. These labeling changes were prompted by spontaneous reports of four deaths and ~190 other serious cardiopulmonary reactions that occurred in temporal relation to contrast agent injection. Many healthcare providers were critical of the FDA action, citing the previously documented excellent safety profile of these agents, the possible confounding effect of ‘pseudocomplication,’ and the known increased risk associated with the more invasive testing that would be necessary in many patients. Since then, several large-scale ultrasound contrast agent safety studies have been completed, including ~200,000 patients. In this article, we review the efficacy of ultrasound contrast agents, implications of the initial FDA action, newly published safety data, and more recent changes to the product labeling for both agents following an FDA Cardio-Renal Advisory Committee meeting in June 2008.

Keywords Ultrasound contrast agents, Definity®, Optison™, US Food and Drug Administration, black box warning

Disclosure: Michael L Main,MD, has received research grants from Lantheus Medical Imaging and GE Healthcare, and has served as a consultant for Acusphere, Inc. Taiyeb M Khumri, MD, has no conflicts of interest to declare.
Received: October 22, 2008 Accepted: November 21, 2008
Correspondence: Michael L Main, MD, Cardiovascular Consultants, 4330 Wornall Road, Suite 2000, Kansas City, MI 64111. E: mmain@cc-pc.com

Ultrasound contrast agents capable of transpulmonary passage following intravenous injection have been commercially available since the 1990s. These agents are microbubbles, which are smaller than red blood cells and persist long enough (due to reduced rate of gas diffusion) to reach the left ventricle (LV). 1–3 Ultrasound contrast agent applications included LV cavity opacification, enhancement of spectral Doppler signals and evaluation of myocardial perfusion at rest or post-stress.3 The commercially available second-generation ultrasound agents are approved by the US Food and Drug Administration (FDA) only for the enhancement of LV endocardial delineation in patients with baseline suboptimal examinations.3 There are currently two commercially available ultrasound contrast agents in the US: Optison™ (perflutren protein-type A microspheres, GE Healthcare, Buckinghamshire, UK) and Definity® (perflutren lipid microspheres, Lantheus Medical Imaging, North Bellirica).

Efficacy of Ultrasound Contrast Agents
Although tissue harmonic imaging has significantly enhanced the diagnostic quality of baseline transthoracic echocardiography,4 the increasing prevalence of obesity and lung disease has added an extra layer of challenge; at least 10–15% of echocardiograms are technically difficult or non-diagnostic despite the use of harmonic imaging. The proportion of nondiagnostic studies is significantly increased during stress echocardiography and in echocardiograms performed in the intensive care unit.3

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