Contrast Echocardiography: Past, Present, and . . . Future?

The history of contrast echocardiography dates back to 1968, when Gramiak and Shah first noted the echocardiographic appearance of bubbles in green dye injections. Commercial contrast agents became available in Europe in 1991 (Echovist, Berlex, Lachine, Quebec City, Canada) and in the U.S. in 1994 (Albunex, Mallinckrodt, St. Louis, Missouri), followed by second generation contrast agents (Optison [GE, Waukesha, Wisconsin], 1997, and Definity [BMS, Billerica, Massachusetts], 2001). Early adopting clinicians celebrated the use of contrast echocardiography in enhancing left ventricular borders in suboptimal studies, whereas scientists investigated their potential to quantify myocardial blood flow. An imaging technique that could simultaneously detect wall motion and measure perfusion was indeed the holy grail of coronary artery disease diagnostic testing. With growing use of these agents in academic and community echocardiography labs and a 2000 American Society of Echocardiography guideline touting that “the use of contrast enables acquisition of ultrasound images of improved quality. The technique is especially useful in...approximately 10% to 20% of routine echocardiographic examinations” (1), the future seemed close at hand indeed. Unfortunately, echocardiography contrast agents have met several challenges. In November 2005, General Electric (GE) voluntarily recalled its agent, Optison, after a Food and Drug Administration (FDA) inspection raised concerns about manufacturing practices. In a consumer letter dated September 6, 2007, GE expressed “great pleasure” in announcing its return to the market in “September/ October” (2), although the drug has yet to make its reappearance. In the meantime, the FDA has been investigating deaths associated with the use of Definity and issued a Black Box warning on October 12, 2007 (3). This labeling change states that “serious cardiopulmonary reactions, including fatalities have occurred during or within 30 min following Definity administration.” The warning goes on to recommend monitoring of vital signs, electrocardiography, and in some patients phosphorus dioxide saturation, during and for 30 min after administration (4). A similar Black Box warning is required by the FDA when Optison returns to the market. Although there is no doubt that the use of contrast enables acquisition of ultrasound images of improved quality, these setbacks in contrast agent safety are not the only problem. Over the years, adoption has been slower than expected, whether owing to initial low reimbursement or the “hassle factor” of an intravenous medication, and no agent has yet been approved for myocardial perfusion. No doubt, the recommendation for 30 min of monitoring could be difficult for busy echo labs to comply with, especially given recent cuts in reimbursement. However, adding it all up....is this simply a temporary setback for a clinically proven and widely valued technique, or is this the straw that will break the camel’s back of contrast echocardiography? What is the future for bubbles? We do realize that there will be a significant delay by the T H E F O O D A N D D R U G A D M I N I S T R A T I O N F D A has recently changed labelling