CONTRAST ECHOCARDIOGRAPHY CaRES (Contrast Echocardiography Registry for Safety Surveillance): A Prospective Multicenter Study to Evaluate the Safety of the Ultrasound Contrast Agent Definity in Clinical Practice Robert J. Weiss, MD, Masood Ahmad, MD, Flordeliza Villanueva, MD, Stephen Schmitz, MD, MPH, Gajanan Bhat, PhD, Mark G. Hibberd, MD, PhD, and Michael L. Main, MD, on behalf of the CaRES Investigators, Auburn, Maine; Pittsburgh, Pennsylvania; Galveston, Texas; Kansas City, Missouri; North Billerica, Massachusetts Background: Definity (perflutren lipid microsphere) is an ultrasound contrast agent approved for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventric- ular endocardial border. This prospective, open-label, nonrandomized, multicenter, phase 4 surveillance registry study was conducted at 15 clinical sites in the United States and was designed to assess the risk for adverse cardio- pulmonary events occurring during or within the initial 30 min after Definity administration in routine clinical practice. Methods: Patients with suboptimal baseline images were consecutively approached regarding study partici- pation. Safety monitoring including vital sign measurements, continuous electrocardiographic monitoring, and continuous oxygen saturation was initiated at baseline before Definity administration and then at regular intervals for 30 min after Definity injection. Patients were assessed for adverse events at 30 min after Definity administration and then contacted by telephone at 24 6 4 hours to record any subsequent adverse events. Results: A total of 1,060 patients were enrolled at 15 clinical sites. Of these, 1,053 (99.3%) received at least one dose of Definity and completed the study. No deaths, serious adverse events, or other significant adverse events occurred during this study. The overall adverse event rate was 10.8% (4.5% in patients undergoing rest echo- cardiography, 13% in patients undergoing rest and exercise stress echocardiography, and 27.7% in patients undergoing rest and pharmacologic stress echocardiography). The overall drug-related adverse event rate (patients with at least one adverse event reported by the principal investigator as related to Definity) was only 3.5%, and most of these (110 of 114 [96.5%]) were reported by the investigator as mild or moderate in intensity. Conclusions: Definity is well tolerated in routine clinical practice in patients with a high prevalence of cardio- pulmonary disease. (J Am Soc Echocardiogr 2012;25:790-5.) Keywords: Ultrasound contrast agents, Contrast echocardiography, Safety Echocardiography is the first-line imaging method of choice for evaluating patients with suspected cardiac disorders because of its ease of use, widespread availability, portability, lack of ionizing radiation exposure, and high diagnostic utility. However, largely be- cause of patient-related factors such as obesity and chronic obstruc- tive pulmonary disease, $10% to 15% of patients are technically difficult to image, which results in reduced image quality and lower diagnostic accuracy. 1 This percentage is as high as 30% in critically ill patients 2 and 33% in patients undergoing stress echocardiography. 3 Definity (perflutren lipid microsphere for injectable suspension; Lantheus Medical Imaging, Inc., North Billerica, MA) is an ultrasound contrast agent consisting of phospholipid-encapsulated octafluoro- propane microspheres. 4 In a multicenter, randomized, placebo- controlled trial evaluating the efficacy and safety of Definity in patients with suspected cardiac disease and suboptimal baseline echocardiograms, improvement in left ventricular endocardial border delineation was demonstrated in patients who received Definity in comparison with those who received placebo. 4 Definity has been approved in the United States since 2001 for ‘‘use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border.’’ 4 From Maine Research Associates, Auburn, Maine (R.J.W.); the University of Pittsburgh Cardiovascular Institute, Pittsburgh, Pennsylvania (F.V.); the University of Texas Medical Branch, Galveston, Texas (M.A.); Saint Luke’s Mid America Heart Institute, Kansas City, Missouri (M.L.M.); and Lantheus Medical Imaging, Inc., North Billerica, Massachusetts (S.S., G.B., M.G.H.). Drs. Schmitz, Bhat, and Hibberd are employees of Lantheus Medical Imaging. This study was sponsored by Lantheus Medical Imaging. The CaRES investigators (or their institutions) listed in the Appendix received research grants from Lantheus Medical Imaging. Reprint requests: Michael L. Main, MD, Saint Luke’s Mid America Heart Institute, 4330 Wornall Road, Suite 2000, Kansas City, MO 64111 (E-mail: mmain@cc-pc. com). 0894-7317/$36.00 Copyright 2012 by the American Society of Echocardiography. doi:10.1016/j.echo.2012.04.002 790