Curr Cardiovasc Imaging Rep (2012) 5:410–419 DOI 10.1007/s12410-012-9162-4

ECHOCARDIOGRAPHY (MH PICARD, SECTION EDITOR)

Update on Contrast Echocardiography: Safety and Utility Hemant Boolani & Michael L. Main

Published online: 14 August 2012 # Springer Science+Business Media, LLC 2012

Since October 2007, there has been increasing interest in ultrasound contrast agents (UCAs) used in echocardiography, initially, due to safety concerns raised by the United States Food and Drug Administration (FDA) [1], and more recently as a result of multiple compelling peer reviewed

publications which have now firmly established the excellent risk: benefit profile for UCAs [2–11, 12•, 13, 14••, 15–17]. This review will focus on the basis for initial safety concerns in October 2007, subsequent regulatory activity, product labeling changes, and FDA Advisory committee activities, as well as detailed information on the multiple investigator initiated and FDA mandated safety studies which have been recently published. Additionally, we will review recent professional society and accreditation body recommendations and new efficacy data which have more firmly established the critical role UCAs play in assessing left ventricular systolic function, diagnosing intracardiac thrombus, detecting myocardial ischemia, and improving patient outcomes due to early and accurate diagnosis [18••, 19–21]. UCAs are approved in the United States for “use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve delineation of the left ventricular endocardial border” [20]. Currently, there are two commercially available agents in the United States, Optison™ (Perflutren Protein Type A Microspheres Injectable Suspension, GE Healthcare, Buckinghamshire, UK) [22] and Definity® (Perflutren Lipid Microsphere Injectable Suspension, Lantheus Medical Imaging, North Billerica, MA) [23] which were approved by the FDA in 1998 and 2001, respectively. By 2007, it was estimated that >2 million doses of these agents had been administered worldwide, and the cardiology community was slowly increasing UCA use in both transthoracic and stress echocardiography [24].

H. Boolani : M. L. Main Saint Luke’s Mid America Heart Institute, Kansas City, MO, USA

Initial FDA Safety Concerns and “Black Box Warning”

M. L. Main (*) Saint Luke’s Cardiovascular Consultants, 4330 Wornall Road, Suite 2000, Kansas City, MO, USA e-mail: [email protected]

In 2007, the FDA announced a new three part product labeling revision for both Optison™ and Definity® following spontaneous reports of ~190 “serious cardiopulmonary reactions” and four deaths which had occurred in close

Abstract In 2007, the United States Food and Drug Administration imposed a “black-box” warning on ultrasound contrast agents (UCAs) following reports of temporally related deaths and “serious cardiopulmonary reactions”. Since then, an excellent risk: benefit profile has been confirmed for UCAs in multiple studies involving several hundred thousand patients, and product labeling for both Optison™ and Definity® has been substantially revised. The American Society of Echocardiography, the revised Appropriate Use Criteria for Echocardiography, and the Intersocietal Accreditation Commission now all recommend routine use of contrast in difficult to image patients. Recent efficacy data confirms that contrast echocardiography not only enhances image quality, but also reduces downstream testing, lowers costs, improves detection of important pathology, and alters patient management. Keywords Contrast echocardiography . Contrast enhanced ultrasound . Ultrasound contrast agents . Optison™ . Definity® . FDA . Black-box warning

Introduction

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temporal relationship to UCA administration, but without other obvious causal relationship [1]. This revised prescribing information revision included: 1) A “black box warning” (which indicated that “serious cardiopulmonary reactions including fatalities have occurred during or within 30 minutes following administration.” 2) Multiple new disease state contraindications to UCA use including “worsening or clinically unstable congestive heart failure, acute myocardial infarction or acute coronary syndromes, serious ventricular arrhythmias or high risk for arrhythmias due to prolongation of the QT interval, and respiratory failure as manifest by signs or symptoms of carbon dioxide retention or hypoxemia, severe emphysema, pulmonary embolic or other conditions that cause pulmonary hypertension due to compromised pulmonary arterial vasculature.” 3) A 30 minute monitoring period including vital sign measurement and electrocardiography in all patients and cutaneous oxygen saturation monitoring in patients “at risk for hypoxemia.” The black box warning and associated restrictions on use in both sick and ambulatory patients had an immediate chilling effect on UCA use in the United States, with many echocardiography laboratories foregoing UCA administration altogether. Marketing data for calendar year 2008 indicates that UCAs were only used in 3.2 % of stress echocardiograms and 0.4 % of resting transthoracic echocardiograms, with both percentages markedly lower than 2007 and previous years [23]; these data were alarming given conservative estimates that 10-15 % of echocardiograms in the United States were technically difficult or inadequate without UCA administration [20]. Many physicians were openly critical of this FDA action citing significant existing safety and efficacy data, lack of a proven causal relationship between the reported adverse events and UCA administration, and the fact that the four reported deaths all occurred in patients with significant underlying cardiovascular or pulmonary thromboembolic disease [1, 25, 26]. Critics also cited the comparative risks of other cardiovascular imaging procedures (which would now be necessary in patients with inadequate non-contrast enhanced echocardiograms), including a 1:1000 risk of death with diagnostic coronary angiography [27], a 1:2500 risk of myocardial infarction or death with exercise treadmill testing [28], and a 1:1000 to 1:10,000 lifetime risk of fatal malignancy following stress single-photon emission computed tomography or radionuclide ventriculography [29, 30]. Additionally, transesophageal echocardiography (oftentimes recommended when baseline transthoracic imaging is difficult) is associated with an approximate 0.2 % to 0.5 % risk of serious complication [31].

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Studies Evaluating the Safety of Optison™ and Definity® Beginning in early 2008, a large body of investigator initiated safety literature began to emerge (see Table 1).The first of these studies, conducted by Kusnetzky and colleagues at Saint Luke’s Mid America Heart Institute [2], was a retrospective comparison of acute mortality in hospitalized patients undergoing echocardiography either with or without an ultrasound contrast agent. In 18,671 consecutive studies, 6196 were performed with the ultrasound contrast agent Definity®, while the remaining 12,475 were unenhanced examinations. At 24 hour follow-up, 0.37 % of the patients undergoing non-contrast enhanced echocardiography had died, compared with a mortality rate of 0.42 % in patients receiving Definity®, a difference that was not statistically significant (p00.60). Additionally, patients who received Definity® were sicker at baseline with a higher prevalence of co-morbidities such as diabetes mellitus, hypertension, chronic obstructive pulmonary disease, coronary artery disease, and left ventricular systolic dysfunction (all p <0.001 compared with non-contrast examination patients) [2]. In a subsequent retrospective study of similar design which utilized the Premier Perspective Database, acute mortality was assessed in 4,300,966 hospitalized patients who underwent echocardiography either with or without an ultrasound contrast agent (Definity® was administered to 58,254 patients) [3]. One day mortality rates were 1.08 % for patients undergoing unenhanced echocardiography and 1.06 % for patients undergoing contrast enhanced studies (p00.613). Multivariate logistic regression analysis revealed that patients receiving a contrast agent were 24 % less likely to die within 1 day in comparison with patients undergoing unenhanced echocardiography (adjusted odds ratio 00.76, 95 % confidence interval 0.70 to 0.82) [3]. Two large registry studies have evaluated the risk of acute serious adverse events associated with ultrasound contrast administration [4, 5]. Herzog reported results from a large prospective registry at the Hennepin County Medical Center in Minneapolis [4]; 3051 patients received Optison™ and 12,974 received Definity®. There were no adverse events with Optison™, while 0.15 % of patients experienced an adverse event with Definity®. Serious but non-fatal cardiopulmonary events (consistent with anaphylactoid reactions) occurred at a rate of 0.031 %. Of the patients experiencing these serious adverse events, 65 % were women and 65 % had a previous history of atopy. A larger multicenter registry study (which incorporated the Herzog data) was subsequently published by Wei and colleagues [5] in the Journal of the American Society of Echocardiography and included 66,164 doses of Definity®, and 12,219 doses of Optison™ (which represented UCA use

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Table 1 Peer reviewed publications evaluating commercially available ultrasound contrast agent safety Study

Patients Receiving Contrast

Objective

Outcome

Kusnetzky et al.[2]

6196

Short term mortality versus non contrast

Main et al. [3]

58,254

Short term mortality versus non contrast

Herzog [4] Wei et al. [5] Dolan et al. [6]

16,025 78,383* 34,447

SAE rate SAE rate Short and intermediate events in rest and stress echocardiography

Gabriel et al. [7] Shaikh et al. [8] Abdelmoneim et al. [9]

4786 5069 10,792

SAE in stress echocardiography SAE in stress echocardiography Short and long term safety in stress echocardiography

No increase in crude mortality in hospitalized patients undergoing contrast echocardiography compared to controls No increase in crude mortality in hospitalized patients undergoing contrast echocardiography compared to controls; lower risk adjusted mortality in patients receiving contrast Serious non-fatal reactions in 0.03 % Serious non-fatal reactions in 0.01 % No short term adverse events with contrast. No increase in MI or mortality compared to control group No increase in SAE rate with contrast No increase in SAE rate with contrast No increase in short or long-term risk of death or MI

Abdelmoneim et al. [10]

6164**

Exuzides et al. [11]

2900

Short and long term safety in stress echocardiography in patients with documented right ventricular systolic pressure Short term mortality in critically ill versus non-contrast

Wei et al. [12•]

32

Pulmonary hemodynamic study in patients at baseline and following contrast administration

Weiss et al. [13]

1053

Risk of SAE within 30 minutes of contrast administration

No increase in short or long-term risk of death or MI

No increase in crude mortality in hospitalized patients undergoing contrast echocardiography compared to case-matched control patients. Administration of contrast does not alter pulmonary or systemic hemodynamics in control patients or patients with baseline mild to moderate pulmonary hypertension Contrast well tolerated in routine clinical practice; no SAEs.

SAE0serious adverse event; MI0myocardial infarction *Includes 14,412 patients also reported on in reference [4] **These patients were also included in reference [9] Adapted from Main ML, Goldman JH, Grayburn PA. Ultrasound contrast agents: balancing safety versus efficacy Expert Opin Drug Saf 2009;8:49–56 [16]

in 5 % of transthoracic and 28 % of stress echocardiograms in the 12 ultrasound laboratories included in the study). Of the total doses, greater than 10,000 were administered to patients who were either critically ill or experiencing acute chest pain. Severe reactions occurred in 0.01 % of patients, and in 0.006 % of the patients (n04) were consistent with an anaphylactoid reaction. No deaths occurred, and all of the patients recovered with medical treatment. Interestingly, no serious adverse events were reported in sick hospitalized patients, and all severe reactions occurred within 30 minutes of contrast agent administration (the majority within 3 minutes of injection).

Safety of UCAs has also been established in patients undergoing stress echocardiography (although neither Optison™ nor Definity® has been expressly approved for a stress echocardiography indication). Dolan and colleagues [6] retrospectively analyzed 42,408 patients who underwent contrast enhanced echocardiography at three institutions, including 18,749 patients who underwent stress echocardiography (13,056 dobutamine stress echocardiography and 5693 exercise echocardiograms). In patients undergoing stress echocardiography, no deaths or myocardial infarctions were observed within 30 minutes, and one death and five non-fatal myocardial infarctions were observed within 24

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hours—these rates are strikingly similar to the historical rates of death or myocardial infarction associated with exercise treadmill exercise testing [28]. Gabriel et al. [7] reported on 2022 patients who underwent dobutamine stress echocardiography and 2764 patients who underwent exercise echocardiography with a UCA at the Cleveland Clinic. Complication rates in these patients were compared with those in a control group of 5012 matched patients who did not receive contrast. There were no differences in the rates of severe adverse events (0.19 % versus 0.17 %, p00.7), death within 24 hours (0 % versus 0.04 %, p00.1), cardiac arrest (0.04 % versus 0.04 %, p0 0.96), or sustained ventricular tachycardia (0.2 % versus 0.1 %, p00.32) in patients who received a UCA versus those who underwent unenhanced stress echocardiography. Shaikh and colleagues [8] evaluated 5069 patients who underwent pharmacologic or exercise echocardiography (2914 of whom received a UCA). Compared to patients undergoing unenhanced studies, patients receiving contrast were older (median age 61 years versus 58 years) and had a higher prevalence of left ventricular systolic dysfunction (14 % versus 11 %) (both p<0.001). No sustained ventricular tachycardia, ventricular fibrillation, cardiac arrest or death occurred in either group. There was one myocardial infarction and one anaphylactoid reaction in the UCA group versus none in the unenhanced group (p00.51). Finally, Abdelmoneim et al. studied 26,774 patients who underwent stress echocardiography [9], 10,792 of who received a UCA. Short-term (<072 hours and<030 days) and long-term (up to 4.5 years) end points included death and myocardial infarction. Patients who received a UCA were older and sicker—despite this, there were no differences in rates of myocardial infarction at 72 hours (0.05 % versus 0.06 %, p0 0.72), death at 72 hours (0.02 % versus 0.03 %, p00.54), myocardial infarction at 30 days (0.2 % versus 0.2 %, p0 0.64) or death at 30 days (0.5 % versus 0.8 %, p00.05) between patients who underwent contrast enhanced versus unenhanced echocardiography, respectively. Over long-term follow-up (up to 4.5 years), there was no difference in the hazard ratio for death or myocardial infarction comparing patients undergoing contrast versus unenhanced echocardiography [9]. Safety of UCAs has also been evaluated in patients with pulmonary hypertension, a subset of patients originally contraindicated for UCA administration by the FDA in 2007 [1]. Abdelmoneim and colleagues separately evaluated a subset of 16,434 patients (of their original 26,774 stress echocardiography patients) [10] in whom right ventricular systolic pressure was determined at the time of contrast administration; of these, 6164 received contrast. In 414 patients with right ventricular systolic pressures>050 mmHg, there was no significant difference in myocardial infarction within 72 hours ( 0 % versus 0.3 %), death within 72 hours (0 % versus 0 %), myocardial infarction within 30 days (0.2%versus 0.3 %), or death within

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30 days (1.9 % versus 1.6 %) in patients undergoing contrast enhanced versus unenhanced stress echocardiography (all p values>0.1) [10]. In addition to these early studies, three recently published reports were performed as part of a post marketing risk mitigation plan developed by the UCA manufacturers and the FDA. In the first of these, the risk of mortality in critically ill patients undergoing contrast enhanced echocardiography (with Optison™) versus unenhanced echocardiography was assessed by Exuzides et al. [11] in a retrospective study using a patient subset derived from the Premier Perspective Database. A total of 2900 patients undergoing Optison™ enhanced echocardiography were each propensity matched with four control patients who underwent unenhanced echocardiography while hospitalized. Contrast echocardiography was not associated with an increase in same day mortality (OR 1.18; 95 % CI 0.82 to 1.71, p00.37). The effect of Definity® on pulmonary and systemic hemodynamics was prospectively determined by Wei and colleagues [12•] in 32 patients undergoing elective right heart cardiac catheterization (16 of whom had normal baseline pulmonary artery systolic pressure and 16 of whom had elevated baseline pulmonary artery systolic pressure). Following administration of a clinically relevant dose of Definity® (10 ul/kg) as a slow bolus, there were no significant changes in pulmonary or systemic hemodynamics in either group. Finally, the risk of adverse cardiopulmonary events in patients undergoing Definity® enhanced echocardiography in routine clinical practice was prospectively assessed in 1053 patients in the multicenter CaRES Study (Contrast Echocardiography Registry for Safety Surveillance) [13]. No deaths, serious adverse events, or other significant adverse events occurred. In a large meta-analysis [14••] including eight of these individual studies (which included 211,162 patients who received an ultrasound contrast agent and 5,078,666 patient who underwent unenhanced echocardiography acting as controls), Khawaja and colleagues reported a pooled odds ratio for all-cause mortality for the contrast group of 0.57 (95 % confidence interval00.32-1.01). Additionally, data was available on the incidence of acute allergic/anaphylactic reactions in 110,500 patients drawn from six individual studies. Overall, allergic reactions occurred in 0.009 % of patients and anaphylactic reactions occurred in 0.004 % of patients [14••].

Product Label Modification and FDA Cardio-Renal Advisory Panel in 2008 In May 2008, following publication of initial safety data, intense advocacy efforts by healthcare professionals, and a

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more complete understanding of the risk: benefit relationship for UCAs, the FDA announced substantive product label revisions for both Optison™ and Definity®. Although a “black box warning” was left in force, disease state contraindications were modified to warnings, and the mandated 30 minute monitoring period was lifted for all patients except those with pulmonary hypertension (not otherwise defined) and patients with “unstable cardiopulmonary conditions” [33]. Additionally, the FDA Cardio-Renal panel was convened on June 24th 2008 to review safety considerations in the development of ultrasound contrast agents. Stated objectives of this meeting included a review of summary data on UCA development, determination of study designs to assess UCA safety, and to reacquaint panel members with UCAs since two additional UCAs were in late stage clinical trial programs (neither of these agents was subsequently approved by the FDA) [34]. Prior to this meeting, the FDA also released details on a post-marketing risk mitigation program developed in conjunction with Lantheus Medical Imaging and GE Healthcare which included three separate safety studies for each manufacturer (results for three of these are detailed above, see also Table 2). Each of the U.S. manufacturers agreed to perform 1) a retrospective observational study using a large administrative database to determine the risk of mortality in critically ill patients undergoing echocardiography either with or without an ultrasound contrast agent, 2) a prospective invasive pulmonary hemodynamic study in patients with normal or elevated baseline pulmonary artery systolic pressure, and 3) a prospective multicenter safety registry in approximately1000 patients [33].

FDA Panel Meeting in May 2011 A combined meeting of the FDA Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety Advisory Panel was held on May 2, 2011 to review the results of the risk mitigation studies previously approved in 2008, and to discuss whether further product label modifications should be considered for the UCA class [15]. Results of the safety studies for both Optison™ and Definity® are shown in Table 2. All six of these studies revealed largely exculpatory results; neither retrospective study in the critically ill showed an increase in mortality in patients undergoing contrast enhanced echocardiography in comparison with patients not receiving a contrast agent (the Lantheus study actually demonstrated a statistically significant lower mortality in the contrast arm), there was no evidence of significant change in pulmonary or systemic hemodynamics in either right heart cardiac catheterization study, and the large (~1000 patient) safety registries were free of any serious adverse events. Despite these findings, the panel was divided on whether further label changes were justified for either agent and no firm consensus emerged [35].

Recent Product Label Revisions On October 24th, 2011, the FDA announced additional safety label modifications for Definity® [35]. These included an acknowledgement that most serious adverse events occur within 30 minutes of administration and are rare, deletion of the required monitoring period in patients with pulmonary hypertension or “unstable cardiopulmonary

Table 2 FDA mandated post marketing safety studies for ultrasound contrast agents* Pulmonary Hemodynamic Study

Critically Ill Propensity Matched Database

Routine Clinical Care Registry

Lantheus Medical Imaging

n032 *

n01053**

GE Healthcare

No change in PA pressure with Definity® No deaths or SAE n030

n015,798 propensity matched patients HR00.683 (0.591-0.789)

No change in PA pressure with Optison™ No deaths or SAEs

n02884 propensity matched patients*** HR01.4 (0.965-2.030)

No deaths or serious adverse events at 24 hours

n01039 No deaths or serious adverse events

* Data from this study separately published as reference [12•] ** Data from this study separately published as reference [13] *** Data from this study separately published as reference [11] *Data available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM256586.pdf Adapted from Patil H, Main ML [32].

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conditions”, and deletion of a previous statement indicating that the “safety and efficacy of Definity® with exercise stress or pharmacologic stress echocardiography has not been determined”. No additional product label changes have been announced for Optison™. However, since the FDA has historically viewed these agents as similar and members of the “perflutren class”, it seems likely that similar prescribing information changes for Optison™ may be issued in the near future.

415 Table 3 Acute hypersensitivity reactions IgE mediated type I

CARPA

- Reaction after repeated exposure - Reaction is stronger upon repeated exposure - Reaction does not cease without treatment - Low reaction rate

- No prior exposure necessary - Reaction is milder or absent upon repeated exposure - Spontaneous resolution - Higher reaction rate

Adapted from Szebeni J. Toxicology 2005. 216: 106-121 [36]

Safety Summary Based upon our current large body of safety data, the following conclusions are justified: 1) There is no increase in mortality in hospitalized patients undergoing echocardiography with a UCA in comparison with patients undergoing unenhanced echocardiography, despite the fact that patients receiving a contrast agent are generally sicker. Some data suggests an association with significantly lower mortality in the UCA patients, perhaps due to earlier and more accurate diagnosis [2, 3, 11]. 2) UCAs are safe for use in exercise or pharmacologic stress echocardiography. Multiple studies reveal no increase in the risk of serious arrhythmia, myocardial infarction or death with contrast enhanced stress echocardiography in comparison with patients undergoing non-contrast enhanced examinations [6–9]. 3) UCA administration appears safe in patients with pulmonary hypertension, and is not associated with significant changes in pulmonary or systemic hemodynamics when administered at clinically relevant doses [10, 11, 12•]. 4) UCA administration is associated with an approximate 1:10,000 dose risk of anaphylactoid reaction [4, 5]. Rare but serious anaphylactoid reactions following UCA administration are believed secondary to a recently described variant of the type 1 hypersensitivity reaction which has been termed complement activation related pseudo allergy, or CARPA reactions [36]. These reactions differ from classic type 1 hypersensitivity reactions in several respects (see Table 3). These reactions can be readily mitigated by prompt recognition and treatment of anaphylaxis—in our laboratory we have placed “allergy kits” in close proximity to all echocardiographic equipment. Automatic injectable epinephrine pens are the most important component of these kits, and our sonographers are trained to recognize and treat severe allergic reactions when they occur. We recommend this approach in all echocardiography laboratories. Although the per dose risk of anaphylactoid reaction is very small, these reactions may be particularly poorly tolerated in patients with limited or no cardiopulmonary reserve.

Recent Professional Society and Accreditation Body Recommendations In 2008, the American Society of Echocardiography published a “Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography” [20]. Although UCAs have been approved by the FDA for “opacification of the left ventricular cavity and enhancement of the left ventricular cavity in patients with technically difficult echocardiograms” this guideline level document suggested UCAs be considered in a much broader context including: 1) All difficult to image patients with reduced image quality presenting for rest echocardiography. 2) All difficult to image patients with reduced image quality presenting for stress echocardiography. 3) All patients presenting for assessment of left ventricular systolic function (in order to reduce variability and increase reader confidence). 4) For confirmation or exclusion of suspected disease entities such as apical hypertrophic cardiomyopathy, ventricular noncompaction, apical thrombus, and complications of myocardial infarction including left ventricular aneurysm, pseudoaneurysm, and myocardial rupture. 5) For assessment of intracardiac masses. 6) In the intensive care unit when unenhanced echocardiography does not yield diagnostic images. 7) For enhancement of spectral Doppler signals when a clearly defined profile is not obtained with baseline imaging. More recently, revised Appropriate Use Criteria (AUC) for Echocardiography were published in 2011 [21]. This document replaces and updates the original transthoracic and transesophageal AUC published in 2007 [37] and the original stress document published in 2008 [38]. An appropriate imaging study is defined as “one in which the expected incremental information, combined with clinical judgment, exceeds the negative consequences by a sufficiently wide margin for a specific indication that the procedure is generally considered acceptable care and a reasonable approach

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for the indication” [21]. This document indicates that contrast use in tranthoracic, transesophageal or stress echocardiography is highly appropriate (with a median score of 8 on a 1-9 scoring system) when “ >02 contiguous segments are not seen on non-contrast images.” However “routine use of contrast” is deemed highly inappropriate (median score of 1) “when all left ventricular segments are visualized on noncontrast images” [21]. Finally, the Intersocietal Accreditation Commission (IAC) recently published new guidance for performance of stress echocardiography. For stress echocardiography, standard elements of exam performance include a UCA indication when “two contiguous segments are not visualized as it provides greater accuracy in determining left ventricular function”. The IAC additionally now mandates that contrast must be used if adequate endocardial visualization is not accomplished with harmonic imaging [39].

Recent Efficacy Studies Although it is well-recognized that contrast enhanced echocardiography improves accuracy and reproducibility in assessment of left ventricular regional and global systolic function (particularly in patients with technically difficult baseline studies) [40–46], large outcomes studies have been previously lacking. In a recent prospective study, Kurt and colleagues [18••] enrolled 632 consecutive patients with technically difficult baseline images; all of these patients subsequently underwent a complete baseline unenhanced echocardiogram and a Definity® enhanced study. The clinician caring for each patient was contacted initially with results of the non-contrast examination and asked whether he would a) plan to order additional cardiac imaging tests and b) whether he would make any changes in the patient’s cardiovascular drug regimen. The clinician was then advised of the UCA enhanced examination results, and again queried regarding potential management changes. The results of this study were quite striking, administration of a UCA reduced the percent of uninterpretable studies from 11.7 % to 0.3 % and the percent of technically difficult studies from 86.7 % to 9.8 % (p<0.0001). Additionally, better image quality resulted in important management changes; additional diagnostic testing was avoided in 32.8 % of patients, and pharmacologic management was altered in 10.4 %. The effect on management was most pronounced in the surgical intensive care unit where 62.9 % of patients had either an imaging test avoided or an important change in prescribed medication resulting from the UCA enhanced examination. Finally, contrast enhanced echocardiography was cost-effective with a savings of $122 per patient [18••].

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Additional recent data also supports the recommendation for contrast enhanced echocardiography for the confirmation or exclusion of left ventricular thrombus. In a study of 121 patients at high risk for left ventricular thrombus due to myocardial infarction or heart failure, Weinsaft and colleagues [19] performed three anatomic cardiac imaging tests (contrast echocardiography, non-contrast echocardiography, cinecardiac magnetic resonance imaging) and one tissue characterization examination (delayed enhancement cine-cardiac magnetic resonance imaging) which acted as a reference standard technique. Left ventricular thrombus was identified in 24 patients by delayed enhancement cardiac magnetic resonance imaging; contrast echocardiography almost doubled the sensitivity for thrombus detection (61 % versus 33 %, p<0.05), and also improved accuracy (92 % versus 82 %, p<0.01) compared with non-contrast echocardiography. Thrombus which was missed by contrast echocardiography tended to be mural or small volume [19]. Left ventricular thrombus detection was also assessed in the Kurt study [18••]. On the baseline non-contrast examination, left ventricular thrombus was suspected in 35 patients and thought “definite” in three patients; after contrast, only one of these 38 patients had suspected thrombus. Importantly, five additional patients with suspected thrombus were identified (p<0.001). The importance of UCA administration in patients undergoing dobutamine stress echocardiography was recently evaluated in a prospective randomized cross-over study [47]. A total of 101 patients underwent two dobutamine stress echo studies, one performed with, and one without, a UCA. Interpretation of wall motion with “high-confidence” improved from 36 % to 74 % with contrast (P< 0.001). Accuracy of stress testing was similar for unenhanced and UCA enhanced exams when only two or fewer myocardial segments were not well visualized at baseline. When >2 myocardial segments were not visualized on the baseline exam, UCA administration improved accuracy (using a coronary angiography reference standard) from 28 % to 59 % (p0.005). These findings compare favorably with recommendations for UCAs in the recently updated Appropriate Use Criteria for Echocardiography [21].

Conclusions Contrast echocardiography is both safe and effective. Published results in several hundred thousand patients since 2008 have confirmed the excellent risk: benefit profile of UCAs in all major patient groups including ambulatory individuals, hospitalized inpatients, patients with pulmonary hypertension and other significant underlying cardiopulmonary disease, as well as patients with known or suspected myocardial ischemia undergoing exercise or pharmacologic stress echocardiography. Professional society guidelines, appropriate use criteria,

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and accreditation bodies all support routine use of contrast echocardiography in difficult to image patients. Recent efficacy studies confirm that contrast-enhanced echocardiography reduces the proportion of technically difficult studies, improves detection of important pathology, reduces cost, and results in important patient management changes.

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11.

12.

Disclosure No potential conflicts of interest relevant to this article were reported. Dr. Main has received research grants from Lantheus Medical Imaging, GE Healthcare and Bracco. 13.

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