ICUS Weekly News Monitor 1-9-2009

1.  Auntminnie,  Jan 8, 2009,    JACC study shows no additional risk from echo contrast agents
By Eric Barnes

2.  Physics in Medicine and Biology,  Feb 2009,    Toward contrast-enhanced microwave-induced thermoacoustic imaging of breast cancer: an experimental study of the effects of microbubbles on simple thermoacoustic targets    By Alireza Mashal, John H Booske and Susan C Hagness

3.  PR Newswire,  Jan 5, 2009,  Micro-Bubble Echo Contrast Procedures Continue to Rebound in October 2008

4.  JACC (Journal of the American College of Cardiology),  Dec 31, 2008    Safety and Efficacy of Commercially Available Ultrasound Contrast Agents for Rest and Stress Echocardiography

5.  World Journal of Gastroenterology,  Dec 29, 2008,    How to enhance nonthermal effects of ultrasound    By Lin Tian


___________
Auntminnie
Jan 8, 2009

JACC study shows no additional risk from echo contrast agents
By Eric Barnes

Despite recent safety warnings, ultrasound contrast agents are safe and effective for assessing patients during echocardiography, concludes a massive review of more than 42,000 patients examined at three institutions in the U.S.
The retrospective study, which appears in this month's Journal of the American College of Cardiology, found no significant differences in death rate or myocardial infarction (MI) between patients who received ultrasound contrast agents and those who did not during stress echocardiography.
In 2007, the U.S. Food and Drug Administration (FDA) mandated the placement of a black box warning for ultrasound contrast agents Definity from Lantheus Medical Imaging (North Billerica, MA) and Optison from GE Healthcare (Chalfont St. Giles, U.K.), following reports of 11 deaths that occurred around the time of their administration.
The warning was modified in July 2008 to exclude only the most unstable patients from use of the agents. However, many institutions had long since stopped using echo contrast, a product that proponents believe significantly improves the quality of many exams that would otherwise be unreadable.
Echo contrast's utility was highlighted in this month's JACC article, authored by Dr. Melda Dolan, from Saint Louis University Hospital in Missouri, as well as colleagues from University of Nebraska Medical Center in Omaha and the Mayo Clinic in Rochester, MN (JACC, January 2009, Vol. 53, pp. 32-38).
"Unfortunately, up to 30% of studies are deemed technically difficult due to poor image quality, making these studies very challenging to interpret," the authors wrote. "Patients with large body habitus, chest wall deformities, and severe chronic lung disease are at higher risk of having suboptimal image quality. Furthermore, bedside echocardiograms are frequently ordered to identify the cause of hemodynamic instability and respiratory failure in critically ill patients."
But while the deaths reported prior to the black box warning (10 from Definity, one from Optison) were temporally related to use of the agents, no causal link was ever found, and many researchers believe that none exists.
"As has been the case, serious adverse events (death or nonfatal MI) within 24 hours of contrast use could be easily explained by the patient's underlying condition at the time of the study or to induced ischemia during stress echocardiography," the authors wrote.
Single-center studies had shown no additional morbidity or mortality resulting from use of the agents; however, their safety had not been comprehensively reviewed in a multicenter setting, Dolan and colleagues wrote. Therefore, the present study aimed to comprehensively define the risks and benefits of ultrasound contrast agents in patients undergoing stress echocardiography.
The group analyzed the records of 42,408 patients at three different institutions who had baseline suboptimal images and/or underwent nuclear myocardial perfusion imaging and received contrast agents between 1999 and 2007. Of these, 18,749 had stress echocardiography exams. Measured outcomes included death and myocardial infarction within 30 minutes, 24 hours, or during long-term follow-up.
Results
There were no deaths or MIs among the 23,659 patients who received contrast for suboptimal resting studies or myocardial perfusion studies. There was one death and five nonfatal MIs within 24 hours of contrast administration.
"This was not different from a matched cohort of 15,989 patients not receiving contrast," Dolan and colleagues wrote. "In the matched group of 5,900 consecutive patients with optimal resting studies and no contrast use, no events occurred within 30 minutes, but seven nonfatal MIs and one death occurred within 24 hours."
Among the 18,749 patients who underwent stress echocardiography, there were no deaths or MIs within 30 minutes, and there was one death and five nonfatal MIs (three after Definity, two after Optison) within 24 hours.
There was no reason to believe that the use of contrast agents contributed to any of the MIs, or to the death of the stress echocardiography patient, who had developed frequent runs of ventricular tachycardia requiring intravenous antiarrhythmic therapy, according to the authors. This patient eventually developed disseminated intravascular coagulation. On day 11, dobutamine stress echocardiography and real-time myocardial contrast echocardiography with Optison contrast were performed without complication, but within 24 hours the patient developed recurring ventricular tachycardia and died 22 hours after contrast administration.
Similarly, at 30 days there were no statistically significant differences between patients undergoing dobutamine stress echocardiography or exercise stress electrocardiography with or without contrast.
In the 10,788 patients who received contrast, 37 (0.34%) died and 68 (0.63%) experienced an MI. In a matched cohort of 15,989 patients who did not receive contrast, there were 62 (0.39%) deaths and 73 (0.46%) MIs.
Additionally, there were no significant differences in 4,011 patients who received contrast for suboptimal image quality during echocardiography versus a matched group of 1,923 patients who had optimal images and did not require contrast.
"Endocardial border visualization in patients with suboptimal images resulted in comparable sensitivity (81% vs. 73%) and diagnostic accuracy (82% vs. 77%) for wall motion analysis compared with patients with optimal image quality," the authors wrote. "At long-term follow-up, abnormal wall motion and/or myocardial perfusion predicted adverse outcomes (20.6%) when compared with patients with normal studies (3.7%)."
Image quality improved with contrast use
Significant incremental value was derived from contrast use at all three participating centers, which used contrast-enhanced left ventricular opacification to yield sensitivity and specificity equivalent to that of patients who had optimal image quality without contrast, the authors wrote.
"The ability of stress echocardiography to detect coronary artery disease is clearly related to the ability to visualize all myocardial segments in each coronary artery territory," they wrote.
When echo studies need to be cancelled due to suboptimal windows and contrast is not available, the alternative tests usually involve the use of ionizing radiation and additional costs and risk to the patient, they added.
In addition, myocardial perfusion imaging with contrast, though not yet FDA approved, added significant incremental value to dobutamine stress echocardiography, the group wrote.
The study was large, but its retrospective design was a limitation, and different cohorts were used to compare patients who received contrast with those who did not, the authors noted.
"The risks of both short-term and long-term events, defined as nonfatal MI and death, after contrast administration are very low and are no different than in patients not receiving contrast during stress echocardiography," Dolan and colleagues concluded. "Contrast use in patients with suboptimal images improves feasibility and accuracy of stress echocardiography testing. Failure to use contrast agents in patients with suboptimal images may result in a misdiagnosis and/or additional alternative imaging techniques with greater inherent risks."
Experience in this and other recent studies comprising more than 60,000 patients demonstrates that "there is no evidence to suggest a causal relationship between the use of commercially available contrast and serious adverse events," they wrote. "The findings in this study provide physicians with the confidence to use contrast agents during stress testing when clinically indicated."


____________________________
Physics in Medicine and Biology
Feb 2009  Issue #3

Toward contrast-enhanced microwave-induced thermoacoustic imaging of breast cancer: an experimental study of the effects of microbubbles on simple thermoacoustic targets
By Alireza Mashal, John H Booske and Susan C Hagness

Department of Electrical and Computer Engineering, University of Wisconsin, Madison, WI, USA
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. , This email address is being protected from spambots. You need JavaScript enabled to view it. and This email address is being protected from spambots. You need JavaScript enabled to view it.

Abstract. Microwave-induced thermoacoustic tomography (MI-TAT) is an imaging technique that exploits dielectric contrast at microwave frequencies while creating images with ultrasound resolution. We propose the use of microbubbles as a dielectric contrast agent for enhancing the sensitivity of MI-TAT for breast cancer detection. As an initial investigation of this concept, we experimentally studied the extent to which the microwave-induced thermoacoustic response of a dielectric target is modified by the presence of air-filled glass microbubbles. We created mixtures of ethylene glycol with varying weight percentages of microbubbles and characterized both their microwave properties (0.5–6 GHz) and thermoacoustic response when irradiated with microwave energy at 3 GHz. Our data show that the microbubbles considerably lowered the relative permittivity, electrical conductivity and thermoacoustic response of the ethylene glycol mixtures. We hypothesize that the interstitial infusion of microbubbles to a tumor site will similarly create a smaller thermoacoustic response compared to the pre-contrast-agent response, thereby enhancing sensitivity through the use of differential imaging techniques.


_____________
PR Newswire
Jan 5, 2009

Micro-Bubble Echo Contrast Procedures Continue to Rebound in October 2008
(Decision Resources, Inc.)

Both Definity(R) and OptisonTM Usage Increased During the Same Study Period, According To New Data from Arlington Medical Resources

MALVERN, Pa., Jan. 5 /PRNewswire/ -- Arlington Medical Resources (AMR), a provider of premier market intelligence for the pharmaceutical and diagnostic imaging industries, finds that the number of micro-bubble echo contrast procedures performed in October 2008 have increased by more than 50 percent, to nearly 18,000 procedures, when compared to May 2008. Micro-bubble echo contrast procedures began declining sharply in October 2007, from nearly 55,000 procedures in September 2007, as a result of a black box warning issued by the FDA in October 2007.

A revised black box warning issued in May 2008 has contributed to this rebound as well as physicians and sonographers reestablishing protocols for contrast usage in their institutions. A micro-bubble echo contrast agent is administered intravenously and used for contrast enhancement during echocardiographic procedures.

The newly released edition of the U.S. Echocardiography Monthly Monitor also finds that both Lantheus Medical Imaging's Definity(R) and GE Healthcare's OptisonTM -- the two FDA approved micro-bubble echo contrast agents -- realized increased usage during the same study period.

"Continued interest in ultrasound contrast is evident with the recently released American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Agents in Echocardiography and the formation of the International Contrast Ultrasound Society (ICUS)," stated Anna Fisher, analyst at AMR.


Why Pharmaceutical & Medical Device Companies Need this Information

The U.S. Echocardiography Monthly Monitor enables pharmaceutical and medical device companies to monitor the utilization rates of echocardiography in the U.S. It is the timeliest data available to gauge movement and direction of the volume of echocardiography studies being performed and cardiac ultrasound contrast agent and pharmacological stressing agent usage.

About the U.S. Echocardiography Monthly Monitor

The U.S. Echocardiography Monthly Monitor is a monthly syndicated audit of echocardiography procedures, ultrasound contrast agents and pharmacologic stress agents used in hospitals and office-based cardiology settings. The study quantifies echocardiography procedure volumes on a national scale, split by type of echo, contrast/non-contrast, type of contrast and stressing method where applicable. The data is available 30 days after the end of each study month.

About AMR

AMR (www.AMR-data.com) serves the market intelligence needs of the pharmaceutical and diagnostic imaging industries. Research includes clinical inpatient databases that directly link anti-infective drug with indication/procedure, formulary and stocking status tracking studies, drug purchasing audits and diagnostic imaging procedure volume/contrast media usage audits. AMR is a Decision Resources, Inc. company.

About Decision Resources, Inc.

Decision Resources, Inc. is a cohesive portfolio of companies that offers best-in-class, high-value information and insights on important sectors of the healthcare industry. Clients rely on this analysis and data to make informed decisions. Please visit Decision Resources, Inc. at www.DecisionResourcesInc.com.

All company, brand or product names contained in this document may be trademarks or registered trademarks of their respective holders.

    For more information, contact:

    Natalia Morales
    Decision Resources
    781-296-2691
    This email address is being protected from spambots. You need JavaScript enabled to view it.

    Elizabeth Marshall
    Decision Resources, Inc.
    781-296-2563
    This email address is being protected from spambots. You need JavaScript enabled to view it.

Website: http://www.decisionresourcesinc.com//


_____________________________________________
JACC (Journal of the American College of Cardiology)
Dec 31, 2008

Safety and Efficacy of Commercially Available Ultrasound Contrast Agents for Rest and Stress Echocardiography
A Multicenter Experience

Melda S. Dolan, MD*,*, Simil S. Gala, MD*, Saritha Dodla, MD, Sahar S. Abdelmoneim, MD, Feng Xie, MD, David Cloutier, MS, Michelle Bierig, MPH, RDCS, RDMS*, Sharon L. Mulvagh, MD, FACC, FRCP, Thomas R. Porter, MD, FACC, FASE and Arthur J. Labovitz, MD, FACC, FACP, FCCP, FASE*
* Division of Cardiology, Saint Louis University Hospital, St. Louis, Missouri
 Section of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska
 Division of Cardiology, Mayo Clinic, Rochester, Minnesota

Manuscript received May 16, 2008; revised manuscript received August 14, 2008, accepted August 25, 2008.

* Reprint requests and correspondence: Dr. Melda S. Dolan, Division of Cardiology, Saint Louis University, 3635 Vista Avenue, 14th Floor, St. Louis, Missouri 63110-0250 (Email: This email address is being protected from spambots. You need JavaScript enabled to view it. ).

Objectives: The authors sought to define the risks versus benefits of ultrasound contrast agents in patients undergoing stress echocardiography.

Background: The Food and Drug Administration recently placed a "black box" warning on the ultrasound contrast agents Definity (Bristol-Myers Squibb Medical Imaging, Billerica, Massachusetts) and Optison (GE Healthcare, Princeton, New Jersey) after their use was temporally related to 4 deaths. The safety of contrast has not been systematically evaluated.

Methods: We retrospectively analyzed 42,408 patients at 3 different institutions who had baseline suboptimal images and/or underwent myocardial perfusion imaging and received contrast agents; 18,749 of these underwent stress echocardiography. The outcomes (death and myocardial infarction [MI]) within 30 min, 24 h, and during long-term follow-up were recorded.

Results: No deaths or MIs were observed within 30 min; 1 death and 5 nonfatal MIs were observed within 24 h. This was not different from a matched cohort of 15,989 patients not receiving contrast. At 1 h and at 30 days after contrast administration, no significant differences in death rates or MIs were observed between patients who did and did not receive contrast during their stress echocardiogram. Endocardial border visualization in patients with suboptimal images resulted in comparable sensitivity (81% vs. 73%, p = NS) and diagnostic accuracy (82% vs. 77%, p = NS) for wall motion analysis compared with patients with optimal image quality. At long-term follow-up, abnormal wall motion and/or myocardial perfusion predicted adverse outcomes (20.6%) when compared with patients with normal studies (3.7%).

Conclusions: Despite recent warnings regarding echocardiographic contrast, our findings indicate it is a safe and useful diagnostic tool in assessment of patients suspected of having coronary artery disease.


_____________________________
World Journal of Gastroenterology
Dec 29, 2008

How to enhance nonthermal effects of ultrasound
By Lin Tian

In recent years HIFU has been widely used for the treatment of solid tumors, such as liver tumor, bone tumor, and breast cancer. The mechanism for therapeutic actions of HIFU includes thermal effects and non-thermal effects with the latter dominated by cavitational effects. Adjusting acoustic parameters of pulsed high intensity focused ultrasound (PHIFU) can control thermal effects and non-thermal effects; short duty cycle and high intensity favors the occurrence of cavitation. Ultrasound contrast agent (UCA) can enhance cavitational effects. Lesions caused by non-thermal effects have characteristic pathological changes quite different from those of thermal lesions.

A research article to be published on November 21, 2008 in the World Journal of Gastroenterology addresses this question. The research group led by Professor Zhi-Biao Wang from Department of Biomedical Engineering of Chongqing Medical University used PHIFU with short duty cycle and high intensity combined with UCA to damage rabbit liver VX2 tumour by non-thermal effect, and the non-thermal damage was evaluated by histopathology.

Liver VX2 tumor model were established in 20 rabbits, which were then divided randomly into PHIFU combined with UCA group (PHIFU+UCA group) and sham group, with 10 rabbits in each group. In the PHIFU+UCA group, 0.2 mL of SonoVue was injected intravenously, followed by rapid injection of 1 mL normal saline. Fifteen seconds after the injection, the tumours were exposed to HIFU with ISP 5900W/cm2 for 90 seconds. Rabbits were sacrificed one day after HIFU exposure. Specimens of the exposed tumor tissues were obtained and observed pathologically under light microscope and transmission electron microscope. The remaining exposed tumor tissues were sent for TTC staining. Before TTC staining, tumor tissues in both the sham and the PHIFU+UCA group resembled gray fish meat; after TTC staining, the tumour tissues were uniformly stained red, with a clear boundary between tumor tissue and normal tissue. For PHIFU + UCA group, light microscopy displayed abundant vacuoles of various sizes in the cytoplasm and in some cells, chromatin margination and karyopyknosis were present. Electron microscopic examination revealed presence of karyopyknosis and chromatin margination in some cells, intercellular space widening, the presence of high electron-density apoptotic bodies and many vacuoles of various sizes in the cytoplasm.

This study found that PHIFU combination with UCA can enhance non-thermal effects of ultrasound, and the pathological characteristics of the non-thermal damage is different from those of thermal damage. Immunohistochemical detection found that PHIFU combined with UCA can promote tumor cell apoptosis and inhibit tumor cell proliferation, which will be reported in another article.

ICUS Weekly News Monitor 12-29-2008

1. Sonography News, Dec 23, 2008, Study Finds Survival Benefit Among Hospitalized Patients Undergoing Definity®- Enhanced Echocardiography 2. ZAMP Bionews, Dec 22, 2008, New Study Finds Survival Benefit Among Hospitalized Patients Undergoing Definity®- Enhanced Echocardiography 3. Associated Press, Dec 8, 2008, FDA cites safety concerns with Acusphere drug By Matthew Perrone _______________ Sonography News Dec 23, 2008 Study Finds Survival Benefit Among Hospitalized Patients Undergoing Definity®- Enhanced Echocardiography Lantheus Medical Imaging, Inc. a worldwide leader in diagnostic imaging, announced recently new data from a retrospective, multicenter, cohort study of over four million hospitalized patients that shows similar unadjusted mortality rates for patients receiving DEFINITY® Vial For (Perflutren Lipid Microsphere) Injectable Suspension enhanced resting echocardiography exams when compared with patients who did not receive DEFINITY®. Although the patients that received DEFINITY® were sicker on average and had a higher baseline mortality risk prior to the exam, following DEFINITY® administration these same patients exhibited a 24% reduced risk of mortality over 24 hours compared to the those patients who received only echocardiography without the ultrasound contrast agent. These study findings were published in the December 2008 issue of The American Journal of Cardiology. "As the largest retrospective, observational study to date to examine the short-term safety profile of perflutren-containing ultrasound contrast agents, the data highlight the relatively low incidence of adverse safety reactions associated with DEFINITY® and demonstrate a significantly lower risk of acute mortality for patients receiving DEFINITY®-enhanced echocardiograms," said Mark Hibberd, M.D., Ph.D., Senior Medical Director, Global Medical Affairs, Lantheus Medical Imaging, Inc. and co-author on the study. ______________ ZAMP Bionews Dec 22, 2008 New Study Finds Survival Benefit Among Hospitalized Patients Undergoing Definity®- Enhanced Echocardiography Lantheus Medical Imaging, Inc. a worldwide leader in diagnostic imaging, announced recently new data from a retrospective, multicenter, cohort study of over four million hospitalized patients that shows similar unadjusted mortality rates for patients receiving DEFINITY® Vial For (Perflutren Lipid Microsphere) Injectable Suspension enhanced resting echocardiography exams when compared with patients who did not receive DEFINITY®. Although the patients that received DEFINITY® were sicker on average and had a higher baseline mortality risk prior to the exam, following DEFINITY® administration these same patients exhibited a 24% reduced risk of mortality over 24 hours compared to the those patients who received only echocardiography without the ultrasound contrast agent. These study findings were published in the December 2008 issue of The American Journal of Cardiology. "As the largest retrospective, observational study to date to examine the short-term safety profile of perflutren-containing ultrasound contrast agents, the data highlight the relatively low incidence of adverse safety reactions associated with DEFINITY® and demonstrate a significantly lower risk of acute mortality for patients receiving DEFINITY®-enhanced echocardiograms," said Mark Hibberd, M.D., Ph.D., Senior Medical Director, Global Medical Affairs, Lantheus Medical Imaging, Inc. and co-author on the study. "These study findings provide the physician community with essential safety information on the use of DEFINITY®, especially among hospitalized patients, and provide valuable information on patient outcomes that bear further investigation." The study was designed to assess short-term (one-day) mortality in hospitalized patients undergoing resting transthoracic echocardiography both with and without DEFINITY®. The study analyzed more than 4.3 million patients undergoing clinically indicated echocardiography from January 1, 2002 through October 31, 2007 using the Premier Perspective Database, the largest U.S. hospital-based, service-level comparative database providing detailed resource utilization data along with patients’ primary and secondary diagnosis and procedure codes. Of this population, 4,242,712 patients received non-enhanced echocardiograms and 58,254 received contrast-enhanced studies using DEFINITY®. One-day mortality rates were 1.08% for patients undergoing non-contrast studies and 1.06% for patients undergoing DEFINITY® contrast-enhanced examinations. However, patients receiving DEFINITY® were more likely to have an increased baseline severity of illness and a higher pre-study risk of mortality. A multivariate logistic regression analysis was used to compare 24-hour mortality, controlling for case mix and clinical covariates. Patients undergoing DEFINITY® -enhanced echocardiograms had a 24% lower risk adjusted odds ratio for mortality within one day than those patients who received only echocardiography without the ultrasound contrast agent. These findings build on and corroborate a recently published multicenter retrospective study that also demonstrated no increased mortality in patients undergoing echocardiography with a contrast agent in comparison with patients undergoing non-contrast-enhanced examinations (Journal of the American College of Cardiology, Volume 51, Number 17, 2008).1 In addition, this multicenter analysis was presented in part at a meeting of the United States Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee in June, 2008. These study findings also confirm the safety profile of ultrasound contrast imaging agents and support the implementation of the recently published American Society of Echocardiography (ASE) Consensus Statement on the Clinical applications of Ultrasound Contrast Agents in echocardiography. "This study is groundbreaking in the echocardiography area, and represents the largest evaluation of resting echocardiography among hospitalized patients," continued Dr. Hibberd of Lantheus. "It is also the first to evaluate the impact of contrast echocardiography on survival among hospitalized patients. The results clearly indicate that there is no additional risk associated with DEFINITY®-enhanced studies, while in fact those patients that received DEFINITY® had improved short-term survival when compared to those who received only transthoracic echocardiograms without DEFINITY®. The study did not address the reason for this effect. These data provide the medical community with further clinical evidence of how DEFINITY® can significantly improve the standard of care for patients undergoing cardiac evaluations, and we are continuing to explore the role of DEFINITY® in specialized patient populations such as those in the ICU and receiving mechanical ventilation." Don Kiepert, President and CEO, Lantheus Medical Imaging added, "We are encouraged by these data that further demonstrate the role and clinical value of DEFINITY®, and believe these findings will answer any remaining safety questions regarding ultrasound contrast agents. Lantheus continues to remain committed to providing important safety information on the use of DEFINITY® in routine clinical practice." ______________ Associated Press Dec 8, 2008 FDA cites safety concerns with Acusphere drug By Matthew Perrone Shares of Acusphere plummeted Monday after federal regulators raised serious safety concerns about an imaging drug the company has touted as a potential blockbuster product. Watertown, Mass.-based Acusphere has asked the Food and Drug Administration to approve its AI-700 formula as an injectable drug to improve the clarity of echocardiograms, medical images of the heart. The FDA said that animal studies of the chemical showed evidence of hypertension, decreased blood pressure and abnormal behavior. The agency is "concerned that the safety risks associated with the product are inappropriate for the product's proposed clinical use," according to documents posted online Monday. Reviewers also said that the company's two studies do not give a clear picture of the product's effectiveness. Acusphere noted in its own briefing documents that there were no deaths or life-threatening side effects reported among nearly 2,000 patients tested with its drug. The company also said the drug's risk are comparable to those of other drugs used in stress testing procedures. "I think that in the vast majority of patients, AI-700 is well tolerated," Acusphere Chief Executive Sherri Oberg said in an interview Monday morning. "I think the FDA and other scientists look to animal studies for supportive evidence, but the most important information is what's found in the human studies." While Acusphere has several other drugs in development, it has no products currently on the market. Acusphere shares plunged 43 cents, or 57.3 percent, to 32 cents in midday trading after earlier hitting a 52- week low of 26 cents. The company's stock had traded between 30 cents and 92 cents in the past year. A panel of experts on Wednesday will give their opinions of the drug's safety and effectiveness. The FDA is not required to follow the group's advice, though it usually does. The Acusphere drug is part of a class of products called contrast imaging agents that are used to diagnose heart problems. The company says the microbubbles in its formulation are designed to last longer, and provide clearer images than products already on the market. The company also said its product is the first contrast agent to reveal information about blood flow through the heart — information currently gathered through exercise stress tests. The FDA's review of AI-700 comes more than a year after reports of fatal side effects with similar drugs already on the market. The agency added its most serious warning to the drugs in October 2007 after receiving about 200 reports of serious adverse reactions, seven of which caused death. In June, the FDA held a meeting to develop new safety requirements for future imaging products. Products already on the market included General Electric's Optison and Lantheus Medical Imaging's Definity.

ICUS Weekly News Monitor 12-19-2008

1. HealthImaging.com, Dec 17, 2008, Large analysis suggests echo contrast agents associated with reduced mortality By Editorial Staff 2. MarketWatch, Dec 15, 2008, Press Release New Study Published in the American Journal of Cardiology Finds Survival Benefit among Hospitalized Patients Undergoing Definity(R)- Enhanced Echocardiography 3. American Journal of Cardiology, Dec 15, 2008 Acute Mortality in Hospitalized Patients Undergoing Echocardiography With and Without an Ultrasound Contrast Agent (Multicenter Registry Results in 4,300,966 Consecutive Patients) By Michael L. Main, MD et al 4. Ultrasound, Jan 2009, Induction of Apoptosis in Sonoporation and Ultrasonic Gene Transfer By HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 Douglas L. Miller, Chunyan Dou HealthImaging.com Dec 17, 2008 Large analysis suggests echo contrast agents associated with reduced mortality. By Editorial Staff Compared with patients not receiving a contrast agent, administration of perflutren lipid microsphere (PLM) injectable suspension contrast agent during echocardiography was associated with a 24 percent decreased risk of mortality, according to a retrospective analysis in the December issue of the American Journal of Cardiology.

The authors noted that although the FDA recently relaxed the issued warnings for perflutren-containing ultrasound contrast agents on May 13, concerns still exist regarding the safety of these compounds, particularly in critically ill patients.

Michael L. Main, MD, of Saint Luke's Mid America Heart Institute in Kansas City, Mo., and colleagues examined patients undergoing echocardiography during hospitalization, which were separated into those performed without contrast enhancement and those performed with PLM injectable suspension contrast agent (Definity from Lantheus Medical Imaging of North Billerica, Mass.). Vital status within one day of the echocardiogram was available for all patients using hospital billing data.

Between Jan. 1, 2002 and Oct. 31, 2007, approximately 4.3 million patients underwent transthoracic echocardiography at rest during hospitalization: unenhanced studies were 4,242,712 and contrast-enhanced studies were 58,254.

The researchers used a multivariate logistic regression analysis to compare 24-hour mortality, controlling for case mix and clinical covariates. They found that one-day mortality rates were 1.08 percent (45,789 deaths) for patients undergoing non-contrast enhanced studies and 1.06 percent (616 deaths) for patients undergoing contrast-enhanced exams.

Main and colleagues found that in patients undergoing an echocardiogram, patients receiving PLM injectable suspension contrast agent were 24 percent less likely to die within one-day than patients not receiving a contrast agent. 

They concluded that acute crude mortality was not increased in patients receiving PLM injectable suspension contrast agent.

Lantheus provided funding for this study MarketWatch Dec 15, 2008 Press Release New Study Published in the American Journal of Cardiology Finds Survival Benefit among Hospitalized Patients Undergoing Definity(R)- Enhanced Echocardiography Multicenter Study Results Find No Difference in Acute Mortality Rates for Patients Undergoing Contrast versus Non-Contrast Echocardiograms NORTH BILLERICA, Mass., Dec 15, 2008 (BUSINESS WIRE) -- Lantheus Medical Imaging, Inc. a worldwide leader in diagnostic imaging, announced today new data from a retrospective, multicenter, cohort study of over four million hospitalized patients that shows similar unadjusted mortality rates for patients receiving DEFINITY(R) Vial For (Perflutren Lipid Microsphere) Injectable Suspension enhanced resting echocardiography exams when compared with patients who did not receive DEFINITY(R). Although the patients that received DEFINITY(R) were sicker on average and had a higher baseline mortality risk prior to the exam, following DEFINITY(R) administration these same patients exhibited a 24% reduced risk of mortality over 24 hours compared to the those patients who received only echocardiography without the ultrasound contrast agent. These study findings were published in the December 2008 issue of The American Journal of Cardiology. "As the largest retrospective, observational study to date to examine the short-term safety profile of perflutren-containing ultrasound contrast agents, the data highlight the relatively low incidence of adverse safety reactions associated with DEFINITY(R) and demonstrate a significantly lower risk of acute mortality for patients receiving DEFINITY(R)-enhanced echocardiograms," said Mark Hibberd, M.D., Ph.D., Senior Medical Director, Global Medical Affairs, Lantheus Medical Imaging, Inc. and co-author on the study. "These study findings provide the physician community with essential safety information on the use of DEFINITY(R), especially among hospitalized patients, and provide valuable information on patient outcomes that bear further investigation." The study was designed to assess short-term (one-day) mortality in hospitalized patients undergoing resting transthoracic echocardiography both with and without DEFINITY(R). The study analyzed more than 4.3 million patients undergoing clinically indicated echocardiography from January 1, 2002 through October 31, 2007 using the Premier Perspective Database, the largest U.S. hospital-based, service-level comparative database providing detailed resource utilization data along with patients' primary and secondary diagnosis and procedure codes. Of this population, 4,242,712 patients received non-enhanced echocardiograms and 58,254 received contrast-enhanced studies using DEFINITY(R). One-day mortality rates were 1.08% for patients undergoing non-contrast studies and 1.06% for patients undergoing DEFINITY(R) contrast-enhanced examinations. However, patients receiving DEFINITY(R) were more likely to have an increased baseline severity of illness and a higher pre-study risk of mortality. A multivariate logistic regression analysis was used to compare 24-hour mortality, controlling for case mix and clinical covariates. Patients undergoing DEFINITY(R) -enhanced echocardiograms had a 24% lower risk adjusted odds ratio for mortality within one day than those patients who received only echocardiography without the ultrasound contrast agent. These findings build on and corroborate a recently published multicenter retrospective study that also demonstrated no increased mortality in patients undergoing echocardiography with a contrast agent in comparison with patients undergoing non-contrast-enhanced examinations (Journal of the American College of Cardiology, Volume 51, Number 17, 2008).(1) In addition, this multicenter analysis was presented in part at a meeting of the United States Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee in June, 2008. These study findings also confirm the safety profile of ultrasound contrast imaging agents and support the implementation of the recently published American Society of Echocardiography (ASE) Consensus Statement on the Clinical applications of Ultrasound Contrast Agents in echocardiography. "This study is groundbreaking in the echocardiography area, and represents the largest evaluation of resting echocardiography among hospitalized patients," continued Dr. Hibberd of Lantheus. "It is also the first to evaluate the impact of contrast echocardiography on survival among hospitalized patients. The results clearly indicate that there is no additional risk associated with DEFINITY(R)-enhanced studies, while in fact those patients that received DEFINITY(R) had improved short-term survival when compared to those who received only transthoracic echocardiograms without DEFINITY(R). The study did not address the reason for this effect. These data provide the medical community with further clinical evidence of how DEFINITY(R) can significantly improve the standard of care for patients undergoing cardiac evaluations, and we are continuing to explore the role of DEFINITY(R) in specialized patient populations such as those in the ICU and receiving mechanical ventilation." Don Kiepert, President and CEO, Lantheus Medical Imaging added, "We are encouraged by these data that further demonstrate the role and clinical value of DEFINITY(R), and believe these findings will answer any remaining safety questions regarding ultrasound contrast agents. Lantheus continues to remain committed to providing important safety information on the use of DEFINITY(R) in routine clinical practice." About DEFINITY(R) Since its launch in 2001, activated DEFINITY(R) Vial For (Perflutren Lipid Microsphere) Injectable Suspension has been administered to over two million patients.(2) In patients with suboptimal echocardiograms, DEFINITY(R) enables physicians to visualize the borders of the heart more clearly.(3,4) In May 2008, Lantheus announced the initiation of CaRES (Contrast Echocardiography REgistry for Safety Surveillance), the first multi-center Phase IV observational registry that will further evaluate the safety profile of DEFINITY(R) in patients with suboptimal echocardiograms and provide safety information on the use of ultrasound contrast agents in routine clinical practice. The open-label, non-randomized registry is being conducted in more than 10 clinical sites in the United States and include at least 1,000 patients. The study will gather data on patient characteristics and demographics, indication for DEFINITY(R)'s use, results of safety monitoring of patients during and after DEFINITY(R) administration, and the nature and frequency of any adverse events that may occur. Important Safety Information about DEFINITY(R) Activated DEFINITY(R) Vial for (Perflutren Lipid Microsphere) Injectable Suspension is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. The safety and efficacy of DEFINITY(R) with exercise stress or pharmacologic stress testing have not been established. WARNING: Serious Cardiopulmonary Reactions Serious cardiopulmonary reactions, including fatalities, have occurred during or following perflutren-containing microsphere administration. Assess all patients for the presence of any condition that precludes DEFINITY(R) administration (see CONTRAINDICATIONS). In patients with pulmonary hypertension or unstable cardiopulmonary conditions, monitor vital sign measurements, electrocardiography and cutaneous oxygen saturation during and for at least 30 minutes after DEFINITY(R) administration (see WARNINGS). Always have resuscitation equipment and trained personnel readily available. Activated DEFINITY(R) should not be administered to patients with known or suspected cardiac shunts (right-to-left, bi-directional or transient right-to-left), or hypersensitivity to perflutren. Do not administer DEFINITY(R) by intra-arterial injection. In postmarketing use, uncommon but serious reactions observed during or shortly following perflutren-containing microsphere administration included fatal cardiac or respiratory arrest, loss of consciousness, convulsions, symptomatic arrhythmias (atrial fibrillation, supraventricular tachycardia, ventricular tachycardia or fibrillation), hypotension, respiratory distress or cardiac ischemia (see ADVERSE REACTIONS). The risk for these reactions may be increased among patients with pulmonary hypertension or unstable cardiopulmonary conditions (acute myocardial infarction, acute coronary artery syndromes, worsening or unstable congestive heart failure, serious ventricular arrhythmias or respiratory failure, including patients receiving mechanical ventilation). In the absence of these underlying conditions, observe patients closely during and following DEFINITY(R) administration. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to DEFINITY(R) administration and monitor all patients for acute reactions. For full prescribing information, please visit www.lantheus.com. American Journal of Cardiology Dec 15, 2008 Acute Mortality in Hospitalized Patients Undergoing Echocardiography With and Without an Ultrasound Contrast Agent (Multicenter Registry Results in 4,300,966 Consecutive Patients) (This study was presented in part at a meeting of the United States Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee on June 24, 2008.) Michael L. Main, MDa Amy C. Ryan, MS, Teresa E. Davis, BS, Maureen P. Albano, RN, Lisa L. Kusnetzky, BA, Mark Hibberd, MD We sought to define acute mortality in a large multicenter cohort of hospitalized patients undergoing clinically indicated echocardiography with and without use of an ultrasound contrast agent. Although the United States Food and Drug Administration recently relaxed the issued warnings for perflutren-containing ultrasound contrast agents on May 13, 2008, concerns still exist regarding the safety of these compounds, particularly in critically ill patients. A retrospective analysis was performed using the Premier Perspective Database. Patients undergoing echocardiography during hospitalization were separated into those performed without contrast enhancement and those performed with perflutren lipid microsphere (PLM) injectable suspension contrast agent (Definity, Lantheus Medical Imaging, North Billerica, Massachusetts). Vital status within 1 day of the echocardiogram was available for all patients using hospital billing data. Between January 1, 2002 and October 31, 2007, 4,300,966 patients underwent transthoracic echocardiography at rest during hospitalization (unenhanced studies n = 4,242,712 and contrast-enhanced studies n = 58,254). Multivariate logistic regression analysis was used to compare 24-hour mortality, controlling for case mix and clinical covariates; 1-day mortality rates were 1.08% (n = 45,789 deaths) for patients undergoing noncontrast studies and 1.06% (n = 616 deaths) for patients undergoing contrast-enhanced examinations (p = 0.613). Multivariate logistic regression analysis revealed that, in patients undergoing an echocardiogram, patients receiving PLM injectable suspension contrast agent were 24% less likely to die within 1-day than patients not receiving a contrast agent (adjusted odds ratio = 0.76, 95% confidence interval 0.70 to 0.82). In conclusion, acute crude mortality was not increased in patients receiving PLM injectable suspension contrast agent. Multivariate logistic regression analysis revealed that, compared with patients not receiving a contrast agent, administration of PLM injectable suspension contrast agent during echocardiography was associated with a 24% decreased risk of mortality. Ultrasound Jan 2009 Induction of Apoptosis in Sonoporation and Ultrasonic Gene Transfer HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 HTMLCONTROL Forms.HTML:Hidden.1 Douglas L. Miller, Chunyan Dou Abstract  The role of apoptosis in sonoporation and ultrasound-enhanced gene transfection of cell suspensions was examined in vitro. Suspensions of HL-60 and of CHO-K1 cells were exposed to 2.25-MHz continuous ultrasound for 1 min in a 60-rpm rotating-tube exposure system, with ultrasound contrast media added to ensure nucleation of cavitation. Cell necrosis was measured by trypan blue dye exclusion (using a hemacytometer) and by propidium iodide nuclear staining (using flow cytometry). Apoptosis was detected by the annexin V method with Alexa Fluor 350 as the fluorescent label, and confirmed by Hoechst 33342 nuclear staining. Sonoporation cell loading was assessed by uptake of large fluorescent-dextran molecules from the medium. Transfection was demonstrated by expression of green fluorescent protein (GFP) from plasmids transferred into the cells by the treatment. Cell scoring was performed by flow cytometry, with necrotic cell events excluded. For HL-60 cells at 0.4 MPa, cell loading and transfection was significantly increased relative to shams at 2, 6 and 24 h post exposure, peaking at 19.0 ± 5.5% and 9.6 ± 4.2% of non-necrotic cells, respectively, at 6 h. However, about one third of the treatment-positive cells were identified as apoptotic. The cell loading and gene transfer effects increased for increasing peak rarefactional pressure amplitude, reaching 24.4 ± 7.7% and 12.7 ± 5.1% of non-necrotic cells, respectively, for 0.6-MPa exposure. However, the lethal cellular injury caused by cavitation in the rotating tube system reduced the overall apparent efficacy of cell loading and gene transfer to 5.1 ± 2.1% and 2.1 ± 0.9%, respectively, after accounting for necrosis and apoptosis. Similar tests with CHO cells showed increased sonoporation but mostly cell death by necrosis, rather than apoptosis. The induction of apoptosis by cavitation treatments should be considered as a possible confounding factor, in addition to necrosis, in sonoporation and ultrasonic gene transfer research. (E-mail This email address is being protected from spambots. You need JavaScript enabled to view it. )

ICUS Sponsors

ICUS gratefully acknowledges its 2017 sponsors:

dentons-logo2

silver-level

samsung-logo

siemens-new-original

philips-icus-logo

mindray

Contact ICUS

  • Address: 1900 K Street, N.W.
    Washington, DC 20006-1102, USA
  • Telephone: 202-408-6199

About ICUS

ICUS is the world’s only professional society exclusively devoted to contrast-enhanced ultrasound (CEUS) medical imaging technology.

Learn more...

You are here: Home ICUS Weekly News