Feature | Contrast Media | July 28, 2017 | By Dave Fornell

Trends in contrast media used in MRI, echocardiography, CT and angiography

Contrast Media from Bayer, trends in contrast media and developments in contrast media

Here are several updates in medical imaging contrast media agents. Two of the biggest news items were related to safety concerns over magnetic resonance imaging (MRI) gadolinium agents and echocardiography contrast agents. However, in both cases the U.S. Food and Drug Administration (FDA) has weighed in that the agents are safe in the majority of patients. 

Concern Over MRI Gadolinium Agents Retained in Brain

Over the past decade, several clinical studies have shown gadolinium-based MRI contrast agents accumulate in tissues inside patients. This has raised concern because prolonged, elevated levels of gadolinium in the body may cause a nephrogenic systemic fibrosis in patients with severe kidney disease. Adding to this concern were three studies in 2015, which raised new gadolinium safety concerns after it was found the agent also accumulates in the brain.  

On its own, gadolinium can be toxic. Therefore, when used in contrast agents, gadolinium is bonded with a molecule called a chelating agent, which controls the distribution of gadolinium within the body. It was thought, prior to 2006, that gadolinium was completely excreted from the body. In patients found to retain traces of the agent, it was believed it was due to severe renal dysfunction. However, the 2015 brain studies found gadolinium retention in the brain also occurred in patients with normal renal function.[1,2] Another 2015 study from the University of Heidelberg Medical Center in Heidelberg, Germany, suggests that the molecular structure of the contrast agent may play a role in gadolinium retention.[3] There are two structurally distinct categories of gadolinium-based contrast agents: linear and macrocyclic. In the macrocyclic structure, the gadolinium is bound more tightly to the chelating agent and, therefore, less likely to release free gadolinium into the body.

However, no studies have yet shown that retained gadolinium in the brain causes negative long term-health effects. This was the determination of the FDA review of the safety ramifications of gadolinium-based contrast agents, released in a drug safety communication in May 2017. The FDA said it has not identified adverse health effects from gadolinium retained in the brain. The FDA said there is no evidence to date that gadolinium retention in the brain from any of the gadolinium agent is harmful, so restricting use of these agents is not warranted at this time. FDA said it will continue to assess the safety of these agents. The FDA reported that studies show linear agents retain more gadolinium in the brain than macrocyclic agents. However, the review did not identify adverse health effects related to this brain retention.

The agency said the agents should be used as is appropriate when considering the use of any medical imaging agent. It also stated healthcare professionals should limit gadolinium contrast use to circumstances in which additional information provided by the contrast agent is necessary and to assess the necessity of repetitive MRIs.

View a comparison chart of MRI contrast agents. This will require a login, but it is free and only takes a minute to complete. 


Echo Contrast Updates

Echocardiography experts say up to 20 percent of all resting echocardiography studies, and up to 30 percent of those conducted in critical care patients, can result in suboptimal echocardiograms. A suboptimal image is one in which two or more contiguous left ventricular segments in any of the three apical views cannot be visualized. The use of contrast in suboptimal echocardiograms can improve the diagnostic quality of these otherwise suboptimal exams.[4,5,6]

Echo contrast agents consist of perflutren lipid or protein microspheres. They contain gas, such as a high-molecular weight perfluorocarbon, which aids in reflecting ultrasound waves and in the stability of the spheres. These micro-bubbles are between 1-8 microns in size, allowing them to pass through the microcirculation.

In the past there was concern about the microspheres embolizing, which was why the FDA issued a “black-box” warning for Lantheus Medical Imaging’s Definity and GE Healthcare’s Optison agents in October 2007. This followed 11 deaths that appeared to be related to the agents. The warning contraindicated use in patients with worsening or unstable heart failure, acute myocardial infarction or serious ventricular arrhythmias and in conditions that cause pulmonary hypertension. However, these events occurred over a period of six years and it was not clear if the contrast was the cause. Thirty minutes of close monitoring with vital signs and ECG after contrast administration were required, and the use of echo contrast use plummeted. 

The FDA revised these guidelines in May 2008 and replaced the extended contraindications with warnings after recognizing the favorable risk/benefit ratio for these contrast agents and the potential risks of alternative procedures. The FDA also considered evidence from several clinical studies initiated after the black box warning, showing the agents had a very good safety profile. Since then, use of echo contrast has been on the rebound.

A lingering contraindication due to the fear of embolization has been a ban on using echo contrast agents if there is a right-to-left or bidirectional cardiac shunt. The restrictions on patients with shunts was lifted for Optison in October 2016, and for Definity in February 2017. Previously, in suspected cardiac shunt populations, an agitated saline procedure was needed to determine if a shunt existed and whether the patient was contraindicated to receive an ultrasound contrast agent.

At the same time, the FDA also expanded Optison’s indication, allowing for administration by intra-arterial injection.  

“Up to one-third of our patients have known or suspected cardiac shunts and, thanks to this important FDA decision, they too will now have access to ultrasound contrast agents, which offer an inexpensive and radiation-free option for diagnostic imaging,” said Steven Feinstein, M.D., co-president of the International Contrast Ultrasound Society. “We applaud the FDA for its decision, and we believe it will benefit individual patients as well as our healthcare delivery system.”

Jonathan Lindner, M.D., M. Lowell Edwards Professor of Cardiology at the Knight Cardiovascular Center, Oregon Health & Science University, said at the time of the FDA announcement that there was an overwhelming amount of evidence from clinical trials and most practitioners in the field of echocardiography already knew the benefits of using echo contrast. “However, a major obstacle to widespread use has been lack of consensus and confusion regarding how far one needs to go to exclude shunts, no matter how small,” he explained. “The decision by the FDA removes a barrier to using this contrast agent, and may result in an increase in the number of labs that will choose to utilize this important technology, which allows clinicians to provide the best care possible.”

In October 2014, the FDA cleared a third echo contrast agent, Bracco’s Lumason (sulfur hexafluoride lipid microsphere). The first U.S. imaging procedures took place in May 2015. The agent is supplied as a three-part kit. Also in 2015, Lumason was approved by the Centers for Medicare and Medicaid Services (CMS) for pass-through payment status under the Hospital Outpatient Prospective Payment System (HOPPS). The agent comes in a kit containing a Lumason vial with 25 mg of lipid-type A lyophilized powder and 60.7 mg sulfur hexafluoride headspace, a prefilled syringe containing 5 mL of sodium chloride 0.9 percent injection, USP (Diluent) and a mini-spike.  

View a comparison chart of echo contrast agents. This will require a login, but it is free and only takes a minute to complete. 


New Contrast Agents, Indications 

In May 2017, the FDA expanded the indication for GE Healthcare’s Visipaque (iodixanol) 320 mg iodine/mL injection for use in coronary computed tomography angiography (CCTA) for diagnostic evaluation of adult and pediatric patients 12 years of age or older with suspected coronary artery disease.  The new CCTA indication allows physicians to non-invasively image the coronary arteries, rather than use of traditional invasive coronary angiography to diagnose coronary artery disease. 

“Coronary heart disease is a major cause of death in the United States,” said Matt Budoff, M.D., FACC, director of cardiac CT and professor of medicine, Harbor-UCLA Medical Center, Torrance, Calif. “We are excited about the label extension of Visipaque as the first FDA approved iodinated contrast media for use in CCTA. Having an approved contrast agent for CCTA may facilitate the use of CCTA as a gatekeeper to invasive coronary angiography in patients with mild to moderate coronary artery disease, sparing patients from a more invasive procedure and long recovery times.”

FDA cleared Bayer’s Gadavist (gadobutrol) injection for use with magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease, in April 2016. The injection was approved for use in adult and pediatric patients (including term neonates).

“Until now, no contrast agents were FDA-approved for use with MRA of the supra-aortic arteries," said Elias Melhem, M.D., chair, Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, and principal investigator for the GEMSAV study, used to gain the new approval. “With FDA's action, radiologists now have an approved MRA contrast agent to help visualize supra-aortic arteries in patients with known or suspected supra-aortic arterial disease, including conditions such as prior stroke or transient ischemic attack (TIA).”

The GEMSAV (Gadavist-Enhanced MRA of the Supra-Aortic Vessels) study evaluated 457 patients with known or suspected disease of the supra-aortic arteries. Efficacy was evaluated based on visualization and performance for distinguishing between normal and abnormal anatomy. Significant stenosis was defined as at least 70 percent. Data showed Gadavist MRA significantly improved visualization across three readers 88-97 percent, as compared to unenhanced MRA of only 24-82 percent.

In January 2015, the FDA approved Gadavist for use with MRI in pediatric patients less than 2 years of age, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system. Gadavist was previously approved in 2011 for this use in patient populations over the age 2. The FDA’s priority review was based on a study showing that the pharmacokinetic (PK) and safety profiles in pediatric patients less than 2 years of age were similar to that of older children and adults at standard dose (0.1 mmol/kg).

View a comparison chart for iodine-based contrast agents for CT and angiography. This will require a login, but it is free and only takes a minute to complete. 


New Types of Contrast Packaging

There have been a few innovations in contrast agent packaging over the past few years, including bulk, multi-dose containers and polymer containers.

In November 2014, Bracco Diagnostics released its Isovue (iopamidol injection) Imaging Bulk Package (IBP), a specific combination multi-patient, multi-dose compliant contrast medium approved by the FDA for point-of-care use in the computed tomography (CT) suite. The IBP was designed to increase safety and improve workflow, while minimizing risk and maintaining compliance regarding the use of multi-dose CT contrast media. Pharmacy bulk packages (PBPs) for multi-dose contrast media were originally approved in the 1990s with prescribing information for use in a “suitable work area, such as laminar flow hood, using an aseptic (sterile) technique,” typically found in the hospital pharmacy setting. Over time, The Joint Commission, which accredits and certifies healthcare organizations nationwide, began issuing citations to medical centers for using PBPs to transfer contrast media outside of the pharmacy in conditions that were not fully compliant with prescribing information. In 2012, the Institute for Safe Medication Practices called for hospital pharmacy oversight on the purchase, distribution, storage and use of intravenous contrast media, the use of single dose vials or pre-filled syringes for radiological use, and the proper use of PBPs. The Isovue IBP allows for easy and cost-effective intravenous contrast enhancement of CT imaging, providing 10-hour on-demand dosing from the same container without the risk of incurring multi-dosing citations.

Some vendors offer polymer bottles rather than the traditional glass packaging. Several years ago GE Healthcare introduced its +PlusPak plastic packaging container for contrast media, which the vendor said offers advantages over traditional glass packaging. This includes reduced storage, improved workplace safety for healthcare workers who administer contrast media to patients, and decreased cost of waste disposal. Radiology departments using the lighter-weight packaging can reduce contrast media red bag waste weight by more than 75 percent. The unbreakable polypropylene bottles feature a metal-free, twist-off cap that is easy to open and avoids cuts from metal crimps, reducing time spent treating sharps injuries while also reducing the associated risk of bloodborne pathogen transmission.


Mallinckrodt Acquisition by Guerbet, Removes Two products From Market

The contrast media market is made up of only a small number of players, and that pool got smaller in July 2015 when Guerbet acquired Mallinckrodt's contrast media and delivery systems (CMDS) business for $270 million. Guerbet said CMDS business was well positioned with Optiray and Optiject (Europe)/Ultraject (United States) in X-ray, whereas Guerbet holds a similar position in MRI with its Dotarem agent. The acquisition opened up technological synergies, with the Mallinckrodt's syringe-based delivery systems and Guerbet’s hydraulic injection technique for softbags. The businesses were also geographically complementary, with the Mallinckrodt's business holding a strong position in the United States and Guerbet likewise in Europe. 

In July 2017, Guerbet announced it will phase out sales throughout the world of two products: Hexabrix (meglumine and sodium ioxaglate) and Optimark (gadoversetamide). The company said the products are redundant after the acquisition of Mallinckrodt’s contrast media and delivery systems business. In 2015, Guerbet announced the withdrawal in the United States of Hexabrix, an iodinated contrast medium for X-ray imaging that has the same indications as two other Guerbet products, Optiray (ioversol) and Xenetix (iobitridol). Hexabrix sales in Europe, Asia and Latin America will progressively cease, by the end of 2019 at the latest. Optiray and Xenetix cover more than 70 countries.

Guerbet’s decision to phase out Optimark is similar: Optimark and Dotarem (gadoteric acid) are both gadolinium-based contrast agents and have similar indications for magnetic resonance imaging (MRI). Optimark is a linear agent and faces decreasing worldwide demand, while Dotarem, a macrocyclic and ionic agent, has seen worldwide demand increase, according to the company. Dotarem is registered in more than 70 countries. Sales of Optimark will end July 26, 2017, in European Union countries. Then, and in order to ensure a smooth transition and continuous supply for patients, Optimark phase-out will be progressively implemented in other geographic areas until the end of 2019.
This move to streamline its gadolinium-based contrast agent portfolio through a focus on Dotarem is consistent with recent recommendations of the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency.


Related Content Links:

Watch the VIDEO “MRI Gadolinium Contrast Retention in the Brain.” Emanuel Kanal, M.D., director of MRI services and professor of radiology and neuroradiology at the University of Pittsburgh Medical Center, explains what is known about MRI contrast retention in the brain and other MRI safety concerns. 

FDA: No Harm in MRI Gadolinium Retention in the Brain

Understanding Contrast-Induced Nephropathy


For more information on contrast agents:








1. Emanuel Kanal, Michael F. Tweedle. “Residual or Retained Gadolinium: Practical Implications for Radiologists and Our Patients.” Radiology, Jun 2015, Vol. 275:630–634, https://doi.org/10.1148/radiol.2015150805

2. Robert J. McDonald, Jennifer S. McDonald, David F. Kallmes, et al. “Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging.” Radiology, Jun 2015, Vol. 275:772–782, https://doi.org/10.1148/radiol.15150025

3. Alexander Radbruch, Lukas D. Weberling, Pascal J. Kieslich, et al. “Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent.” Radiology, Jun 2015, Vol. 275: 783–791, https://doi.org/10.1148/radiol.2015150337.

4. Cohen JL, Cheirif J, Segar DS et al. Improved left ventricular endocardial border delineation and opacification with Optison (FS069), a new echocardiographic contrast agent: results of a phase III multicenter trial. J Am Coll Cardiol 1998;32:746-52.

5. Vlassak I, Rubin DN, Odabashian JA et al. “Contrast and harmonic imaging improves accuracy and efficiency of novice readers for dobutamine stress echocardiography.” Echocardiography 2002;19:483-8.

6. Plana JC, Mikati IA, Dokainish H et al. “A randomized cross-over study for evaluation of the effect of image optimization with contrast on the diagnostic accuracy of dobutamine echocardiography in coronary artery disease: the OPTIMIZE trial.” J Am Coll Cardiol Img 2008;1:145-52.

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