Users Hold Firm on the Value of Echo Contrast Agents

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Figure 1. Baseline (noncontrast) apical 4-chamber and apical long-axis images (end-diastolic frames). Note the prominent posteromedial papillary muscle and the poorly visualized interface between the left ventricular cavity and endocardium.
The FDA’s warning on echo contrast agents galvanized physicians and sonographers to fight back. They enjoy a partial victory, but the fight is still on to prove safety and efficacy.

The echocardiography community responded vociferously in the negative to the FDA’s 2007 black box warning on the two U.S. approved echo contrast agents: Definity (Lantheus Medical) and Optison (GE Healthcare). To its credit, the FDA responded to the clinical pressure and changed the warning a year later to a less restrictive one. Since that time, cardiologists across the country have continued to use these agents, collecting data to prove their safety and efficacy.

“I think the black box warning is overly conservative. Echo contrast is clearly very safe,” says Michael Farrar, MD, director of the noninvasive lab at North Kansas City Hospital in North Kansas City, Mo. Farrar handles about 30,000 echocardiograms a year, one-quarter of which require the use of contrast.

Whether the FDA further revises or removes the black box warning won’t overly affect Farrar and colleagues. Where the warning will have the most impact, he says, are in labs that order contrast through the pharmacy, instead of the cardiology department. “Pharmacies and pharmacists by their nature will be more concerned about the black box warning, rather than the clinicians who are actually using it on a day-to-day basis to make clinical decisions,” he says. 

Like many facilities, North Kansas City Hospital  has a sonographer-driven protocol for the use of contrast. If a patient has relative contraindications, however, such as pulmonary hypertension, respiratory failure, patent foramen ovale (PFO) or a recent acute event, sonographers consult with the cardiologist.

A sonographer-driven contrast protocol leads to improved workflow and patient management. “I tell my staff that if they have a technically challenging patient who may require contrast, make that decision up front rather than struggling through the whole exam,” says Karl Q. Schwarz, MD, director, echocardiography and mobile echocardiography services at the University of Rochester Medical Center in New York. “A suboptimal exam carries a burden with it that is ongoing,” particularly for referring physicians if the patient returns with chest pain.

Prior to stress echo contrast reimbursement, Schwarz and colleagues conducted a study to determine contrast’s efficacy (J Am Soc Echocardiogr 2004;17(1):15-20). He says  they were “very judicious in contrast use so as not to lose too much money.” Contrast was used in about 10 to 15 percent of patients, which were “the toughest of the tough,” Schwarz says. Researchers achieved diagnostic images in more than 90 percent of the nearly 300 patients, but they also had a better than 95 percent negative predictive value. “If we have a test that can rule out cardiac pathology as the cause of pain, that’s very helpful,” he adds. Now Schwarz and colleagues use contrast in about half of the stress echo patients—“the tough cases, but also in those with limited pictures as well.”

Softer, but still chilling
Even though the FDA “softened” the black box warning, it continues to have a chilling effect on use, says Michael L. Main, MD, director, echocardiography at Saint Luke’s Mid America Heart Institute in Kansas City, Mo. “Many clinicians have medico-legal concerns. They know that these agents are safe in comparison to other contrast agents and other tests, but they are concerned. Many labs that have previously used echo contrast agents have stopped altogether and have not resumed even after the modification last year.”

Since those initial warnings, many large safety studies have been published, signaling the appearance of safe agents. At the 2009 American College of Cardiology meeting, Main presented the results of a retrospective study of nearly 40,000 severely ill patients, some 20,000 of whom received contrast (78 percent Definity, 22 percent Optison). Patients who received contrast had a 26 percent lower risk of short-term mortality within 48 hours after the exam. Analysis of a subset using mechanical ventilation also showed lower short-term mortality rates for those receiving contrast. Another Main et al retrospective study of more than 4 million hospitalized patients revealed that patients who received contrast (nearly 60,000, Definity) had a 24 percent lower risk of short-term mortality compared with those receiving non-contrast echocardiograms (Am J Cardiol 2008;102[12]:1742-1746).

One thing that has emerged from the data is that the risk of an anaphlactoid reaction from echo contrast agents is about one in 10,000, which is the same level of safety with radio-contrast agents and many cardiac drugs. “We need to be attuned to recognize and treating those reactions, but they’re very rare,” Main says. 

Thomas Porter, MD, a professor of internal medicine at the University of Nebraska Medical Center, Omaha, has seen one anaphlactoid reaction in the last seven years. He estimates he’s performed about 10,000 contrast studies in that time. He believes the benefits of contrast echo far outweigh the small risk. “The ability to provide left ventricular (LV) opacification in our portable studies is critical,” Porter says. “You need extreme accuracy for regional myocardial wall motion to make a positive diagnosis.”

Porter and colleagues are halfway into a prospective randomized study, sponsored by Lantheus, evaluating 3,000 patients who receive either conventional stress echo or real-time perfusion stress echo. It’s a single site, multi-reader study with endpoints of death and nonfatal MI. They typically perform 30 to 50 echocardiograms per day, with 15 to 20 of them being stress tests.

The argument could be made to use contrast in almost every stress echo exam, especially exercise stress when patients are breathing harder and the images can be challenging, says Schwarz. “We don’t do that now because the indication is when you have limited pictures to start with, but I could see the indications expanding in that regard.”

Main says he uses contrast in all patients who have reduced LV function because “it’s difficult to measure LV ejection fraction—even in patients with adequate baseline endocardial resolution—unless we use contrast agents” (see Figures 1 and 2). He also uses contrast echo to follow patients on chemotherapy for possible cardiotoxicity.

Regardless of how it is used, the key to controlling contrast risks and optimizing its employ is to have appropriate training, standard protocols for its use and administration, and operators in the lab who are believers, says Schwarz. “If contrast is used occasionally and if there are no protocols in place, results will not be consistently good. Echocardiography is an extremely powerful tool when performed correctly, and the use of contrast only serves to enhance its accuracy.”