The FDA issued a warning in late 2013 about rare but serious adverse events in some patients who received regadenoson, one of nuclear cardiology’s favorite pharmacologic stress agents. That didn’t dampen enthusiasm for it in the least. Instead, physicians show it has much more to offer.
Ups & downs
A selective adenosine A2A receptor agonist, regadenoson offers an attractive alternative to adenosine for evaluating patients suspected of having coronary artery disease who are not good candidates for a treadmill stress test. It is as effective as adenosine but with fewer side effects, well tolerated by most patients, fast and easier to use. It requires no pump and no dosing, making it a darling among nursing staff.
The FDA approved regadenoson (Lexisan, CV Therapeutics/Astellas) in 2008 for use in radionuclide myocardial perfusion imaging (MPI) in patients who cannot undergo adequate treadmill testing. Within four months it gained an 11 percent share of the market for stress agents and surpassed 80 percent by 2013 (J Am Coll Cardiol 2009;54:1123–1130 and J Nucl Cardiol online Feb. 14, 2015). In late November of 2013, the FDA put out a notice alerting cardiologists that a review of its Adverse Event Reporting System database found 26 cases of MI and 29 cases of death in patients with unstable angina or pre-existing cardiovascular instability within six hours of administration of regadenoson. The communication also listed possible risks with adenosine and recommended equipment and staff be available to intervene if complications arise.
“We don’t know if this risk of MI with regadenoson is different from the risk with adenosine or other stress agents or exercise,” says Fadi G. Hage, MD, director of nuclear cardiology at the University of Alabama at Birmingham. Hage has reviewed safety data from regadenoson’s clinical trials, postmarketing surveillance, other prospective studies and case reports and cautions about limitations with some of these data sources (J Nucl Cardiol 2014;21:871-876). “What do you do? If you are not going to do this stress test, are you going to go straight to angiography? Do you do other stress agents? We don’t have that comparative data. What we know is that the risk is relatively low.”
The FDA’s warning succeeded in making physicians sensitive to potential problems that may surface in a pool of patients much larger than those enrolled in the clinical trials. They reported other rare but serious complications—in particular, asystole and seizures—which allowed cardiologists to put protocols in place to minimize problems.
“The take-home message was that the medicine we give to reverse regadenoson is not wise to give while someone is having a seizure,” explains Thomas A. Holly, MD, medical director of nuclear cardiology at Northwestern Memorial Hospital in Chicago. “Let it run its course or treat them for the seizure specifically.”
In adenosine’s shadow
As the new kid on the block, regadenoson was in catch-up mode with established agents that had accrued piles of evidence of safety and efficacy in diverse patient populations and applications. Regadenoson’s ease made it a tempting option in patients who were referred for but failed an exercise stress test, although it hadn’t been tested in that context. “As soon as regadenoson was approved, a lot of physicians were saying, ‘Now we have a medicine that can be given as a bolus injection. I wonder if you can give it as needed,” Holly recalls. “Put them on a treadmill and if they didn’t reach the target heart rate, pull a syringe out of your pocket and inject them. People started doing that right away without any real data to show it was safe.”
Holly’s research group, which previously had pioneered protocols for symptom-limited exercise stress tests with adenosine, showed that regadenoson was safe and feasible to use adjunctively at peak exercise, providing image quality on par with regadenoson at rest (J Nucl Cardiol 2013;20:197-204). Hage’s group has been challenging adenosine, but on another front: They have shifted regadenoson from the realm of diagnostic to prognostic.
“There is a lot of data on the prognostic value of adenosine, but prior to our two papers, there has not been much looking at prognostic data with regadenoson,” Hage says. Those two papers detail the prognostic value of regadenoson, first with normal MPIs and most recently in patients with abnormal perfusions on MPI.
They first compared 1,000 patients who had a normal MPI on regadonoson