Stress Test: Evidence Mounts in Regadenoson’s Favor

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 with 1,000 patients with a normal MPI on adenosine, from a period before their center switched to the newer agent. They tracked major adverse cardiovascular events—cardiac death, nonfatal MI and coronary revascularization— out to two years. After propensity score matching, they found no significant difference between the two groups.

“That gives us in day-to-day practice the assurance that by doing the study with regadenoson, which is easier to use, we are not giving up any of the prognostic data that you would get with an adenosine scan,” Hage says.

His group then moved on to studying regadenoson in 1,400 patients, half with a normal MPI and half with an abnormal scan (J Nucl Cardiol online Feb. 14, 2015). They divided patients into groups stratified by perfusion defect and ischemia, ranging from none to more than 20 percent. Hage and his colleagues showed that the risk of death and revascularization increased in concert with the increase in perfusion defect and extent of the ischemia. Only 0.7 percent of patients with a normal MPI went on to require revascularization.

“Patients who had a normal scan not only did not get revascularization in the short term but also did well over the five-year period, which implies it was appropriate to not revascularize them,” he says. “Also, the patients who had an abnormal perfusion scan had a higher event rate—death, heart attacks or further revascularization—and an increase in a proportionate manner to the size of the defect.”

The prognostic power of regadenoson can serve as a gatekeeper, helping cardiologists determine which patients would benefit from coronary angiography and possibly further intervention and which likely would have more to lose than gain from further testing, Hage proposes. 

Going off-label 

Physicians have other reasons for referring patients for an exercise or pharmaceutical stress test. Given the interplay between diabetes, renal dysfunction and cardiovascular diseases, some doctors request stress tests to evaluate patients with end-stage kidney disease prior to adding then to a transplantation wait list. The mismatch between patients in need and available donor organs means patients may remain on the list for years.

“Some guidelines would suggest to retest them on an annual or maybe biannual basis, the reason being that end-stage kidney disease causes accelerated coronary atherosclerosis,” says Rami Doukky, MD, MSc, a cardiologist at Rush University Medical Center and interim chief of cardiology at Cook County Hospital in Chicago. “They may develop progressive coronary disease while they are waiting for kidney transplant. It is highly controversial. However, it is not an uncommon practice.”

That means that a large segment of patients at hospitals with transplant programs may send these patients for a stress test. Many are not suitable for the treadmill, especially those with uncontrolled blood pressure, which can cause or be a product of end-stage kidney disease. “With exercise, blood pressure is expected to go up and sometimes uncontrolled blood pressure makes an unfavorable candidate for exercise testing,” Doukky says. Also, patients with long-standing diabetes may have related complications such as exercise-limiting neuropathy or peripheral artery disease.

The catch for Doukky and physicians like him is that the clinical trials for regadenoson did not include patients with end-stage kidney disease, and these patients’ renal impairment affects how regadenoson is cleared form the body. Consequently, he and his colleagues prospectively evaluated its safety and tolerability in these patients, using pooled data from two clinical studies that had enrolled a large number of participants with end-stage kidney disease (J Nucl Cardiol 2013;20:205-213). Those trials had randomized patients to regadenoson stress with aminophylline or with placebo.

For their analysis, they focused on only patients in the placebo (regadenoson only) groups. They then stratified them to either end-stage kidney disease, that is, an estimated glomerular filtration rate (GFR) of less than 15 or on dialysis, or a control group, with a GFR of greater than 30. The two groups had similar rates of adverse events, with none of the events major. Their process for determining adverse events was painstaking: one question at a time to give patients an opportunity to address each potential side effect.

“When you collect your data this way you end up finding more than what your patients volunteer,” Doukky says. “The majority of these [side effects] are mild and not disabling or severely discomforting to the patient as evidenced by, when we ask would you take this test again, the vast majority of patients said they would.” 

Regadenoson use in these populations currently is off-label, which makes some cardiologists and labs wary. Doukky hopes these results and other data can change that and win them over. “Having an FDA label would end that chapter.”

From MPI to CMR

Regadenoson’s simplicity also appeals to cardiologists who see advantages in perfusion cardiac MR. The more often used adenosine is a comparative pain, because it requires MR-compatible pumps and weight-based infusions. Andrew E. Arai, MD, chief of advanced cardiovascular imaging at the National Heart, Lung, and Blood Institute in Bethesda, Md., proposes cardiac MR might rival nuclear stress testing, and regadenoson might facilitate its uptake. 

“A lot of studies out in the literature suggest the sensitivity and specificity of nuclear stress isn’t as good as what the textbooks say it should be,” Arai says. “A more accurate stress test might be a great alternative. One of the things about an MRI that I find particularly intriguing is that we can quantify the results, like in a PET scan, but at a much lower cost than a PET scan and a much higher quality level, a higher resolution, than any technique I know.”

To assess regadenoson’s tolerability, Arai and his team evaluated symptoms and adverse effects in 728 patients and 25 volunteers who underwent regadenoson stress imaged by MRI (Eur Heart J Cardiovasc Im 2014; 15:753-760). They reported few adverse events, no deaths or MIs and the drug was well tolerated.

Mean heart rate response was higher in both patients and volunteers, but the change in heart rate was more pronounced in volunteers than patients. Arai acknowledges that regadenoson’s effect on the heart rate response is “a moderate disadvantage.  It gets harder to get as many slices through the heart during the stress test portion if the heart rate goes up too high.”

He sees their findings as part of accumulated evidence that can be used to establish the drug’s safety profile. Alerts such as the FDA’s raises awareness but the FDA’s system doesn’t capture the overall number of tests conducted. “What people want to see is how does that fit overall,” Arai says. “The more and the bigger studies we publish … helps put in perspective what the FDA sees.”