ASNC: Pharmacologic stress update: Adenosine A2a agonists

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Exercise myocardial perfusion SPECT imaging has its advantages; however, the number of people who cannot exercise continues to increase. The use of pharmacologic stress imaging is on the rise and a new class of stressors – the "denosons" – promises to advance stress imaging even further.

"If you don't understand pharmacologic stress in 2010, then you don't understand nuclear cardiology, because most of nuclear cardiology is pharmacologic stress these days," said Dennis Calnon, MD, director of nuclear cardiology at Riverside Methodist Hospital and at MidOhio Cardiology and Vascular Consultants in Columbus, Ohio.

Calnon spoke at the American Society of Nuclear Cardiology meeting for the office-based practices in Philadelphia last week

The relative use of pharmacologic stress has increased over the years, going from 28 percent in 1996 to 41 percent in 2002. At Calnon's outpatient office lab in 2005, adenosine stress accounted for about 45 percent of cases.

At Riverside, the number of patients undergoing pharmacologic stress is even higher: 86 percent (77 percent adenosine, 9 percent dobutamine).

Calnon said that the ideal pharmacologic stressor will have a rapid onset and termination, will be given as a bolus, produce no bronchospasm and have no caffeine interaction. The stressor that best fits this description is regadenoson, one of a new class of stressors that selectively stimulates the A2a receptor.

Typical stressors include adenosine, dipyridamole and regadenoson, which are all vasodilators, as well as dobutamine, which is a catecholamine, meaning it increases myocardial blood flow indirectly by increasing contractility and heart rate.

Adenosine acts directly to increase blood flow by stimulating the A2a receptor, whereas dipyridamole acts indirectly by delaying the reuptake of intracellular adenosine. One of the problems with adenosine and dipyridamole is that they also stimulate the A1, A2b and A3 receptors, which can lead to side-effects such as chest pain, atrioventricular block, flushing, nausea and bronchospasm.

Regadenoson, as well as other "denoson" agents that are not yet FDA-approved such as binodenoson and apadenoson, selectively stimulate the A2a receptor, which theoretically results in fewer side-effects.

A close look at study results, however, reveals that the overall incidence of side-effects with regadenoson is not that much different from the older and more established agents. There is a slight decrease in chest pain and flushing, but more headaches and abdominal and gastrointestinal discomfort, Calnon said.

Some reports of "explosive diarrhea" with regadenoson could be problematic, especially with the increased use of thallium during the current isotope shortage, as the stress image must be taken 10 minutes after injection of the radiopharmaceutical. "You don't want to be waiting for the patient to come out of the bathroom," Calnon said.

Regadenoson also was associated with a significant increase in heart rate, which could potentially lead to false-positive rates in patients with right ventricular (RV) pacemakers, left bundle branch block (LBBB) and Wolff-Parkinson-White (WPW) syndrome.

Preliminary data suggest that regadenoson can be used in patients with moderate but stable chronic obstructive pulmonary disease, as well as asthma. The use of caffeine also does not seem to interfere with regadenoson's ability to achieve hyperemia.

"On the plus side, the 'denosons' are selective, have a rapid onset and termination of action, can be delivered in a bolus and in a fixed dose," Calnon said. "We are hopeful because the preliminary data indicate they are not associated with bronchspasms, nor do they have caffeine interaction."

Calnon and his colleagues often utilize low-level treadmill exercise during pharmacologic stress. The advantages of this protocol include reduced splanchnic tracer activity, which results in a better heart-to-background activity ratio, enhanced diagnostic accuracy and allows for earlier post-stress imaging; and side-effects also are reduced.

Low-level exercise is not for all patients, especially those with LBBB, WPW syndrome and RV pacemakers because increased heart rate during exercise in these patients may produce septal perfusion defects.

"We will start using low-level exercise in patients with biventricular pacemakers," Calnon said. "Theoretically, the contractions should be synchronous and false positives shouldn't be an issue, but there are no data yet to support this. It's just a hypothesis."