New Pharmacologic Agents

Manuel Cerqueira, MD, Cleveland Clinic, Cleveland, OH, provided an overview of pharmacologic stress agents, focusing on the identification and development of agents that can maximize overall laboratory efficiency and improve patient satisfaction. One of the most common stress agents currently used (adenosine) stimulates all adenosine receptors and has several disadvantages, most notably, undesirable side effects and inconvenient administration.

Dr. Cerqueira described the ideal features of a pharmacologic stress agent, noting that a selective adenosine agonist (A_2A agent) could reduce the frequency and intensity of side effects caused by adenosine, such as atrioventricular node (AV) block and bronchoconstriction, thus allowing its use in a broader range of patients. The ideal agent also would selectively vasodilate the coronary circulation without affecting the peripheral circulation, thus minimizing the decrease in systemic blood pressure. Agents that have a rapid onset and termination of action would reduce the duration of side effects and allow rapid reversal without the need for intervention. Lastly, he said, the ability to administer a bolus rather than a continuous infusion would increase the ease of use.

Three A_2A agents are currently in development: CVT-3146 (regadenoson), MRE-0470 (binodenoson), and BMS-068645 (apadenoson). All of these agents can be administered as a bolus infusion and produce the desired augmentation in coronary arterial blood flow without the undesirable side effects due to stimulation of the other adenosine receptors. Dr. Cerqueira noted that early studies have shown these agents to be comparable with adenosine for the detection of ischemia. In addition, regadenoson has been evaluated in two phase 3 studies (ADVANCE MPI 1 and 2), and the agent is comparable with adenosine in assessing the extent of reversible perfusion abnormalities and in detecting the defect type while being associated with significantly fewer occurrences of first-degree AV block and with lower overall summed symptom scores.

Regadenoson administered in a standard dose of 400 μg achieves a >2.4-fold increase in coronary blood flow in 33 seconds and maintains it for 2.3 minutes. Treatment with aminophylline returns coronary blood flow to the baseline level.

“New vasodilatory pharmacologic stress agents may simplify the stress SPECT MPI procedure and extend its use to a greater number of patients,” said Dr. Cerqueira.

Hybrid Imaging

Marcelo Di Carli, MD, Brigham and Women's Hospital, Boston, MA, discussed the limitations of computed tomography angiography (CTA) and myocardial perfusion imaging (MPI) and then presented several case examples of how integration of the two modalities could offer benefits in terms of diagnosis, risk assessment, and treatment guidance. Dr. Di Carli pointed out that the frequency of abnormalities on CTA in patients with an intermediate likelihood of CAD is >50%, and this modality will be an inefficient “gate-keeper” for this cohort because of the low prevalence of normal results. MPI is limited because it underestimates the extent of anatomic CAD, and it cannot detect atherosclerosis. Integrating CTA and MPI offers better identification of culprit coronary stenosis, because MPI provides improved detection of CAD in small vessels (<2 mm), while CTA provides assessment of multivessel disease.

Hybrid imaging can also enhance risk assessment. MPI is an excellent tool for identifying ischemic burden and assessing endothelial health, and when coupled with CTA's ability to delineate multivessel disease, plaque characteristics, and subclinical atherosclerosis, the combined use of these two modalities, which integrate structure and function, will allow for a more personalized approach to management, said Dr. Di Carli.

Dr. Di Carli noted that both of the key diagnostic objectives of identification of ischemic burden that requires revascularization and elucidation of the detailed anatomic burden, thus determining the goals and intensity of medical therapy, can be achieved with hybrid imaging. “It is likely that future approaches to CAD management will evolve toward more individualized strategies that better match patients' risk with intensity and goals of therapy,” said Dr. Di Carli. He added that the hybrid approach is most apt to benefit individuals with an intermediate to high likelihood of CAD, with CT offering the best approach for individuals with a low likelihood of disease.