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Cardiac PET Perfusion Imaging: AURORA Lights the Way to a New Era Free Access

Editorial Comment

J Am Coll Cardiol, 82 (16) 1611–1613


Functional imaging provides important diagnostic and prognostic information in the evaluation of patients with known and suspected ischemic heart disease.1 Single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) has been the long-time leader in this space, providing extensive information on the presence and extent of ischemia, scar, and functional abnormalities.2 However, advanced imaging with positron emission tomography (PET) MPI has important advantages that have propelled its growing adoption. In this issue of the Journal of the American College of Cardiology, Maddahi et al3 present the results from the AURORA (International Study to Evaluate Diagnostic Efficacy of Flurpiridaz [18F] Injection PET MPI in the Detection of Coronary Artery Disease [CAD]) trial, the second pivotal phase 3 randomized controlled trial (RCT) supporting the approval of an exciting novel PET MPI perfusion tracer, 18F-flurpiridaz, which will support the expansion and application of this burgeoning imaging modality.

PET MPI has technical advantages including higher count sensitivity, greater spatial and contrast resolution, improved temporal resolution, reduced soft tissue attenuation, and lower radiation doses.4 Important additional information available includes quantification of absolute myocardial blood flow (MBF) and myocardial perfusion reserve (MPR), calculation of changes in left ventricular ejection fraction with stress (left ventricular ejection fraction reserve), and coronary anatomic stenosis and calcification information available through hybrid imaging. Given these strengths, it is not surprising that PET MPI has superior comparative effectiveness across multiple comparisons with other advanced modalities.5 PET MPI has been recommended as preferred over SPECT because of higher diagnostic accuracy and a lower rate of nondiagnostic test results in the latest chest pain guidelines.6 Joint American Society of Nuclear Cardiology–Society of Nuclear Medicine and Molecular Imaging recommendations state that PET should be the first-line preferred test for anyone unable to undergo exercise stress.7 This statement stops short of a blanket recommendation for all patients, given an inability to easily perform exercise stress with current tracer limitations. Exercise stress provides numerous advantages, including more sensitive electrocardiogram changes; induced symptoms; and measurement of exercise workload, the most powerful prognostic marker and a helpful diagnostic tool.8,9

Absolute MBF and MPR (a noninvasive analogue to coronary flow reserve) provide important incremental diagnostic and prognostic information. In macrovascular obstructive epicardial coronary artery disease (CAD), they clarify functional significance, predict mortality and risk of cardiac events, and increase identification of balanced ischemia.4,5 In patients with signs/symptoms of ischemia and no obstructive CAD, MBF and MPR identify coronary microvascular dysfunction. Added characterization of this population is particularly important given immense functional impairment.10 Noninvasive assessment of MBF and MPR have been limited by tracer roll-off at higher flow rates, leading to underestimation challenging interpretation.

Robust comparative advantages and an improved reimbursement landscape have fueled a rapid expansion of laboratories performing PET MPI. Camera access limits volumes, but limitations in clinically available radiotracers remain an important additional roadblock preventing the large-scale adoption of PET MPI. 82Rubidium is not available in unit dosing and, thus, can be expensive for low-volume centers. It has increased tracer roll-off and high positron travel distance, which affect the benefits of PET MPI, though the modality remains highly effective.11 13N-ammonia has improved tracer flow characteristics and is available in unit dosing with a better cost structure at lower volumes. However, its 10-minute half-life mandates an onsite cyclotron, which limits its applicability, as do some unique artifacts that can complicate interpretation. 15O-water has very high concordance with blood flow. It is not currently available clinically in the United States, though there is exciting research evaluating improved delivery systems and software.

Into this challenging situation steps 18F-flurpiridaz, a new tracer with promise to address the limitations of currently available radiotracers. 18F-flurpiridaz promises greater availability, with a longer half-life of 110 minutes that supports acquisition from a regional cyclotron. The unit dosing supports use in low-volume centers, such as those starting new PET MPI programs, where the high number of referrals necessary to make a high-cost generator financially feasible are not attained.11 The longer half-life also supports the routine use of exercise stress, with all the associated diagnostic and prognostic advantages.8,9,11 18F-flurpiridaz provides high myocardial extraction across the entire range of achievable flows and, thus, provides precise estimation with improved diagnostic and prognostic calibration.12 It has other beneficial characteristics, including high spatial resolution from the decreased positron range of 18F and improved defect contrast.11

The U.S. Food and Drug Administration (FDA) requires 2 phase 3 studies showing safety and sufficient diagnostic performance. The first phase 3 RCT for 18F-flurpiridaz examined the diagnostic efficacy of this tracer vs SPECT MPI. 18F-flurpiridaz PET MPI was safe and well tolerated, with reduced radiation dose and improved imaging quality. The sensitivity for ≥50% stenosis was significantly greater (71.9% vs 53.7%; P < 0.001), but the specificity did not meet prespecified noninferiority criteria (76.2% vs 86.6%; P = not significant).13 Receiver-operating characteristic curve analysis showed greater diagnostic accuracy in the overall study population and in women, obese subjects, and those undergoing pharmacologic stress.

Into this clinical context enters the AURORA trial, the second FDA-mandated phase 3 RCT to facilitate the approval of this tracer for clinical use. The methods of this second trial are similar to those of the first.14 Lessons learned in the first RCT have been incorporated, including changing the primary study objective to identification of obstructive CAD with the comparison to SPECT MPI transitioned to a secondary endpoint.13 Patients with known CAD were excluded from AURORA to minimize discordant results from prior coronary revascularization. Referral bias was minimized by requiring both SPECT and PET studies to be performed before invasive coronary angiography. Finally, more contemporary hardware was used with allowance for solid-state cadmium zinc telluride cameras.

The final study population of AURORA included 578 subjects (mean age: 64 years; 32.5% women; 33.6% with diabetes). AURORA demonstrated that 18F-flurpiridaz was safe and well tolerated, with an almost 50% radiation dose reduction compared with 99mTc-sestamibi and sensitivity and specificity greater than the prespecified 60% threshold. Sensitivity was superior to SPECT MPI (sensitivity: 80.3% vs 68.7%; P < 0.0004) and specificity was noninferior: 63.8% vs 61.7%. Receiver-operating characteristic curve analysis showed greater diagnostic performance compared with SPECT MPI in the overall population and in women and obese patients. Defect size, image quality, and diagnostic certainty were all superior, with P < 0.001. Results were similar using a cutoff of ≥70% stenosis on quantitative coronary angiography.

Limitations of the AURORA trial included continued use of the FDA-mandated ≥50% stenosis criterion, which causes an underestimation of sensitivity and an overestimation of specificity. There were reduced use of exercise stress (17% of subjects) and lack of incorporation of absolute MBF/MPR data. Further study to clarify the role of these adjuncts will be essential (substudies pending). Additional future directions could include examination of 18F-flurpiridaz use in specific populations, such as patients undergoing evaluation for renal transplant. Finally, comparisons with other PET perfusion agents already available and in patients with known CAD will be important and enlightening.

Cardiac PET MPI is positioned to serve as the leading modality for the functional evaluation of suspected and known CAD. 18F-flurpiridaz will facilitate this upward progression with beneficial tracer characteristics that will increase access and availability, enable exercise stress, and optimize MBF quantification. AURORA is lighting the way to an exciting new era in cardiac imaging.

Funding Support and Author Disclosures

Dr Bourque has served on a GE Healthcare Advisory Board for amyloid imaging.


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