Fluorine-18 flurpiridaz is a novel positron emission tomography (PET) myocardial perfusion imaging tracer.
This study sought to assess the diagnostic efficacy of flurpiridaz PET versus ...technetium-99m–labeled single photon emission computed tomography SPECT for the detection and evaluation of coronary artery disease (CAD), defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA). Flurpiridaz safety was also evaluated.
In this phase III prospective multicenter clinical study, 795 patients with known or suspected CAD from 72 clinical sites in the United States, Canada, and Finland were enrolled. A total of 755 patients were evaluable, and the mean age was 62.3 ± 9.5 years, 31% were women, 55% had body mass index ≥30 kg/m2, and 71% had pharmacological stress. Patients underwent 1-day rest-stress (pharmacological or exercise) flurpiridaz PET and 1- or 2-day rest-stress Tc-99m–labeled SPECT and ICA. Images were read by 3 experts blinded to clinical and ICA data.
Sensitivity of flurpiridaz PET (for detection of ≥50% stenosis by ICA) was 71.9% (95% confidence interval CI: 67.0% to 76.3%), significantly (p < 0.001) higher than SPECT (53.7% 95% CI: 48.5% to 58.8%), while specificity did not meet the prespecified noninferiority criterion (76.2% 95% CI: 71.8% to 80.1% vs. 86.6% 95% CI: 83.2% to 89.8%; p = NS). Receiver-operating characteristic curve analysis demonstrated superior discrimination of CAD by flurpiridaz PET versus SPECT in the overall population, in women, obese patients, and patients undergoing pharmacological stress testing (p < 0.001 for all). Flurpiridaz PET was superior to SPECT for defect size (p < 0.001), image quality (p < 0.001), diagnostic certainty (p < 0.001), and radiation exposure (6.1 ± 0.4 mSv vs. 13.4 ± 3.2 mSv; p < 0.001). Flurpiridaz PET was safe and well tolerated.
Flurpiridaz PET myocardial perfusion imaging shows promise as a new tracer for CAD detection and assessment of women, obese patients, and patients undergoing pharmacological stress testing. A second phase III Food and Drug Administration trial is ongoing. (A Phase 3 Multi-center Study to Assess PET Imaging of Flurpiridaz F 18 Injection in Patients with CAD; NCT01347710)
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The performance of SPECT myocardial perfusion imaging (MPI) may deteriorate in smaller hearts, primarily because of the lower resolution of conventional Anger cameras.
F-flurpiridaz is a novel PET ...MPI agent with superior image and defect resolution. We sought to determine the diagnostic performance of
Tc-labeled SPECT MPI compared with
F-flurpiridaz PET MPI according to left ventricle (LV) size.
We conducted a substudy of the phase III clinical trial of flurpiridaz (
= 750) and stratified diagnostic performance according to the median PET LV end-diastolic volume (LVEDV), with smaller LVs defined as having an LVEDV of less than 113 mL (
= 369) and larger LVs defined as having an LVEDV of at least 113 mL (
= 381). Images were interpreted by the majority rule of 3 independent masked readers. The reference standard was quantitative invasive angiography, with at least 50% stenosis in at least 1 coronary artery considered significant.
SPECT performance decreased significantly from an area under the curve (AUC) of 0.75 in larger LVs to 0.67 in smaller LVs (
= 0.03), whereas PET performance was similar in larger and smaller LVs (AUC, 0.79 vs. 0.77,
= 0.49). Accordingly, in smaller LVs, PET had a higher AUC (0.77) than the SPECT AUC (0.67) (
< 0.0001), a phenomenon driven by female patients (
< 0.0001). In smaller LVs, there was a degradation of SPECT sensitivity that was highly significant (
< 0.001), whereas there was no significant change in PET sensitivity according to LV size (
= 0.07). Overall, PET had significantly higher sensitivity than SPECT in both smaller LVs (67% vs. 43%,
< 0.001) and larger LVs (76% vs. 61%,
< 0.001). The specificities of PET and SPECT were similar in larger LVs (76% vs. 83%,
= 0.11). Although SPECT specificity improved in smaller compared with larger LVs (90% vs. 83%,
= 0.03), the PET specificity did not change with LV size (76% vs. 76%,
= 0.9).
The diagnostic performance of
F-flurpiridaz PET MPI is not affected by LV size and is superior to SPECT MPI in patients with smaller LVs, highlighting the importance of appropriate test selection in these patients.
A novel PET radiotracer, Flurpiridaz F 18, has undergone phase II clinical trial evaluation as a high-resolution PET cardiac perfusion imaging agent. In a subgroup of patients imaged with this agent, ...we assessed the feasibility and benefit of simultaneous correction of respiratory and cardiac motion.
In 16 patients, PET imaging was performed on a 4-ring scanner in dual cardiac and respiratory gating mode. Four sets of data were reconstructed with high-definition reconstruction (HD•PET): ungated and 8-bin electrocardiography-gated images using 5-min acquisition, optimal respiratory gating (ORG)-as developed for oncologic imaging-using a narrow range of breathing amplitude around end-expiration level with 35% of the counts in a 7-min acquisition, and 4-bin respiration-gated and 8-bin electrocardiography-gated images (32 bins in total) using the 7-min acquisition (dual-gating, using all data). Motion-frozen (MF) registration algorithms were applied to electrocardiography-gated and dual-gated data, creating cardiac-MF and dual-MF images. We computed wall thickness, wall/cavity contrast, and contrast-to-noise ratio for standard, ORG, cardiac-MF, and dual-MF images to assess image quality.
The wall/cavity contrast was similar for ungated (9.3 ± 2.9) and ORG (9.5 ± 3.2) images and improved for cardiac-MF (10.8 ± 3.6) and dual-MF images (14.8 ± 8.0) (P < 0.05). The contrast-to-noise ratio was 22.2 ± 9.1 with ungated, 24.7 ± 12.2 with ORG, 35.5 ± 12.8 with cardiac-MF, and 42.1 ± 13.2 with dual-MF images (all P < 0.05). The wall thickness was significantly decreased (P < 0.05) with dual-MF (11.6 ± 1.9 mm) compared with ungated (13.9 ± 2.8 mm), ORG (13.1 ± 2.9 mm), and cardiac-MF images (12.1 ± 2.7 mm).
Dual (respiratory/cardiac)-gated perfusion imaging with Flurpiridaz F 18 is feasible and improves image resolution, contrast, and contrast-to-noise ratio when MF registration methods are applied.
Computerized methodologies standardize the myocardial perfusion imaging (MPI) interpretation process.
To develop an automated relative perfusion quantitation approach for 18F-flurpiridaz, PET MPI ...studies from all phase III trial participants of 18F-flurpiridaz were divided into 3 groups. Count distributions were obtained in N = 40 normal patients undergoing pharmacological or exercise stress. Then, N = 90 additional studies were selected in a derivation group. Following receiver operating characteristic curve analysis, various standard deviations below the mean normal were used as cutoffs for significant CAD, and interobserver variability determined. Finally, diagnostic performance was compared between blinded visual readers and blinded derivations of automated relative quantitation in the remaining N = 548 validation patients.
Both approaches yielded comparable accuracies for the detection of global CAD, reaching 71% and 72% by visual reads, and 72% and 68% by automated relative quantitation, when using CAD ≥ 70% or ≥ 50% stenosis for significance, respectively. Similar results were observed when analyzing individual coronary territories. In both pharmacological and exercise stress, automated relative quantitation demonstrated significantly more interobserver agreement than visual reads.
Our automated method of 18F-flurpiridaz relative perfusion analysis provides a quantitative, objective, and highly reproducible assessment of PET MPI in normal and CAD subjects undergoing either pharmacological or exercise stress.
A novel (18)F-labeled ligand for the norepinephrine transporter (N-3-bromo-4-(3-(18)F-fluoro-propoxy)-benzyl-guanidine LMI1195) is in clinical development for mapping cardiac nerve terminals in vivo ...using PET. Human safety, whole-organ biodistribution, and radiation dosimetry of LMI1195 were evaluated in a phase 1 clinical trial.
Twelve healthy subjects at 3 clinical sites were injected intravenously with 150-250 MBq of LMI1195. Dynamic PET images were obtained over the heart for 10 min, followed by sequential whole-body images for approximately 5 h. Blood samples were obtained, and heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. Residence times were determined from multiexponential regression of organ region-of-interest data normalized by administered activity (AA). Radiation dose estimates were calculated using OLINDA/EXM. Myocardial, lung, liver, and blood-pool standardized uptake values were determined at different time intervals.
No adverse events due to LMI1195 were seen. Blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart over 4 h. Liver and lung activity cleared relatively rapidly, providing favorable target-to-background ratios for cardiac imaging. The urinary bladder demonstrated the largest peak uptake (18.3% AA), followed by the liver (15.5% AA). The mean effective dose was 0.026 ± 0.0012 mSv/MBq. Approximately 1.6% AA was seen in the myocardium initially, remaining above 1.5% AA (decay-corrected) through 4 h after injection. The myocardium-to-liver ratio was approximately unity initially, increasing to more than 2 at 4 h.
These preliminary data suggest that LMI1195 is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggest that cardiac imaging should be possible with acceptable patient radiation dose.
Objectives This was a phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for positron emission tomography (PET) myocardial perfusion imaging (MPI) with Tc-99m ...single-photon emission computed tomography (SPECT) MPI with regard to image quality, interpretative certainty, defect magnitude, and detection of coronary artery disease (CAD) (≥50% stenosis) on invasive coronary angiography (ICA). Background In pre-clinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer. Methods One hundred forty-three patients from 21 centers underwent rest-stress PET and Tc-99m SPECT MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers. Results A higher percentage of images were rated as excellent/good on PET versus SPECT on stress (99.2% vs. 88.5%, p < 0.01) and rest (96.9% vs. 66.4, p < 0.01) images. Diagnostic certainty of interpretation (percentage of cases with definitely abnormal/normal interpretation) was higher for PET versus SPECT (90.8% vs. 70.9%, p < 0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT (78.8% vs. 61.5%, respectively, p = 0.02). Specificity was not significantly different (PET: 76.5% vs. SPECT: 73.5%). Receiver-operating characteristic curve area was 0.82 ± 0.05 for PET and 0.70 ± 0.06 for SPECT (p = 0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p = NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p = 0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort. Conclusions In this phase 2 trial, PET MPI with flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis.
(18)F-labeled BMS747158 is a novel myocardial perfusion imaging tracer that targets mitochondrial complex 1. The objectives of this phase I study were to evaluate radiation dosimetry, ...biodistribution, human safety, tolerability, and early elimination of (18)F activity in urine after injection of a single dose of the tracer at rest in healthy subjects.
Thirteen healthy subjects were injected with 170-244 MBq (4.6-6.6 mCi) of BMS747158 intravenously. Dynamic PET was obtained over the heart for 10 min, followed by sequential whole-body imaging for 5 h. Blood samples and urinary excretion were collected for up to 8 h. Heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. The residence times were determined from multiexponential regression of organ region-of-interest data normalized by injected dose. Absorbed dose estimates for all target organs were determined using MIRD schema with OLINDA/EXM software.
The organ receiving the largest mean absorbed dose was the kidneys at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi). The heart exhibited high and sustained retention of BMS747158 from the earliest images through approximately 5 h after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Mean urinary excretion was 4.83 percentage injected dose (range, 0.64-12.41 percentage injected dose).
These preliminary data suggest that (18)F-labeled BMS747158 appears to be well tolerated and has a unique potential for myocardial perfusion PET.
This was a phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for positron emission tomography (PET) myocardial perfusion imaging (MPI) with Tc-99m ...single-photon emission computed tomography (SPECT) MPI with regard to image quality, interpretative certainty, defect magnitude, and detection of coronary artery disease (CAD) (≥50% stenosis) on invasive coronary angiography (ICA).
In pre-clinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer.
One hundred forty-three patients from 21 centers underwent rest-stress PET and Tc-99m SPECT MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers.
A higher percentage of images were rated as excellent/good on PET versus SPECT on stress (99.2% vs. 88.5%, p < 0.01) and rest (96.9% vs. 66.4, p < 0.01) images. Diagnostic certainty of interpretation (percentage of cases with definitely abnormal/normal interpretation) was higher for PET versus SPECT (90.8% vs. 70.9%, p < 0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT (78.8% vs. 61.5%, respectively, p = 0.02). Specificity was not significantly different (PET: 76.5% vs. SPECT: 73.5%). Receiver-operating characteristic curve area was 0.82 ± 0.05 for PET and 0.70 ± 0.06 for SPECT (p = 0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p = NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p = 0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort.
In this phase 2 trial, PET MPI with flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis.
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