Skip to main content
Skip main navigationClose Drawer MenuOpen Drawer Menu

Flurpiridaz F-18 PET Myocardial Perfusion Imaging in Patients With Suspected Coronary Artery DiseaseFree Access

Original Investigation

J Am Coll Cardiol, 82 (16) 1598–1610
Sections

Central Illustration

Abstract

Background

Flurpiridaz F-18 (flurpiridaz) is a novel positron emission tomography (PET) myocardial perfusion imaging tracer.

Objectives

The purpose of this study was to further assess the diagnostic efficacy and safety of flurpiridaz for the detection and evaluation of coronary artery disease (CAD) defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA).

Methods

In this second phase 3 prospective multicenter clinical study, 730 patients with suspected CAD from 48 clinical sites in the United States, Canada, and Europe were enrolled. Patients underwent 1-day rest/stress flurpiridaz PET and 1- or 2-day rest-stress Tc-99m–labeled single photon emission computed tomography (SPECT) before ICA. PET and SPECT images were read by 3 experts blinded to clinical and ICA data.

Results

A total of 578 patients (age 63.7 ± 9.5 years) were evaluable; 32.5% were women, 52.3% had body mass index ≥30 kg/m2, and 33.6% had diabetes. Flurpiridaz PET met the efficacy endpoints of the study; its sensitivity and specificity were significantly higher than the prespecified threshold value by 2 of the 3 readers. The sensitivity of flurpiridaz PET was higher than SPECT (80.3% vs 68.7%; P = 0.0003) and its specificity was noninferior to SPECT (63.8% vs 61.7%; P = 0.0004). PET area under the receiver-operating characteristic curves were higher than SPECT in the overall population (0.80 vs 0.68; P < 0.001), women, and obese patients (P < 0.001 for both). Flurpiridaz PET was superior to SPECT (P < 0.001) for perfusion defect size/severity evaluation, image quality, diagnostic certainty, and radiation exposure. Flurpiridaz PET was safe and well tolerated.

Conclusions

This second flurpiridaz PET myocardial perfusion imaging trial shows that flurpiridaz has utility as a new tracer for CAD detection, specifically in women and obese patients. (An International Study to Evaluate Diagnostic Efficacy of Flurpiridaz [18F] Injection PET MPI in the Detection of Coronary Artery Disease [CAD]; NCT03354273)

Introduction

Myocardial perfusion imaging (MPI) with positron emission tomography (PET) has a Class I indication for assessment of patients with known or suspected coronary artery disease (CAD); however, each currently available PET MPI tracer has characteristics that can limit widespread clinical use. Flurpiridaz F-18 (flurpiridaz) is a novel PET MPI tracer labeled with fluorine-18 (18F), which has a high myocardial extraction across a wide range of myocardial blood flow values, superior in the upper range of flow compared with other tracers,1-6 and can be produced as a unit dose from a regional cyclotron, obviating the need for an on-site cyclotron or generator.7,8 Phase 1 studies9,10 have shown that flurpiridaz is clinically safe, has acceptable clinical dosimetry, and provides high-quality images in conjunction with exercise treadmill and pharmacological stress testing. A phase 2 flurpiridaz trial11 demonstrated improved CAD diagnostic performance, image quality, and confidence of interpretation over Tc-99m–labeled single photon emission computed tomography (SPECT) MPI in 143 patients with suspected CAD. In the first phase 3 trial, flurpiridaz PET was compared with Tc-99m–labeled SPECT MPI for detection and evaluation of CAD in 755 patients.12 Flurpiridaz PET reached significantly higher sensitivity for CAD detection, although its specificity did not meet the prespecified noninferiority criterion.

This paper reports the second phase 3, open-label, multicenter international trial in which the primary efficacy endpoint was to assess the diagnostic efficacy (sensitivity and specificity) of flurpiridaz PET MPI for the detection of significant CAD (≥50% by quantitative invasive coronary angiography [ICA]). The secondary efficacy endpoints were to evaluate the diagnostic performance of flurpiridaz PET MPI vs Tc-99m SPECT MPI in the detection of CAD in all patients (key secondary efficacy endpoint) and in the prespecified clinically important subgroups of women, patients with body mass index (BMI) ≥30 kg/m2, and those with diabetes. The safety of flurpiridaz PET MPI was also evaluated.

Methods

Details of the methodology of this study has been previously published13 and are included in the Supplemental Appendix.

Study patients

A total of 48 clinical sites in the United States, Canada, and Europe enrolled 730 patients with suspected CAD who were referred for a clinically indicated ICA from June 5, 2018, to May 9, 2022. Institutional Review Board or ethics committee approval was obtained at each study site. All patients provided written informed consent. The main exclusion criteria were unstable cardiovascular status (myocardial infarction [MI]/unstable angina pectoris within 6 months; transient ischemic attack/stroke within 3 months; symptomatic valvular disease; significant congenital heart disease; NYHA functional class III/IV heart failure), history of known CAD (prior coronary artery bypass grafting, percutaneous coronary intervention, MI), nonischemic cardiomyopathy, and history of heart transplantation.

Study design

The design of this second phase 3 multicenter trial of flurpiridaz differs from the first phase 3 multicenter trial as follows: 1) only patients with suspected CAD were enrolled, and those with known CAD were excluded; 2) the primary efficacy endpoint was sensitivity and specificity of flurpiridaz PET for overall detection of CAD, defined as ≥50% stenosis by quantitative invasive coronary angiography; 3) PET and SPECT studies were both performed before ICA to minimize referral bias; and 4) SPECT studies included cadmium zinc telluride cameras. All SPECT and PET studies were performed in any preferred order within 60 days before ICA. All patients were followed up 2 to 3 days and 14 to 17 days after flurpiridaz injection (Figure 1).

Figure 1
Figure 1

Patient Disposition

Of 730 enrolled patients, 604 patients received at least 1 dose of flurpiridaz and were evaluated for safety of flurpiridaz. Of these 604 patients, 578 also had evaluable single photon emission computed tomography (SPECT) and invasive coronary angiograms and were designated as the study population. The primary and secondary endpoints of this study were evaluated in these 578 patients. Prevalence of coronary artery disease was 43%. Overall, of the 730 screened patients, 152 were not included in the study population for the following reasons: 34 withdrew consent to participate, 21 failed screening, 5 had adverse events, 4 were lost to follow-up, and 58 were excluded for a variety of other reasons. Angio = angiography; PET = positron emission tomography.

Radionuclide imaging

All SPECT and PET cameras used for this study were qualified for technical capability and quality. SPECT MPI was performed according to American Society of Nuclear Cardiology guidelines.14 Prespecified SPECT tracer dosing was 8.0 to 12.0 mCi for rest and 24.0 to 36.0 mCi for stress with a minimum stress/rest ratio of 3.0. Flurpiridaz doses were prespecified as 2.5 to 3.0 mCi for rest, 9.0 to 9.5 mCi for exercise (minimum 1-hour rest-exercise dose interval), and 6.0 to 6.5 mCi for pharmacological stress (minimum 30-minute rest-stress dose interval).10 The same stress modality and stress agent was used for both PET and SPECT MPI. Electrocardiography (ECG)-gated MPI for assessment of ventricular function was required for rest and stress PET and for stress SPECT. Reconstructed images were submitted to a central laboratory (BioClinica, Inc) for quality control and preparation for blinded read.

Image interpretation

All flurpiridaz PET and SPECT images were read randomly by 3 independent expert blinded readers (P.C., R.P., and R.R; separate from the study team and sites) who were board certified in nuclear cardiology and were blinded to patient characteristics, site, clinical data, and the type of study. Readers followed specific and similar prespecified rules for overall interpretation of PET and SPECT, image quality, diagnostic certainty, and segmental defects.13 Readers scored each PET and SPECT study as positive or negative for presence of disease. These dichotomized scores were used to determine sensitivities and specificities of PET and SPECT. In addition, all 17 myocardial segments were scored for presence and intensity of a perfusion defect. Stress segmental defect scores (0 = normal; 4 = absent uptake) were then summed to derive the summed stress score (SSS) which served as a measure of extent and severity of perfusion defects (ie, defect size) and the summed difference score reflecting the extent/severity of ischemia by each modality. Readers also scored image quality on a 5-point scale from excellent to unevaluable. Diagnostic certainty was expressed as the percentage read as definitely normal or definitely abnormal. Based on the overall interpretation of the rest and stress perfusion images as well as the gated data, readers provided an overall binary assessment of presence/absence of CAD (“disease positive/negative”), which was used for primary efficacy endpoint determination.

Invasive coronary angiography

ICA was performed using investigational site practice protocols. After completion of catheterization, data were submitted to the sponsor core laboratory for quality control. Coronary artery narrowing was measured using quantitative coronary analysis by a blinded core laboratory expert.

Definition of CAD positive

Patients were considered disease positive if quantitative coronary analysis revealed ≥50% stenosis in ≥1 major epicardial coronary artery or major branch. A stenosis cutoff of ≥70% was also assessed as a prespecified secondary analysis.

Study efficacy endpoints

The primary efficacy endpoints were sensitivity and specificity of flurpiridaz for detection of CAD. The prespecified criteria were statistical superiority of both the sensitivity and specificity of flurpiridaz PET MPI in the detection of CAD over the threshold of 60% in agreement with the U.S. Food and Drug Administration. Thus, the lower bound of the 2-sided 95% CI for both sensitivity and specificity must exceed 60%. Secondary efficacy endpoints included comparison of the diagnostic performance of flurpiridaz PET and SPECT in all patients (key secondary efficacy endpoint) and in women, obese patients, and patients with diabetes. The same 2 of 3 blinded readers had to demonstrate significantly higher sensitivity and noninferior specificity of flurpiridaz PET vs SPECT. Additional secondary efficacy endpoints were comparisons for image quality, diagnostic certainty, defect size, and radiation dose to patients.13

Statistical analysis

Diagnostic performance of PET and SPECT was assessed in an evaluable population defined as patients who had evaluable rest/stress flurpiridaz PET, rest/stress SPECT, and ICA. Safety of flurpiridaz was assessed in a population defined as patients who received at least ≥1 dose of flurpiridaz. The statistical superiority of both sensitivity and specificity to a threshold of 60% in flurpiridaz PET was performed using a 1-sided 1-sample z-test at α = 0.025. The criteria for comparison between flurpiridaz PET and SPECT was statistical superiority in sensitivity and noninferiority in specificity. The test of superiority of sensitivity in flurpiridaz PET over SPECT was performed with a 1-sided McNemar’s test at α = 0.025. Similarly, the test of specificity noninferiority between flurpiridaz PET and SPECT was performed with Nam’s RMLE method for noninferiority (margin = 0.1) at a 1-sided α = 0.025. Methods for determination of sample size have been published.13 The primary criteria for meeting each statistical endpoint were based on individual reader result. “Majority rule” (results based on agreement of 2 of 3 readers) was considered independently. Secondary endpoints were tested when primary endpoint was met. To control the false-positive rate at a 1-sided 0.025 level across the testing of the secondary efficacy endpoints, the secondary efficacy endpoints were tested hierarchically in a prespecified order. Each endpoint was tested sequentially at a 1-sided 0.025 level of significance; when a statistical test for a given endpoint failed to reach statistical significance in the appropriate direction, testing on all remaining secondary efficacy endpoints in the hierarchy were ceased and the study was considered successful on all secondary efficacy endpoints up to that point. There was no multiplicity adjustment among the additional endpoints.

The proportion of patients whose images rated as “excellent” or “good” were compared between PET and SPECT using a 2-sided McNemar’s test at 5% level of significance by rest and stress imaging separately. The proportion of patients whose images rated as “definitely” (either normal or abnormal) were compared between PET and SPECT using a 2-sided McNemar’s test at 5% level of significance. Stress defect size and severity (SSS) was compared between PET and SPECT using a 2-sided paired Student's t-test (or equivalent nonparametric test if an assumption of normality is not met) at 5% level of significance. Receiver-operating characteristic (ROC) curves were generated from logistic regression and were derived from the middle (median) SSS value of the 3 readers. Sensitivity vs (1 − specificity) was plotted for all possible values of the SSS cutoff criterion defining normal and abnormal. Points were then connected by straight lines to improve visualization.

Results

Patient population

Figure 1 shows the enrolled population and disposition. Table 1 shows patient demographics and characteristics in the 578 evaluable patients and the 604 patients who were included in the safety analysis population. Concomitant medications are shown in Supplemental Table 1. Pharmacological stress was used in 503 patients (83% of evaluable patients) and treadmill exercise in the remaining patients. The pharmacological stress agents were regadenoson (53%), dipyridamole (41%), or adenosine (6%).

Table 1 Patient Demographics and Baseline Characteristics

Safety Population (n = 604)Without CAD (n = 329)WithCAD(n = 249)
Age, y62.9 ± 9.764.9 ± 9.063.6 ± 9.4
Sex
 Female147 (44.7)41 (16.5)196 (32.5)
 Male182 (55.3)208 (83.5)408 (67.5)
Race
 White or Caucasian266 (80.9)207 (83.1)488 (80.8)
 Black or African American31 (9.4)4 (1.6)43 (7.1)
 Asian2 (0.6)4 (1.6)8 (1.3)
 American Indian or Alaska Native1 (0.3)0 (0.0)1 (0.2)
 Native Hawaiian or other Pacific Islander1 (0.3)2 (0.8)3 (0.5)
 Other1 (0.3)2 (0.8)3 (0.5)
 Not reported27 (8.2)30 (12.0)58 (9.6)
Weight, kg91.3 ± 22.291.0 ± 20.091.4 ± 21.4
Height, cm167.0 ± 10.2173.5 ± 9.0171.4 ± 9.86
Mean BMI, kg/m231.5 ± 7.030.1 ± 5.831.0 ± 6.6
BMI ≥30 kg/m2181 (55.0)117 (47.0)316 (52.3)
History of
 Diabetes mellitus103 (31.3)91 (36.5)209 (34.6)
 Stroke/TIA26 (7.9)17 (6.8)117 (19.4)
 Hypertension251 (76.3)174 (69.9)29 (4.8)
 Hyperlipidemia246 (74.8)205 (82.3)95 (15.7)
 Smoking172 (52.3)143 (57.4)327 (54.1)
Chest pain
 Typical/definite angina94 (28.6)96 (38.6)193 (32.0)
 Atypical/probably angina153 (46.5)73 (29.3)240 (39.7)
 Nonanginal23 (7.0)23 (9.2)51 (8.4)
 Asymptomatic59 (17.9)57 (22.9)120 (19.9)
Pretest probability of CAD41.7 ± 27.349.7 ± 32.245.0 ± 29.6
Multivessel CAD0 (0.0)117 (20.2)117 (19.4)
Rest LVEF, %60.4 ± 8.2559.4 ± 8.260.0 ± 8.24

Values are mean ± SD or n (%).

BMI = body mass index; CAD = coronary artery disease; LVEF = left ventricular ejection fraction; TIA = transient ischemic attack.

Primary efficacy endpoint

Sensitivities and specificities of flurpiridaz PET for detection of ≥50% by ICA for each of the 3 readers are shown in Table 2. In 2 of the 3 readers, sensitivity and specificity of flurpiridaz were significantly higher than the prespecified threshold value (sensitivity: P < 0.0001 for both readers; specificity: P = 0.018 and P = 0.0002 for readers 1 and 2, respectively). The third reader’s sensitivity was also significantly higher than the prespecified threshold (P < 0.0001), although the specificity was not significant (P = 0.997). Therefore, the primary efficacy endpoint of the study was met by the same 2 of 3 readers exceeding the prespecified threshold for both sensitivity and specificity.

Table 2 Sensitivity and Specificity of Flurpiridaz Positron Emission Tomography for Overall Detection of Coronary Artery Disease

Sensitivity (95% CI)P ValueSpecificity (95% CI)P Value
Reader 177.1 (71.9-82.3)<0.000165.7 (60.5-70.8)0.0182
Reader 273.5 (68.0-79.0)<0.000169.6 (64.6-74.6)0.0002
Reader 388.8 (84.8-92.7)<0.000152.6 (47.2-58.0)0.9970
Majority rule80.3 (75.4-85.3)<0.000163.8 (58.6-69.0)0.0781

Secondary efficacy endpoints

The secondary efficacy endpoints were to evaluate the diagnostic performance of flurpiridaz PET vs Tc-99m SPECT for the detection of CAD in all patients (key secondary efficacy endpoint) and in the clinically important subgroups of women, patients with body mass index (BMI) ≥30 kg/m2, and patients with diabetes. Several exploratory objectives were also evaluated including comparison of flurpiridaz PET vs SPECT with respect to image quality, diagnostic certainty, radiation exposure, and detection of ≥70% coronary artery stenosis by ICA.

All patients

Sensitivities and specificities of flurpiridaz PET vs SPECT for detection of ≥50% by ICA for each of the 3 readers are shown in Table 3. In all 3 readers, flurpiridaz PET sensitivities were significantly higher and specificities were noninferior than those of SPECT. Furthermore, by the majority rule, the sensitivity of flurpiridaz PET (80.3% [95% CI: 75.4%-85.3%]) was significantly higher (P = 0.0003) than SPECT (68.7% [95% CI: 62.9%-74.4%]) and the specificity of flurpiridaz PET (63.8% [95% CI: 58.6%-69.0%]) was noninferior (P = 0.0004) compared with SPECT (61.7% [95% CI: 56.4%-67.0%]). ROC analysis confirmed superior discrimination of CAD with flurpiridaz PET vs SPECT (P < 0.0001) (Figure 2).

Table 3 PET vs SPECT for Overall Detection of CAD

PET MPISPECT MPIDF: Difference, %P Valueb
Sensitivitya: patients with CAD (n = 249)
 Reader 1192/249 (77.1)
(71.9–82.3)
156/249 (62.7)
(56.6–68.7)
14.5 (6.5 to 22.4)<0.0001
 Reader 2183/249 (73.5)
(68.0–79.0)
151/249 (60.6)
(54.6–66.7)
12.9 (4.7 to 21.0)0.0002
 Reader 3221/249 (88.8)
(84.8–92.7)
188/249 (75.5)
(70.2–80.8)
13.3 (6.6 to 19.9)<0.0001
 Majority rule200/249 (80.3)
(75.4–85.3)
171/249 (68.7)
(62.9–74.4)
11.6 (4.1 to 19.2)0.0003
Specificityb: patients without CAD (n = 329)
 Reader 1216/329 (65.7)
(60.5–70.8)
208/329 (63.2)
(58.0–68.4)
2.4 (−4.9 to 9.7)0.0004
 Reader 2229/329 (69.6)
(64.6–74.6)
213/329 (64.7)
(59.6–69.9)
4.9 (−2.1 to 11.8)<0.0001
 Reader 3173/329 (52.6)
(47.2–58.0)
169/329 (51.4)
(46.0–56.8)
1.2 (−6.0 to 8.4)0.0011
 Majority rule210/329 (63.8)
(58.6–69.0)
203/329 (61.7)
(56.4–67.0)
2.1 (−5.0 to 9.3)0.0004

Values are n/N (%) (95% CI) or difference (95% CI).

MPI = myocardial perfusion imaging; PET = positron emission tomography; SPECT = single photon emission computed tomography.

a Sensitivity was based on data from subjects with coronary artery disease (CAD) (n = 249) and specificity was based on data from subjects without CAD (n = 329).

b Specificity P values represent noninferiority analyses.

Figure 2
Figure 2

Flurpiridaz PET vs Tc-99m SPECT in Different Patient Subsets

Flurpiridaz PET’s area under the receiver-operating characteristic curve values were significantly higher than those of Tc-99m SPECT in all patients (A), women (B), patients with body mass index (BMI) ≥30 kg/m2 (C), and patients with diabetes (D). CAD = coronary artery disease; other abbreviations as in Figure 1.

As shown in Figure 3, the flurpiridaz PET area under the ROC curve was significantly higher than those of Anger camera SPECT (P = 0.0001), and cadmium zinc telluride SPECT (P = 0.0002).

Figure 3
Figure 3

Flurpiridaz PET vs Different Tc-99m SPECT Methods

Flurpiridaz positron emission tomography (PET) area under the receiver-operating characteristic curve values were significantly higher than those of Tc-99m single photon emission computed tomography (SPECT), Anger camera, and cadmium zinc telluride (CZT) SPECT camera.

When ≥70% was used to define CAD, for both modalities, sensitivity values increased (92.1% [95% CI: 87.4%-96.8%] for PET and 79.5% [95% CI: 72.5%-86.5%] for SPECT) and specificity values declined (55.5% [95% CI: 50.9%-60.1%] for PET and 56.6% [95% CI: 52.0%-61.2%] for SPECT). Nevertheless, PET sensitivity was statistically higher than SPECT (P = 0.001) and PET specificity was noninferior vs SPECT (P = 0.001). For detection of single-vessel CAD, by the majority rule, the sensitivity of flurpiridaz PET (20.3% [95% CI: 13.5%-27.1%]) was significantly higher (P = 0.01) than SPECT (9.8% [95% CI: 4.7%-14.8%]) and the specificity of flurpiridaz PET (84.9% [95% CI: 81.6%-88.3%]) was noninferior (P = 0.0003) compared with SPECT (92.1% [95% CI: 89.6%-94.6%]). Furthermore, using majority rule for correct identification of multivessel CAD, the sensitivity of flurpiridaz PET (39.7% [95% CI: 30.8%-48.6%]) was significantly higher (P < 0.001) than SPECT (14.7% [95% CI: 8.2%-21.1%]) and the specificity of flurpiridaz PET (89.6% [95% CI: 86.8%-92.4%]) was noninferior (P = 0.032) compared with SPECT (93.3% [95% CI: 91.0%-95.6%]).

The inter-reader and intrareader agreements were high for SPECT and PET interpretations (Supplemental Tables 2 to 4).

Prespecified populations of special interest

Table 4, Supplemental Tables 5 to 7, and the Central Illustration show comparative sensitivity and specificity of flurpiridaz PET and SPECT for CAD assessment in different patient subgroups. In at least 2 of 3 readers, flurpiridaz PET sensitivities were significantly higher, and specificities were noninferior compared with SPECT in all 3 subgroups, meeting the study’s secondary efficacy endpoint. Using the majority rule analysis, sensitivity of flurpiridaz PET was significantly higher and its specificity was noninferior compared with SPECT in women. Using the majority rule analysis, a similar trend was observed for the 3 subgroups with significantly higher sensitivity of flurpiridaz PET achieved in women only and noninferior specificity for all subgroups compared with SPECT according to their respective reduced sample size. In all subgroups except the diabetic subgroup, the area under the ROC curve for flurpiridaz PET was significantly higher than SPECT.

Table 4 Comparative Sensitivity, Specificity, and Area Under the ROC Curve of Flurpiridaz PET MPI and SPECT MPI for CAD Assessment in Different Patient Subgroups

Sensitivity, %Specificity, %AUC
PETSPECTP ValuePETSPECTP ValueaPETSPECTP Value
Overall CAD (n = 578)80.368.70.000363.861.70.00040.800.68<0.0001
Women (n = 188)82.965.90.044872.866.00.00040.840.700.0091
BMI ≥30 kg/m2 (n = 298)76.969.20.064166.961.90.00100.790.670.0008
Diabetic patients (n = 194)75.871.40.216461.251.50.00060.760.690.0887

Sensitivity and specificity values are based on majority rule (results based on agreement of 2 of 3 readers). Please refer to the Methods section for detail of how receiver-operating characteristic curves were generated. For all categories, sensitivity values of flurpiridaz PET were significantly higher and specificities were noninferior compared with SPECT except for the diabetic subgroup, in which sensitivity differences were not statistically significant.

Abbreviations as in Tables 1 and 3.

a Specificity P values represent noninferiority analyses.

Central Illustration
Central Illustration

Overview of Results for Flurpiridaz Positron Emission Tomography vs Tc-99m–Labeled Single Photon Emission Computed Tomography Performance

For overall detection of coronary artery disease (CAD), sensitivity (200 of 249) and specificity (210 of 329) of flurpiridaz positron emission tomography (PET) were significantly higher than the prespecified threshold value. Furthermore, sensitivity of flurpiridaz PET was significantly higher and its specificity was noninferior than those of single photon emission computed tomography (SPECT) (top left). Area under the receiver-operating characteristic (ROC) curve analysis (top right) showed that flurpiridaz PET sensitivities were significantly higher and specificities were noninferior than those of SPECT in women and patients with a body mass index (BMI) of ≥30. Flurpiridaz PET was superior to SPECT (bottom) with respect to image quality, diagnostic certainty, and patient radiation.

In the 97 patients who underwent treadmill exercise PET and SPECT, the area under the ROC curve for detection of CAD was 0.7692 for PET and 0.7340 for SPECT, which were not statistically different from one another (P = 0.4714), most likely because of the relatively small number of patients.

Image quality

Perfusion image quality (% rated excellent or good) was higher for PET than SPECT for rest, pharmacological stress, and treadmill exercise stress (Supplemental Table 8, Central Illustration).

Diagnostic certainty

Diagnostic certainty (% studies rated as definitively normal or abnormal) was higher for PET than SPECT (Supplemental Table 9, Central Illustration).

Ischemic defect extent/severity

For all 3 readers, the summed difference score reflecting the extent and severity of ischemia was significantly higher in the flurpiridaz PET studies than the SPECT studies (Supplemental Table 10).

Radiation exposure

Radiation exposure, evaluated in 604 dosed patients, was less for PET (including a 0.64-mSv radiation dose from computed tomography-based attenuation correction) than same-day rest/stress SPECT using either tetrofosmin or sestamibi with a mean total decay-corrected effective dose (rest + stress) of 6.25 ± 0.74 mSv for flurpiridaz PET, 9.86 ± 2.74 mSv for 99mTc-tetrofosmin, and 12.41 ± 2.44 mSv for 99mTc-sestamibi (Central Illustration).

Case illustrations

Figure 4 illustrates a patient with significant RCA disease by ICA whose SPECT study was interpreted as definitely normal (false negative), but the flurpiridaz PET study was interpreted as definitely abnormal, showing reversible perfusion defects in the distribution of the diseased RCA. Figure 5 illustrates rest-regadenoson pharmacological stress Tc-99m SPECT and flurpiridaz PET images in a 64-year-old woman with a BMI of 52 kg/m2 who had normal coronary arteries by ICA. The SPECT was interpreted as probably abnormal (false positive) with reversible inferior, lateral, and apical defects. The flurpiridaz PET study was interpreted as definitely normal (true negative).

Figure 4
Figure 4

False Negative Tc-99m SPECT and True Positive Flurpiridaz PET Example

Rest-regadenoson pharmacological stress Tc-99m SPECT and flurpiridaz PET images in a 60-year-old woman with a body mass index of 46 kg/m2 who had 54% mid and 67% distal right coronary artery disease by invasive coronary angiography. The SPECT was interpreted as definitely normal (false negative). The flurpiridaz PET study was interpreted as definitely abnormal (true positive) showing reversible inferior wall defects. Abbreviations as in Figure 1.

Figure 5
Figure 5

False Positive Tc-99m SPECT and True Negative Flurpiridaz PET Example

Rest-regadenoson pharmacological stress Tc-99m SPECT and flurpiridaz PET images in a 64-year-old woman with a body mass index of 52 kg/m2 who had normal coronary arteries by invasive coronary angiography. The SPECT was interpreted as probably abnormal (false positive) with reversible inferior, lateral, and apical defects. The flurpiridaz PET study was interpreted as definitely normal (true negative). Abbreviations as in Figure 1.

Clinical safety

Treatment emergent adverse events (TEAEs) (defined as an adverse event [AE] with an onset date on or after the first injection of flurpiridaz up to the end of the last injection of flurpiridaz + 17 days [inclusive] or from first injection of flurpiridaz to the time of first injection of the SPECT MPI agent, whichever interval was shorter) were reported in 274 (45.4%) subjects, with clinically expected TEAEs recorded in 189 (31.3%) subjects. TEAEs related to stress agent/exercise were recorded for 188 (31.1%) subjects, TEAEs related to procedure were recorded for 111 (18.4%) subjects, and TEAEs related to underlying disease were recorded for 74 (12.3%) subjects. A total of 14 serious TEAEs were observed in 10 patients, but none related to flurpiridaz. In 19 patients, 25 TEAEs were judged to be possibly related to flurpiridaz, but none were serious. In 14 patients, 20 AEs were classified as serious, but none related to flurpiridaz. One AE led to death but was not related to flurpiridaz.

No significant laboratory changes from baseline were reported as AEs. No clinically relevant ECG changes were noted after flurpiridaz injection.

Discussion

Overall detection of CAD

In this phase 3 multicenter trial, flurpiridaz met the primary efficacy endpoint of the study by demonstrating significantly higher sensitivity and specificity for detection of CAD compared with prespecified threshold criteria.

PET vs SPECT in all patients and clinically important patient subsets

The observed noninferiority of flurpiridaz PET specificity vs SPECT may be related to readers’ bias toward higher SPECT specificity by assigning true defects as artifacts. This is supported by the observation that the area under the ROC curve was significantly higher for flurpiridaz PET vs SPECT in the overall population as well as the subgroup who underwent attenuation-corrected SPECT studies. Diagnostic performance of flurpiridaz was superior to that of SPECT in women and patients with BMI ≥30 kg/m2, with higher sensitivity, noninferior specificity, and greater area under the ROC curve. In the diabetic subgroup, sensitivity of PET was higher, and its specificity was noninferior compared with SPECT in 2 of 3 readers. PET vs SPECT differences, however, were not significantly different from one another by majority rule and area under the ROC curve analyses. The clinical importance of these findings is highlighted by the fact that the majority of patients undergoing stress MPI for evaluation of CAD fall in 1 or more of these clinical subsets that are not well assessed by SPECT MPI.15-19

Comparison with previous studies

As detailed earlier, the design of this second phase 3 multicenter trial of flurpiridaz differs from the first phase 3 multicenter trial. These study design differences are most likely responsible for flurpiridaz PET achieving specificity noninferiority vs SPECT in this study as opposed to the first phase 3 trial. The remaining results (flurpiridaz PET vs SPECT ROC comparisons in all patients, women, and patients with BMI ≥30 kg/m2; image quality; diagnostic certainty; and radiation exposure) were similar between this and the first phase 3 trials.

Meta-analysis of other PET MPI tracers compared with SPECT MPI20,21 has shown higher sensitivity and specificity values than those reported in our study. The following factors may have influenced sensitivity and specificity values that are observed in this study:

1.

The 50% criterion for stenosis by ICA as the reference standard, the criterion required for U.S. Food and Drug Administration approval, has been shown to have a poor relationship to hemodynamic significance of CAD as measured by fractional flow reserve and coronary flow reserve,22-26 with an underestimation of sensitivity and an overestimation of specificity.

2.

Patients with high-risk CAD and presumably greater abnormalities by PET and SPECT may not have been enrolled in this study because of clinical concerns related to exposing the patient to a second stress test and/or delaying ICA. This tends to lower test sensitivity.

3.

In this study, visual interpretation was performed by independent readers blinded to the ICA, patient history, and ECG findings. Image interpretation in many published retrospective studies may not have been blinded.

4.

In this study, specificity was measured in patients with <50% coronary stenosis by ICA. In some of the published literature, however, patients with a low pretest likelihood of CAD have been used that tends to raise the measured test specificity.

Assessment of the extent/severity of ischemia

A widely recognized and important limitation of SPECT MPI is the underestimation of the extent and severity of CAD. We observed that the size/severity of stress defects (SSS) was greater on flurpiridaz PET vs Tc-labeled SPECT images. This is most likely related to the substantially higher myocardial extraction fraction of flurpiridaz PET vs Tc-labeled SPECT,7,8 the better tracking of perfusion across a wide range of flow, and the high resolution afforded by the flurpiridaz PET.

Treadmill exercise PET MPI

An important attribute of flurpiridaz is that in can easily be used in conjunction with exercise treadmill testing, because of the longer (110-minute) half-life of F-18 compared with other PET tracers. Although treadmill exercise PET MPI is feasible using N-13 ammonia, it is not practical and not commonly used. Exercise Rb-82 studies are not performed because of the very short half-life of Rb-82 (75 seconds).

Radiation exposure

Current guidelines recommend dose reduction strategies whereby ≥50% of patients undergoing SPECT MPI would receive a total effective dose <9 mSv.27 In our study, all patients received the recommended radiation dose of <9 mSv by flurpiridaz PET MPI. This was significantly lower (by about 50%) than that of the SPECT MPI patients. Despite the lower dose, good to excellent image quality was observed in 89% of the studies.

Image quality and diagnostic certainty

The observed superior image quality and diagnostic certainty of flurpiridaz PET MPI vs SPECT is likely caused by higher flurpiridaz PET image resolution, the higher extraction fraction of flurpiridaz, and routine application of attenuation correction. Superior image quality and diagnostic certainty of flurpiridaz PET MPI will likely reduce additional diagnostic testing and cost.17 It is important to note that the dose range considered for that study was providing similar image quality for all patients regardless of their body habitus.

Study limitations

As part of the regulatory requirement, SPECT MPI and PET MPI images were visually interpreted by 3 blinded readers. As such, automated “relative” quantitation and absolute quantitation of MBF were beyond the scope of this research. A limitation of visual analysis is that reader bias cannot be entirely avoided. Furthermore, the blinded readers had a vast amount of experience and familiarity with interpretation of SPECT compared with the investigational flurpiridaz PET images. This unavoidable limitation may result in some underestimation of performance characteristics of the investigational flurpiridaz PET. Moreover, because of regulatory requirements, ≥50% stenosis by ICA was the “gold standard” comparator. Thus, other ICA findings such as fractional flow reserve, IFR, filling time, or myocardial blush were not accepted as part of a truth standard for detection of CAD. To represent the most common clinical practice, attenuation correction was not used routinely for SPECT MPI. However, in the subgroup of patients in whom attenuation-corrected SPECT was used, PET was superior to SPECT by ROC analysis.

Conclusions

In this report of the second phase 3 multicenter trial, flurpiridaz PET met the primary efficacy endpoint of the study by demonstrating sensitivity and specificity for detection of CAD, which significantly exceeded prespecified threshold criteria. By ROC analysis, the diagnostic performance of flurpiridaz PET MPI was shown to be superior to Tc-labeled SPECT MPI for detection of CAD in the overall population as well as in a subset of women and obese patients. Furthermore, flurpiridaz PET was superior to SPECT MPI with respect to image quality, confidence of interpretation, and radiation dose to patients. Flurpiridaz PET was found to be clinically safe. Higher image resolution and myocardial extraction fraction, potential for single-dose delivery, and use in conjunction with treadmill exercise distinguishes flurpiridaz from the currently available PET perfusion tracers, and this tracer may enable broader use of PET imaging.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: F-18–labeled flurpiridaz myocardial perfusion PET imaging used with treadmill or pharmacologic stress testing appears to be superior to SPECT imaging for detection of CAD, especially in women and obese patients, while reducing radiation exposure.

TRANSLATIONAL OUTLOOK: Further studies are needed to establish the added value of flow quantification by flurpiridaz PET compared with currently available PET tracers.

Funding Support and Author Disclosures

This study was funded by GE Healthcare Ltd and its Affiliates, Chalfont St Giles, United Kingdom. Drs Bax, Dorbala, Garcia, Heller, Tamaki, and Udelson have served as a consultant to GE Healthcare Ltd and its Affiliates. Drs Maddahi, Agostini, Bateman, Beanlands, Berman, and Knuuti have served as a consultant to and received a research grant from GE Healthcare Ltd and its Affiliates. Dr Beanlands has served as a consultant for and received research grants from Lantheus Medical Imaging and Jubilant DraxImage. Drs Feldman, Martinez-Clark, Pelletier-Galarneau, and Shepple have received a research grant from GE Healthcare Ltd and its Affiliates. Dr Tranquart is an employee and Global Head of Development of GE Healthcare Ltd and its Affiliates.

Abbreviations and Acronyms

18F

fluorine-18

CAD

coronary artery disease

ICA

invasive coronary angiography

MI

myocardial infarction

MPI

myocardial perfusion imaging

PET

positron emission tomography

ROC

receiver operating curve

SPECT

single photon emission computed tomography

References

  • 1. Yalamanchili P., Wexler E., Hayes M., et al. "Mechanism of uptake and retention of 18F BMS747158-02 in cardiomyocytes: A novel PET myocardial imaging agent". J Nucl Cardiol . 2007;14:6: 782-788.

    CrossrefMedlineGoogle Scholar
  • 2. Yu M., Guaraldi M.T., Mistry M., et al. "BMS-747 158-02: a novel PET myocardial perfusion imaging agent". J Nucl Cardiol . 2007;14:789-798.

    CrossrefMedlineGoogle Scholar
  • 3. Huisman M., Higuchi T., Reder S., et al. "Initial characterization of an 18F-labeled myocardial perfusion tracer". J Nucl Med . 2008;49:4: 630-636.

    CrossrefMedlineGoogle Scholar
  • 4. Nekolla S.G., Reder S., Higuchi T., et al. "Evaluation of the novel myocardial perfusion PET tracer 18F-BMS747158-02: comparison to 13N ammonia and validation with microspheres in a pig model". Circulation . 2009;119:17: 2333-2342.

    CrossrefMedlineGoogle Scholar
  • 5. Yu M., Guaraldi M., Kagan M., et al. "Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates". Eur J Nucl Med Mol Imaging . 2009;36:63-72.

    CrossrefMedlineGoogle Scholar
  • 6. Yu M., Bozek J., Guaraldi M., Kagan M., Azure M., Robinson S.P. "Cardiac imaging and safety evaluation of BMS747158, a novel PET myocardial perfusion imaging agent, in chronic myocardial compromised rabbits". J Nucl Cardiol . 2010;17:631-636.

    CrossrefMedlineGoogle Scholar
  • 7. Maddahi J. "Properties of an ideal PET perfusion tracer: new PET tracer cases and data". J Nucl Cardiol . 2012;19:Suppl 1: S30-S37.

    CrossrefMedlineGoogle Scholar
  • 8. Maddahi J., Packard R.R. "Cardiac PET perfusion tracers: current status and future directions". Semin Nucl Med . 2014;44:333-343.

    CrossrefMedlineGoogle Scholar
  • 9. Maddahi J., Czernin J., Lazewatsky J., et al. "Phase I, first-in-human study of BMS747158, a novel F-18 labeled tracer for myocardial perfusion PET imaging: dosimetry, biodistribution, safety, and imaging characteristics after a single injection at rest". J Nucl Med . 2011;52:9: 1490-1498.

    CrossrefMedlineGoogle Scholar
  • 10. Maddahi J., Bengel F., Czernin J., et al. "Dosimetry, biodistribution, and safety of flurpiridaz F18 in healthy subjects undergoing rest and exercise or pharmacological stress PET myocardial perfusion imaging". J Nucl Cardiol . 2019;26:6: 2018-2030.

    MedlineGoogle Scholar
  • 11. Berman D.S., Maddahi J., Tamarappoo B.K., et al. "Phase II safety and clinical comparison with single-photon emission computed tomography myocardial perfusion imaging for detection of coronary artery disease: flurpiridaz F 18 positron emission tomography". J Am Coll Cardiol . 2013;61:469-477.

    View ArticleGoogle Scholar
  • 12. Maddahi J., Lazewatsky J., Udelson J.E., et al. "Phase-III clinical trial of fluorine-18 flurpiridaz positron emission tomography for evaluation of coronary artery disease". J Am Coll Cardiol . 2020;76:4: 391-401.

    View ArticleGoogle Scholar
  • 13. Bourque J.M., Hanson C.A., Agostini D., et al. "Assessing myocardial perfusion in suspected coronary artery disease: rationale and design of the second phase 3, open-label multi-center study of flurpiridaz (F-18) injection for positron emission tomography (PET) imaging". J Nucl Cardiol . 2021;28:3: 1105-1116.

    CrossrefMedlineGoogle Scholar
  • 14. Holly T.A., Abbott B.G., Al-Mallah M., et al. "ASNC imaging guidelines for nuclear cardiology procedures –single photon emission computed tomography". J Nucl Cardiol . 2010;17:941-973.

    CrossrefMedlineGoogle Scholar
  • 15. Iskandar A., Limone B., Parker M.W., et al. "Gender differences in the diagnostic accuracy of SPECT myocardial perfusion imaging: a bivariate meta-analysis". J Nucl Cardiol . 2013;20:53-63.

    CrossrefMedlineGoogle Scholar
  • 16. Bateman T.M., Heller G.V., McGhie A.I., et al. "Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT". J Nucl Cardiol . 2006;13:24-33.

    CrossrefMedlineGoogle Scholar
  • 17. Duvall W.L., Croft L.B., Corriel J.S., et al. "SPECT myocardial perfusion imaging in morbidly obese patients: image quality, hemodynamic response to pharmacologic stress, and diagnostic and prognostic value". J Nucl Cardiol . 2006;13:202-209.

    CrossrefMedlineGoogle Scholar
  • 18. Bateman T.M., Dilsizian V., Beanlands R.S., DePuey E.G., Heller G.V., Wolinsky D.A. "American Society of Nuclear Cardiology and Society of Nuclear Medicine and Molecular Imaging joint position statement on the clinical indications for myocardial perfusion PET". J Nucl Med . 2016;57:10: 1654-1656.19.

    CrossrefMedlineGoogle Scholar
  • 19. Packard R.R.S., Lazewatsky J.L., Orlandi C., Maddahi J. "Diagnostic performance of PET versus SPECT myocardial perfusion imaging in patients with smaller left ventricles: a substudy of the 18F-Flurpiridaz Phase III clinical trial". J Nucl Med . 2021;62:6: 849-854.

    CrossrefMedlineGoogle Scholar
  • 20. Mc Ardle B.A., Dowsley T.F., deKemp R.A., Wells G.A., Beanlands R.S. "Does rubidium-82 PET have superior accuracy to SPECT perfusion imaging for the diagnosis of obstructive coronary disease? A systematic review and meta-analysis". J Am Coll Cardiol . 2012;60:18: 1828-1837.

    View ArticleGoogle Scholar
  • 21. Parker M.W., Iskandar A., Limone B., et al. "Diagnostic accuracy of cardiac positron emission tomography versus single photon emission computed tomography for coronary artery disease: a bivariate meta-analysis". Circ Cardiovasc Imaging . 2012;5:6: 700-707.

    CrossrefMedlineGoogle Scholar
  • 22. Pijls N.H., van Schaardenburgh P., Manoharan G., et al. "Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study". J Am Coll Cardiol . 2007;49:2105-2111.

    View ArticleGoogle Scholar
  • 23. Tonino P.A., De Bruyne B., Pijls N.H., et al. "Fractional flow reserve versus angiography for guiding percutaneous coronary intervention". N Engl J Med . 2009;360:213-224.

    CrossrefMedlineGoogle Scholar
  • 24. Tonino P.A., Fearon W.F., De Bruyne B., et al. "Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation". J Am Coll Cardiol . 2010;55:25: 2816-2821.

    View ArticleGoogle Scholar
  • 25. Nappi A.G., Boden W.E. "Does physiology trump anatomy as the “best course” to guide PCI decision making and outcomes?"J Am Coll Cardiol . 2016;67:14: 1712-1714.

    View ArticleGoogle Scholar
  • 26. Gould K.L., Johnson N.P., Bateman T.M., et al. "Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making". J Am Coll Cardiol . 2013;62:18: 1639-1653.

    View ArticleGoogle Scholar
  • 27. Einstein A.J., Tilkemeier P., Fazel R., Rakotoarivelo H., Shaw L.J. "American Society of Nuclear Cardiology. Radiation safety in nuclear cardiology-current knowledge and practice: results from the 2011 American Society of Nuclear Cardiology member survey". JAMA Intern Med . 2013;173:1021-1023.

    CrossrefMedlineGoogle Scholar

Footnotes

Listen to this manuscript's audio summary by Editor-in-Chief Dr Valentin Fuster on www.jacc.org/journal/jacc.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.