Diagnostic Performance of the Simultaneous Acquisition Rest ^{99 m}Tc-Tetrofosmin/Stress ²⁰¹Tl Dual-Isotope Protocol With a Semiconductor Camera　― Comparison With the Rest-Stress ^{99 m}Tc-Tetrofosmin Protocol ―

Abstract

Background: This study compared the diagnostic value of myocardial perfusion imaging (MPI) between the rest-stress ^{99 m}Tc-tetrofosmin protocol (Tc/Tc protocol) and simultaneous acquisition rest ^{99 m}Tc-tetrofosmin/stress ²⁰¹Tl dual-isotope protocol (SDI protocol) with a semiconductor camera.

Methods and Results: We retrospectively studied 147 patients who underwent stress MPI using a cadmium-zinc-telluride camera and invasive coronary angiography within a 3-month interval. The Tc/Tc and SDI protocols were used in 59 and 88 patients, respectively. The sensitivity, specificity, and accuracy of the summed difference score in per-patient analysis were 56%, 85%, and 69%, respectively, for the Tc/Tc protocol and 89%, 82%, and 85%, respectively, for the SDI protocol. The area under the receiver operating characteristic curve was significantly better for the SDI than Tc/Tc protocol for the left anterior descending artery (0.836 vs. 0.674; P=0.0380), the left circumflex artery (0.754 vs. 0.599; P=0.0441), and in per-patient analysis (0.875 vs. 0.707; P=0.0135). There was no significant difference in the diagnostic accuracy of the summed stress score for any vessel or in per-patient analysis between the 2 protocols.

Conclusions: The SDI protocol had a higher diagnostic accuracy for the detection of coronary ischemia than the Tc/Tc protocol.

Stress myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is the standard modality for the diagnosis and risk stratification of patients with known or suspected coronary artery disease (CAD).^1–4

The D-SPECT system, which is a dedicated cardiac cadmium-zinc-telluride (CZT) gamma camera system, has recently been introduced to MPI.^5–7 In this system, both energy and spatial resolution have been improved, and reductions in acquisition time or radiotracer dose have been reported without loss of image quality.^8–11

Previous studies have demonstrated that ²⁰¹Tl visualizes myocardial perfusion under hyperemic conditions better than ^{99 m}Tc-labeled myocardial perfusion tracers, such as tetrofosmin and sestamibi, owing to the high extraction fraction.^12–14 However, stress MPI using ²⁰¹Tl is not recommended due to the higher radiation exposure. Moreover, the standard stress MPI protocol using ²⁰¹Tl requires a longer examination time because there is a 3- to 4-h waiting time between the first and second acquisitions. Makita et al. conducted simultaneous acquisition rest ^{99 m}Tc-tetrofosmin/stress ²⁰¹Tl MPI using the D-SPECT system in 2016, and found a high diagnostic accuracy for CAD with a short examination time.¹⁵ However, the superiority of the diagnostic value of the simultaneous acquisition rest ^{99 m}Tc-tetrofosmin/stress ²⁰¹Tl dual-isotope (SDI) protocol has not yet been compared with that of the rest-stress ^{99 m}Tc-tetrofosmin protocol (Tc/Tc protocol). Therefore, in the present study we retrospectively evaluated and compared the diagnostic values of these 2 protocols.

Methods

Patients

We retrospectively studied 147 consecutive patients who underwent both stress MPI using a CZT camera and invasive coronary angiography within a 3-month interval between July 2016 and December 2016. Patients were divided into 2 groups: (1) the first group included consecutive patients who underwent imaging between July and September 2016 (only the Tc/Tc protocol was used during this period) and (2) the second group included consecutive patients who underwent imaging between October and December 2016 (only the SDI protocol was used during this period).

The exclusion criteria were as follows: (1) exercise stress MPI; (2) a history of coronary artery bypass grafting; (3) a recent history of acute myocardial infarction or unstable angina within 1 month prior to the SPECT study; and (4) a recent history of percutaneous coronary intervention within 1 month before the SPECT study. This study was approved by the ethics committee of our institution.

Stress Protocol

Patients were instructed to abstain from any products containing caffeine for 12 h before the test. Beta-blockers, calcium channel antagonists, and nitrates were stopped for at least 12 h before the test. Stress testing was performed using adenosine (140 μg·kg⁻¹·min⁻¹) for 6 min; when possible, low-level adjunctive ergometer exercise was performed during adenosine infusion.¹⁶

Tc/Tc Protocol

For the Tc/Tc protocol,¹⁷ patients were injected with a mean (±SD) 182±22 MBq ^{99 m}Tc-tetrofosmin (Nihon Medi-Physics, Tokyo, Japan) at rest. The rest image was acquired for 8 min, on average, beginning at 15 min after injection. The patients then underwent the adenosine stress test with injection of 817±94 MBq ^{99 m}Tc-tetrofosmin 3 min after the start of adenosine infusion. The stress image was acquired for 2 min, on average, 30 min after the end of the adenosine stress test. Patients were asked to ingest some food during the interval (Figure 1).

Figure 1.

Stress protocols. Tc/Tc protocol, rest-stress ^{99 m}Tc-tetrofosmin protocol; SDI protocol, simultaneous acquisition rest ^{99 m}Tc-tetrofosmin/stress ²⁰¹Tl dual-isotope protocol; MPS, myocardial perfusion single-photon emission computed tomography.

SDI Protocol

For the SDI protocol,¹⁵ patients were first injected with a mean (±SD) 305±72 MBq ^{99 m}Tc-tetrofosmin. After injection of ^{99 m}Tc-tetrofosmin, the patients underwent an adenosine stress test with injection of 74 MBq ²⁰¹Tl (Nihon Medi-Physics) 3 min after the start of adenosine infusion. The first simultaneous acquisition was performed after the end of the adenosine stress test. The second simultaneous acquisition started 1 h after the first acquisition. Each acquisition time was 12 min, on average. Patients were asked to ingest some food during the first and second acquisitions (Figure 1). The first acquisition image was used primarily for interpretation. The second acquisition image was used to evaluate the transient ischemic dilation (TID) and redistribution of ²⁰¹Tl. When the first acquisition image of ^{99 m}Tc was not good due to extracardiac uptake, the second acquisition image of ^{99 m}Tc was helpful in interpreting the rest image.

Acquisition Protocol and Image Reconstruction

Data were acquired in the list mode using the CZT camera (D-SPECT; Spectrum Dynamics). As described previously, this camera operates with 9 mobile blocks of pixelated CZT detectors associated with a wide-angle square-hole tungsten collimator. Each block records a total of 120 projections via a region-centric acquisition that maximizes counts emanating from the heart area, previously defined on a short prescan acquisition.^18–20 The selected photopeak windows were 130–150 keV for ^{99 m}Tc, and 64–77 and 157.4–177.4 keV for ²⁰¹Tl.²¹ Scatter correction via the iterative deconvolution method was applied to the ²⁰¹Tl images. In the Tc/Tc protocol, the image was acquired by setting the left ventricular (LV) count to 1.2-M counts for the rest image and a 2.0-M counts for the stress image. In the SDI protocol, the image was acquired by setting the scan time to obtain at least 1-M LV counts of ²⁰¹Tl after scatter correction.

Image Interpretation

The SPECT images were semiquantitatively scored by 2 experienced physicians. The LV wall was divided into 17 segments according to the American Heart Association consensus, and a semiquantitative 5-point scoring system was used in each of the 17 segments as follows: 0, normal uptake; 1, mildly reduced uptake; 2, moderately reduced uptake; 3, severely reduced uptake; and 4, almost no uptake.^22,23 The total score of the 17 segments in the stress and rest images provided the summed stress score (SSS) and the summed rest score (SRS), respectively. The summed difference score (SDS) was defined as the difference between the SSS and SRS.²⁴ In this model, the left anterior descending artery (LAD) distribution territory consists of 7 segments (i.e., Segments 1, 2, 7, 8, 13, 14, and 17), the left circumflex artery (LCx) consists of 5 segments (i.e., Segments 5, 6, 11, 12, and 16), and the right coronary artery (RCA) consists of 5 segments (i.e., Segments 3, 4, 9, 10, and 15). The MPI findings were considered positive in the relevant coronary territory when the SSS, SDS, or SRS in each territory was ≥2.²⁵ The TID ratio was also calculated by dividing end-diastolic LV volume during stress by end-diastolic LV volume at rest.²⁶

Image Quality Analysis

Image quality was graded visually using a 3-point scale as excellent (no extracardiac uptake), good (small extracardiac uptake) or poor (perfusion defect in the inferior wall by the adjacent extracardiac uptake).¹⁵

Coronary Angiography

Multidirectional coronary angiography was performed in all patients. Significant stenosis was accepted as ≥70% using quantitative coronary angiography. Patients with left main coronary artery stenosis were considered to have stenosis in both the LAD and LCx.

Radiation Exposure

The precise value of radiation exposure for each patient was calculated individually using International Commission on Radiological Protection (ICRP) substances.^27,28

Statistical Analysis

Patient characteristics are summarized as the mean±SD for continuous variables and as frequencies and proportions for categorical variables. The significance of differences in the distribution of continuous and categorical variables between the 2 groups was determined using Student’s t-test test (or the Wilcoxon rank-sum test) and Chi-squared test, respectively. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy in detecting significant CAD on a per-patient or per-vessel basis were analyzed. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of the quantification to predict ≥70% stenoses in the coronary arteries. The area under the ROC curve (AUC) between the 2 groups was compared using DeLong’s test. Two-sided P<0.05 was considered significant. All analyses were performed using SPSS and R software.

Results

Patient Characteristics

Patient characteristics are summarized in Table 1. The Tc/Tc protocol was used in 59 patients, whereas the SDI protocol was used in 88 patients. No significant differences were observed the 2 groups in terms of age, sex, classical coronary risk factors, prior coronary events, and medications.

Table 1. Patient Characteristics

	Tc/Tc (n=59)	SDI (n=88)	P value
Age (years)	69.3±10.0	71.6±10.2	0.18
Male sex	49 (83)	66 (75)	0.59
Body weight (kg)	62.1±10.8	62.1±10.7	0.98
BMI (kg/m2)	23.6±3.2	23.9±3.2	0.48
Hypertension	39 (66)	60 (68)	0.86
Dyslipidemia	41 (69)	60 (68)	1.00
Diabetes	20 (34)	29 (33)	1.00
Current smoker	13 (22)	16 (18)	0.67
CKD	14 (24)	16 (18)	0.41
Prior AMI	14 (24)	15 (17)	0.4
Prior PCI	27 (46)	28 (32)	0.12
Atrial fibrillation	3 (5)	4 (5)	1.00
CLBBB	1 (2)	2 (2)	1.00
β-blockers	9 (15)	21 (24)	0.22
Nitrates	9 (15)	19 (22)	0.4
CCB	23 (39)	33 (38)	0.86
ACEI/ARB	23 (39)	33 (38)	0.86
Statin	30 (51)	44 (50)	0.12
Aspirin	33 (56)	46 (52)	0.74

Data are given as the mean±SD or as n (%). ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin II receptor blocker; BMI, body mass index; CCB, calcium channel blocker; CKD, chronic kidney disease; CLBBB, complete left bundle branch block; PCI, percutaneous coronary intervention; SDI, simultaneous acquisition rest ^{99 m}Tc-tetrofosmin/stress ²⁰¹Tl dual-isotope protocol; Tc/Tc, rest-stress ^{99 m}Tc-tetrofosmin protocol.

Myocardial Perfusion and Electrocardiogram-Gated Parameters

SSS and SRS did not differ significantly between the 2 groups, with median (minimum-maximum) values of 2.0 (0.0–30.0) and 0.0 (0.0–29.0), respectively, for the Tc/Tc protocol and 3.0 (0.0–44.0) and 0.0 (0.0–43.0), respectively, in the SDI protocol. Although the SDS tended to be higher for the SDI than Tc/Tc protocol, the difference was not statistically significant (0.0 [0.0–11.0] vs. 1.0 [0.0–17.0], respectively; P=0.056; Table 2).

Table 2. Myocardial Perfusion and Electrocardiogram-Gated Parameters

	Tc/Tc	SDI	P value
SSS			0.898
Median (range)	2.0 (0.0–30.0)	3.0 (0.0–44.0)
Mean±SD	5.7±8.2	5.0±7.3
SRS			0.083
Median (range)	0.0 (0.0–29.0)	0.0 (0.0–43.0)
Mean±SD	4.1±6.8	2.3±6.0
SDS			0.056
Median (range)	0.0 (0.0–11.0)	1.0 (0.0–17.0)
Mean±SD	1.4±2.6	2.5±3.5
EF at stress	64.0 (25.0–87.0)	62.5 (11.0–88.0)	0.811
EF at rest	60.0 (22.0–84.0)	64.5 (16.0–90.0)	0.028
EDV at stress	86.0 (31.0–245.0)	74.5 (30.0–279.0)	0.268
EDV at rest	78.0 (24.0–221.0)	78.0 (26.0–256.0)	0.975
TID ratio	1.0 (0.8–1.5)	1.1 (0.8–1.8)	0.319

Unless indicated otherwise, data are given as median values with the range (minimum−maximum) in parentheses. EDV, end-diastolic volume; EF, ejection fraction; SDS, summed difference score; SRS, summed rest score; SSS, summed stress score; TID, transient ischemic dilation. Other abbreviations as in Table 1.

Image Quality Analysis

The quality of all images in both groups was excellent or good (83% and 10%, respectively, for the Tc/Tc protocol; 91% and 9%, respectively, for the SDI protocol). There were no poor-quality images in either group (Table 3).

Table 3. Image Quality Analysis

	Tc/Tc	SDI
Excellent	49 (83)	80 (91)
Good	10 (17)	8 (9)
Poor	0 (0)	0 (0)

P=0.200. Data are given as n (%). Abbreviations as in Table 1.

Coronary Angiography

Twenty-nine percent of patients in the Tc/Tc group and 31% of patients in the SDI group had single-vessel disease; 20% and 15% of patients in the Tc/Tc and SDI groups, respectively, had 2-vessel disease and 5% and 7% of patients in the Tc/Tc and SDI groups, respectively, had 3-vessel disease (Table 4).

Table 4. Angiographic Findings

	Tc/Tc	SDI
No. vessels with disease (P=0.854)
0	27 (46)	42 (47)
1	17 (29)	27 (31)
2	12 (20)	13 (15)
3	3 (5)	6 (7)
No. vessels with stenosis (P=0.551)
LMT	0 (0)	2 (2)
LAD	20 (34)	26 (30)
LCx	18 (31)	22 (25)
RCA	12 (20)	24 (27)

Data are given as n (%). LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; LMT, left main trunk; RCA, right coronary artery. Other abbreviations as in Table 1.

Thirty-four percent of patients in the Tc/Tc group and 30% of those in the SDI group had an LAD stenosis; 31% and 25% of patients in the Tc/Tc and SDI groups, respectively, had an LCx stenosis; and 20% and 27% of patients in the Tc/Tc and SDI groups, respectively, had an RCA stenosis. Two cases of left main trunk stenosis (2%) were observed only in the SDI group (Table 4).

Detection of Coronary Artery Stenosis

Per-patient analysis of SDS revealed sensitivity, specificity, PPV, NPV, and accuracy of 56%, 85%, 82%, 62%, and 69%, respectively, for the Tc/Tc protocol and 89%, 82%, 83%, 88%, and 85%, respectively, for the SDI protocol. Per-vessel analysis for the LAD revealed sensitivity, specificity, PPV, NPV, and accuracy of 45%, 90%, 69%, 76%, and 75%, respectively, for the Tc/Tc protocol and 82%, 95%, 88%, 92%, and 91%, respectively, for the SDI protocol. In the LCx, per-vessel analysis revealed sensitivity, specificity, PPV, NPV, and accuracy of 22%, 98%, 80%, 74%, and 75%, respectively, for the Tc/Tc protocol and 52%, 99%, 92%, 87%, and 88%, respectively, for the SDI protocol. For the RCA, per-vessel analysis revealed sensitivity, specificity, PPV, NPV, and accuracy of 42%, 96%, 71%, 87%, and 85%, respectively, for the Tc/Tc protocol and 67%, 100%, 100%, 89%, and 91%, respectively for the SDI protocol (Figure 2A). On a per-patient basis, the AUC was 0.707 and 0.875 for the Tc/Tc and SDI protocols, respectively. For each of the coronary vessels, the AUC for the Tc/Tc and SDI protocols was 0.674 and 0.836, respectively, for the LAD, 0.599 and 0.754, respectively for the LCX, and 0.687 and 0.813, respectively, for the RCA (Figure 3A).

Figure 2.

Sensitivity (Sens.), Specificity (Spec.), positive predictive value (PPV), negative predictive value (NPV), and accuracy of the diagnostic performance of (A) the summed difference score (SDS) and (B) the summed stress score (SSS) for coronary stenosis. Tc/Tc, rest-stress ^{99 m}Tc-tetrofosmin protocol; SDI, simultaneous acquisition rest ^{99 m}Tc-tetrofosmin/stress ²⁰¹Tl dual-isotope protocol; LAD, left anterior descending coronary artery; LCx, left circumflex coronary artery; RCA, right coronary artery.

Figure 3.

Receiver operating characteristic curve of (A) the SDS and (B) the SSS for the detection of coronary artery stenosis. AUC, area under the curve. Other abbreviations as in Figure 2.

The AUC revealed significantly better results on a per-patient basis (P=0.0135), as well as for the LAD (P=0.0380) and LCx (P=0.0441), with the SDI than Tc/Tc protocol.

With regard to SSS analysis, the sensitivity, specificity, PPV, NPV, and accuracy in the per-patient analysis were 81%, 78%, 81%, 78%, and 80%, respectively, for the Tc/Tc protocol and 89%, 79%, 82%, 87%, and 84%, respectively, for the SDI protocol (Figure 2B). The AUC for the Tc/Tc and SDI protocols was 0.755 and 0.814, respectively, on a per-patient basis. In terms of individual coronary vessels, the AUC for the Tc/Tc and SDI protocols was 0.798 and 0.796, respectively, for the LAD, 0.642 and 0.750, respectively, for the LCX, and 0.780 and 0.872, respectively, for the RCA (Figure 3B). The AUC did not differ significantly between the groups, although the AUC for the LCx, RCA, and per-patient analysis tended to be better for the SDI than Tc/Tc protocol.

Radiation Exposure

The Tc/Tc protocol using 182±22 MBq and 817±94 MBq ^{99 m}Tc-tetrofosmin delivered an effective dose of 7.11±0.77 mSv, whereas the SDI protocol using 74 MBq ²⁰¹Tl and 305 MBq ^{99 m}Tc-tetrofosmin delivered, on average, an effective dose of 12.77±0.91 mSv. The radiation dose was significantly higher for the SDI than Tc/Tc protocol (P<0.001).

Discussion

Comparison of Diagnostic Performance and Examination Time

The present study is the first to show that the SDI protocol has a higher diagnostic accuracy for the detection of coronary ischemia than the Tc/Tc protocol. This study has shown that the SDI protocol using the D-SPECT has good diagnostic value in detecting individual coronary artery stenoses and patients with coronary stenosis, as reported previously.¹⁵ The sensitivity, specificity, and accuracy of the Tc/Tc protocol were similar with values reported previously,²⁹ and the SDI protocol revealed better results regarding SDS with a shorter examination time than the Tc/Tc protocol. We infer that these results were observed because of the higher extraction fraction of ²⁰¹Tl than ^{99 m}Tc-tetrofosmin.³⁰ However, SSS in the SDI protocol did not exhibit better diagnostic accuracy than in the Tc/Tc protocol. Especially for LAD, the PPV tended to lower for the SDI than Tc/Tc protocol. These results depended on the presence of patients with prior myocardial infarction without residual stenosis. In these cases, SDS analysis identified the patients as true RI negative, whereas they were identified as false RI positive in the SSS analysis. For the LAD in this study, there were only 3 such cases in the Tc/Tc group, compared with 7 cases in the SDI group.

SPECT is known to underestimate multivessel disease (balanced ischemia). Many studies have reported useful markers, such as washout in the case of ²⁰¹Tl MPI and TID in the case of ^{99 m}Tc MPI, to overcome this problem. In the SDI protocol used in this study, both the washout and TID may not be exact because of the protocol: a relatively short time between the first and second acquisitions, and only 1 ^{99 m}Tc-tetrofosmin injection for the rest image. In this study, 3 patients in the Tc/Tc group and 6 patients in the SDI group had triple-vessel disease. All patients in the Tc/Tc group and 5 patients in the SDI group revealed ischemic SPECT findings at least for 1 vessel territory.

If physicians do not need the TID ratio or a delayed image of ²⁰¹Tl, the second acquisition may not be necessary. A protocol with a single simultaneous acquisition only may reduce the total examination time to less than 30 min.

Radiation Exposure

Stress MPI using ²⁰¹Tl is not recommended due to the higher radiation exposure. Stress MPI using 111 MBq ²⁰¹Tl resulted in an effective dose of almost 16 mSv; moreover, the conventional dual-isotope MPI using 111 MBq ²⁰¹Tl and 740 MBq ^{99 m}Tc resulted in an effective dose of almost 30 mSv.^28,31 Radiation exposure with the SDI protocol used in the present study was lower than that for these protocols, but higher than with the Tc/Tc protocol or any protocol recommended by the American Society of Nuclear Committee (ACNC).³² It may be possible to perform examination using lower doses of both ^{99 m}Tc and ²⁰¹Tl without losing image quality, as recommended by the ACNC.

Image Quality

The image quality score was sufficient for both protocols due to the high spatial resolution and acquisition in the sitting position. There were more excellent images obtained using the SDI than Tc/Tc protocol, although the difference between the groups was not significant. Concentration of ^{99 m}Tc-tetrofosmin below the diaphragm usually leads to low image quality. In the SDI protocol, the second acquisition of the ^{99 m}Tc-tetrofosmin image was sometimes helpful because the extracardiac concentration of ^{99 m}Tc-tetrofosmin was eliminated in many cases because of the ingestion of a light meal before the second acquisition.

Cost Performance

The cost of the drugs was ¥56,684 for the SDI protocol and ¥48,247 for the Tc/Tc protocol (US$1≈¥110). The difference in the medical fee for the 2 protocols was not remarkable in the Japanese medical insurance systems.

Study Limitations

The present study has some limitations. This study was conducted retrospectively in a single institution and included a small number of patients. Therefore, a multicenter prospective approach including a large number of patients is required.

Although fractional flow reserve is the current gold standard for evaluating the physiological significance of coronary stenosis, only anatomical stenosis was assessed in the present study.

Conclusions

Compared with the Tc/Tc protocol, the SDI protocol using the D-SPECT exhibited better diagnostic ability for the detection of coronary ischemia.

Sources of Funding / Conflicts of Interest

None.

Acknowledgment

The authors thank Editage (www.editage.jp) for English language editing of the manuscript.

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