Abstract

Aims

Hybrid myocardial perfusion imaging with single photon emission computed tomography (SPECT) and CT coronary angiography (CCTA) has the potential to play a major role in patients with non-conclusive SPECT or CCTA results. We evaluated the performance of hybrid SPECT/CCTA vs. standalone SPECT and CCTA for the diagnosis of significant coronary artery disease (CAD) in patients with an intermediate to high pre-test likelihood of CAD.

Methods and results

In total, 98 patients (mean age 62.5 ± 10.1 years, 68.4% male) with stable anginal complaints and a median pre-test likelihood of 87% (range 22–95%) were prospectively included in this study. Hybrid SPECT/CCTA was performed prior to conventional coronary angiography (CA) including fractional flow reserve (FFR) measurements. Hybrid analysis was performed by combined interpretation of SPECT and CCTA images. The sensitivity, specificity, positive (PPV), and negative (NPV) predictive values were calculated for standalone SPECT, CCTA, and hybrid SPECT/CCTA on per patient level, using an FFR <0.80 as a reference for significant CAD. Significant CAD was demonstrated in 56 patients (57.9%). Non-conclusive SPECT or CCTA results were found in 32 (32.7%) patients. SPECT had a sensitivity of 93%, specificity 79%, PPV 85%, and NPV 89%. CCTA had a sensitivity of 98%, specificity 62%, PPV 77%, and NPV 96%. Hybrid analysis of SPECT and CCTA improved the overall performance: sensitivity, specificity, PPV, and NPV for the presence of significant CAD to 96, 95, 96, and 95%, respectively.

Conclusions

In > 40% of the patients with a high pre-test likelihood no significant CAD was demonstrated, emphasizing the value of accurate pre-treatment cardiovascular imaging. Hybrid SPECT/CCTA was able to accurately diagnose and exclude significant CAD surpassing standalone myocardial SPECT and CCTA, vs. a reference standard of FFR measurements.

Introduction

Cardiac hybrid myocardial perfusion imaging with single photon emission computed tomography (SPECT) and CT coronary angiography (CCTA) has been proposed in patients with an intermediate risk of coronary artery disease (CAD).1,2 Hybrid cardiac imaging seems particularly useful in patients with multi-vessel disease, perfusion defects in the lateral and inferior wall, and in patients with non-conclusive results of either technique.1–4

Diagnostic performance of standalone SPECT is limited in patients with an intermediate to high pre-test likelihood of CAD with a broad range of reported sensitivities between 56 and 94%,5–7 probably due to an important fraction of non-conclusive results.3 Small perfusion defects (one to two segments), inadequate heart rate response [e.g. failure to reach 85% of maximum predicted heart rate or five metabolic equivalents (MET) during exercise], and discrepant clinical data (e.g. typical angina per history or ≥2 mm ST-segment depression on ECG during exercise) could be reasons to regard SPECT non-conclusive.8,9

In patients with an intermediate to high pre-test likelihood also CCTA is prone to non-conclusive results. This is mainly due to non-evaluable coronary segments as a result of coronary calcifications and artefacts that decrease diagnostic performance.10–15 As such, even with the latest scanner generations, CCTA still has moderate specificity.10–12,16,17

Evidence is emerging that the diagnostic performance of hybrid SPECT/CCTA is superior to standalone SPECT and CCTA.15,18 In selected populations, sensitivity and specificity values of 94–96 and 92–95% have been reported.15,18

In our study, we focus on patients with an intermediate to high pre-test likelihood of CAD and subsequently high rates of equivocal and non-diagnostic imaging results. We hypothesized that hybrid SPECT/ CCTA has an incremental diagnostic accuracy over standalone SPECT or CCTA.

Methods

Patient population and imaging schedule

We prospectively conducted a single-centre cross-sectional cohort study.19 Patients with an intermediate to high pre-test likelihood of CAD were consecutively recruited for this study from September 2010 until December 2011. Boundaries for low, intermediate, and high pre-test likelihood were set at <20, 20–80, and >80%, respectively, and calculated according to Diamond and Forrester criteria.20,21 Excluded were patients with a history of surgical revascularization, stent implantation, patients with an unstable cardiac condition or a cardiac rhythm other than sinus rhythm. The study conformed to the principles outlined in the declaration of Helsinki and was approved by the local Ethics Committee. Written informed consent was obtained from all patients.

Of the 143 patients that underwent hybrid SPECT and prospectively triggered CCTA, 98 patients (69%) received invasive coronary angiography (CA) and fractional flow reserve (FFR) measurements (Figure 1). Gated SPECT and CCTA data were acquired on a hybrid SPECT-CT system, CardioMD gamma camera, and Brilliance 64-slice CT scanner (Philips Medical Systems, Best, The Netherlands). The components share a common table that is aligned to allow sequential image acquisition. On the first imaging day, stress SPECT and CCTA data were acquired. Patients started with bicycle or pharmacological stress after which stress SPECT was acquired directly followed by CCTA. In patients with a normal stress SPECT (normal perfusion and gated data), no rest SPECT was acquired. CA and FFR measurements were performed in all patients, including those with normal non-invasive test results, within 14 days from the first image acquisition. If indicated, CA was preceded by rest SPECT image acquisition.

Figure 1

Flowchart for patients included in this analysis. Hybrid SPECT/CCTA, Hybrid myocardial perfusion single photon emission computed tomography and CT coronary angiography. CA, invasive coronary angiography; FFR measurement, fractional flow reserve measurement.

Figure 1

Flowchart for patients included in this analysis. Hybrid SPECT/CCTA, Hybrid myocardial perfusion single photon emission computed tomography and CT coronary angiography. CA, invasive coronary angiography; FFR measurement, fractional flow reserve measurement.

Myocardial perfusion SPECT

SPECT images were acquired with a 2-day stress/rest MPI protocol. Of 98 patients included in the analysis, 82 patients (83.7%) underwent bicycle stress according to a stepwise protocol for stress image acquisition. Sixteen (16.3%) patients underwent pharmacological stress (adenosine at a standard rate of 0.14 mg/kg/min over 6 min). For stress and rest SPECT, a weight-adjusted dose of 400–600 MBq of 99mTc-sestamibi was used. SPECT imaging was performed using a dual headed gamma camera, equipped with low-energy, high-resolution collimators. Sixty-four projections were acquired with 40 s per projection and stored on a 64 × 64 matrix. Energy window was set at 20% around the 140-keV photon peak. Reconstruction was performed by means of filtered back projection using a Butterworth filter, to produce transverse tomograms. Short-axis, vertical, and horizontal long-axis tomograms were produced from transverse tomograms by performing co-ordinate transformation. Attenuation correction was performed for all images using a non-enhanced CT scan. Semi-quantitative visual analysis was performed in consensus by two experienced nuclear medicine physicians. Attenuation corrected and non-attenuation corrected images and auxiliary findings (results of stress testing, gated data, and semi-quantitative perfusion data) were included in the analysis. Stress and rest SPECT images were interpreted as previously described according to a 17-segment model and scored for perfusion defects using a five-point scoring system (0 = normal to 4 = absence of tracer uptake).8,22,23 Gated data and semi-quantitative perfusion data were assessed using the QGS/QPS software package (Cedars-Sinai Medical Center, Los Angeles, CA, USA). The analysing physicians were blinded for other imaging data. For the definition of normal, equivocal, and abnormal myocardial perfusion on SPECT according to segmental scores, we used the definition provided by Abidov et al.8 SPECT with an equivocal perfusion score was regarded non-conclusive, a (probably) normal perfusion score was regarded normal and a (probably) abnormal perfusion score was regarded abnormal.

Coronary computed tomography angiography

All patients underwent prospectively ECG-triggered axial CCTA according to the guidelines provided by the society of cardiovascular computed angiography.24 All participants received oral metoprolol tartrate at the start of the stress test preceding SPECT imaging. Preceding CCTA additional i.v. metoprolol was administered to achieve a heart rate <62 bpm. Prior to CCTA, a non-enhanced scan to calculate the coronary calcium score (CCS) was performed. CCTA data were acquired with a collimation of 64 × 0.625 mm. A bolus-tracking protocol was used to determine the time of optimal contrast. During CCTA 90–110 mL iodinated contrast medium (lobitridol, Xenetix 350, Guerbet) was administered, followed by a saline flush. Tube current was 500 mA at 80–120 kV for patients according to their body weight. CCTAs were read by two cardiologists for obstructive severity according to a 16-segment model and five categories of luminal loss: no CAD (0% area stenosis), mild lesion severity (0–50% area stenosis), intermediate lesion severity (50–70% area stenosis), severe lesions (70–99% area stenosis), and total occlusion. If the category of luminal loss could not be determined (e.g. due to motion artefact or severe calcifications), a segment was categorized as un-evaluable. Subsequently, a vessel-based analysis was performed from which diagnostic accuracy on a per-patient level was determined. Vessels were categorized as normal if all segments were evaluable and none had lesions >50% area stenosis. Abnormal vessels (significant CAD) were defined as vessels with at least one segment with a lesion of >50% area stenosis. Vessels with at least one severe lesion were regarded completely evaluable despite any un-evaluable segments. Non-conclusive vessels were defined as vessels with at least one un-evaluable segment, without any segments with lesions >50% area stenosis. A CCTA was defined non-conclusive if one or more vessels were un-evaluable and no vessel was abnormal.

Invasive CA

As part of the prospective study, CA and FFR measurements were performed in all patients, including those with normal non-invasive test results. CA was acquired on Allura (Philips Medical Systems, Best, The Netherlands) catheterization equipment. FFR measurements were obtained from all patients with angiographically estimated 50–95% obstructive disease. Lesions with <50% obstructive disease (according to the interpretation on a consensus basis by two experienced cardiologists) were considered normal; no significant CAD.25 Occluded vessels were considered abnormal. Vessels with angiographically >95% obstructive disease were considered severely stenotic with an FFR <0.80. During FFR measurement, distal coronary pressure was measured with a pressure guidewire (Certus Wire, Radi Medical Systems, Uppsala, Sweden) during maximal hyperaemia induced by adenosine i.v. as previously described.26 An FFR measurement <0.80 was defined abnormal and classified as significant CAD. An FFR measurement >0.80 was defined normal.27,28 Vessel-based analysis was performed from which diagnostic accuracy on a per-patient level was determined.

Hybrid SPECT/CCTA imaging analysis

According to our pre-defined protocol, all patients were included in hybrid image evaluation. Interpretation was performed by two experienced, independent physicians blinded for CA and FFR measurements. The integrated interpretation of all imaging data led to the categorization of all vessels and patients as normal or abnormal. Concordant normal or abnormal SPECT and CCTA findings led to a similar interpretation of the hybrid imaging result. Discordant SPECT and CCTA findings were interpreted as follows. In patients with normal CCTA and abnormal or non-conclusive SPECT, the hybrid imaging result was defined normal. In patients with non-conclusive CCTA and normal SPECT, the hybrid imaging result was defined normal. In patients with non-conclusive CCTA and abnormal SPECT, the hybrid imaging result was defined abnormal. In patients with abnormal CCTA and normal SPECT, CCTA prevailed only in those patients with a definitely abnormal CCTA (Figure 5). In patients with abnormal CCTA and non-conclusive SPECT, the hybrid imaging result was defined abnormal.4

Statistical analysis

Statistical analyses were performed with the SPSS software (V. 18.0, IBM Corporation, Somers, New York, USA). Variables were expressed as mean ± standard deviation (SD) or median and range, and categorical variables as frequencies and percentages. Continuous variables were compared by means of Student's t-test or Mann–Whitney U-test where appropriate. Categorical variables were compared by means of the χ2 test. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) with their 95% confidence intervals (CIs) were calculated. A P-value of <0.05 was considered statistically significant.

Results

Study population

Of a total of 143 patients that underwent hybrid imaging, 98 patients with an FFR-measurement were included in this study. During the first months of this study, FFR measurement was performed at the discretion of the performing operator. Afterwards, the protocol was changed and FFR measurement was performed in all patients. Baseline characteristics from patients excluded from this analysis [mean age 61.8 ± 10.2 years, 73% male and median pre-test likelihood 87% (range 22–95)] did not differ significantly from patients included in the analysis. Complete characteristics of the study population are presented in Table 1. In total, 32 patients (32.7%) had either a non-conclusive SPECT or CCTA (Table 2).

Table 1

Characteristics of the patients included in the analysis (n = 98)

Age (years)a 62.5 ± 10.1 (%) 
Gender, men/women 67/31 68.4/31.6 
Risk factors 
 Smoking 
  Current 26 26.5 
  Past 13 13.3 
 Hypertension 62 63.3 
 Diabetes mellitus 12 12.2 
 Dyslipidaemia 59 60.2 
 Family history of pre-mature atherosclerosis 60 61.2 
Risk factors ≥3 44 44.9 
Angina pectoris 
 Non-anginal 
 Atypical 31 31.6 
 Typical 67 68.4 
CCS angina class 
 Class I 7.1 
 Class II 80 81.6 
 Class III 11 11.2 
 Class IV 
Pre-test likelihoodb 0.87 (0.22–0.95)  
 Low 
 Intermediate 40 40.8 
 High 53 54.1 
 Unknownc 5.1 
Age (years)a 62.5 ± 10.1 (%) 
Gender, men/women 67/31 68.4/31.6 
Risk factors 
 Smoking 
  Current 26 26.5 
  Past 13 13.3 
 Hypertension 62 63.3 
 Diabetes mellitus 12 12.2 
 Dyslipidaemia 59 60.2 
 Family history of pre-mature atherosclerosis 60 61.2 
Risk factors ≥3 44 44.9 
Angina pectoris 
 Non-anginal 
 Atypical 31 31.6 
 Typical 67 68.4 
CCS angina class 
 Class I 7.1 
 Class II 80 81.6 
 Class III 11 11.2 
 Class IV 
Pre-test likelihoodb 0.87 (0.22–0.95)  
 Low 
 Intermediate 40 40.8 
 High 53 54.1 
 Unknownc 5.1 

Values are shown as number and percentage unless otherwise noted.

aValues expressed as mean ± standard deviation.

bValues expressed as median (range).

cPatients with atypical angina pectoris and >70 years old.

CCS, Canadian Cardiovascular Society.

Table 2

Characteristics of the imaging results of all patients (n = 98)

CT coronary angiogram (%) 
Coronary calcium scoring  
 0 26 26.5 
 1–400 24 34.7 
 >400 38 28.7 
CCS in patients with significant CADa 497.5 (0–3719)  
CCS in patients without significant CADa 1 (0–1966)  
CT coronary angiography 
 Intravenous metoprolol prior to CCTA, mgb 13.1 ± 6.1  
 Heart rate during CCTA, bpmb 59.9 ± 4.8  
Non-conclusive CCTA 23 23.5 
 Calcifications 18 18.4 
 Motion artefact 4.1 
 Poor contrast opacification 1.0 
Myocardial perfusion SPECT 
 Exercise stress 82 83.7 
 Adenosine stress 16 16.3 
Non-conclusive SPECT 11 11.2 
Non-conclusive SPECT or CCTA 32 32.7 
Conventional coronry angiogram with FFR—measurements 
 No significant CADc 42 42.9 
 One-vessel diseasec 15 15.3 
 Two-vessel diseasec 21 21.4 
 Three-vessel disease or left main stenosisc 20 20.4 
CT coronary angiogram (%) 
Coronary calcium scoring  
 0 26 26.5 
 1–400 24 34.7 
 >400 38 28.7 
CCS in patients with significant CADa 497.5 (0–3719)  
CCS in patients without significant CADa 1 (0–1966)  
CT coronary angiography 
 Intravenous metoprolol prior to CCTA, mgb 13.1 ± 6.1  
 Heart rate during CCTA, bpmb 59.9 ± 4.8  
Non-conclusive CCTA 23 23.5 
 Calcifications 18 18.4 
 Motion artefact 4.1 
 Poor contrast opacification 1.0 
Myocardial perfusion SPECT 
 Exercise stress 82 83.7 
 Adenosine stress 16 16.3 
Non-conclusive SPECT 11 11.2 
Non-conclusive SPECT or CCTA 32 32.7 
Conventional coronry angiogram with FFR—measurements 
 No significant CADc 42 42.9 
 One-vessel diseasec 15 15.3 
 Two-vessel diseasec 21 21.4 
 Three-vessel disease or left main stenosisc 20 20.4 

Values are shown as number and percentage unless otherwise noted.

aValues expressed as median (range), significant CAD according to a reference standard of fractional flow reserve (FFR) measurements.

bValues expressed as mean ± standard deviation.

cFFR <0.80 was defined haemodynamically significant.

CA, coronary angiography; CAD, coronary artery disease; CCS, Coronary Calcium Score; CCTA, CT coronary angiogram; ECG, electrocardiogram; SPECT, single photon emission computed tomography.

Invasive CA including FFR measurements

The CA showed significant CAD in 56 patients (57.1%). FFR measurements were available from all patients with angiographically estimated 50–95% obstructive disease and performed in 225 vessels (57.4%) (Table 2). FFR measurements were positive in 80 vessels (35.6%).

Myocardial perfusion SPECT

The diagnostic accuracy of SPECT in all patients is presented in Figure 2. For this analysis, non-conclusive scans (n = 11) were regarded abnormal. Five of these patients (45%) suffered from significant CAD. None of the patients that underwent X-ECG prior to stress SPECT (n = 82) had an inadequate heart rate response, we either administered atropine in these patients (n = 28, 29%) or switched to adenosine stress (n = 16, 16%). No patients with normal perfusion and anginal complaints during stress suffered from significant CAD. Out of the four patients with positive stress ECG findings (≥2 mm ST-segment depression) and normal perfusion, two patients suffered from significant CAD.

Figure 2

The diagnostic performance of myocardial perfusion SPECT, CT coronary angiography (CCTA), and hybrid SPECT/CCTA in all patients (n = 98), using a fractional flow reserve <0.80 as a reference standard. Patients with one or more non-conclusive vessels and no definitely abnormal vessels were considered abnormal. Patients with non-conclusive SPECT results were considered normal. PPV, positive predictive value; NPV, negative predictive value.

Figure 2

The diagnostic performance of myocardial perfusion SPECT, CT coronary angiography (CCTA), and hybrid SPECT/CCTA in all patients (n = 98), using a fractional flow reserve <0.80 as a reference standard. Patients with one or more non-conclusive vessels and no definitely abnormal vessels were considered abnormal. Patients with non-conclusive SPECT results were considered normal. PPV, positive predictive value; NPV, negative predictive value.

Eighty-seven (89%) patients had a conclusive SPECT, 51 (59%) of these patients suffered from significant CAD. The diagnostic performance of SPECT in patients with conclusive results is presented in Figure 3.

Figure 3

The diagnostic performance of standalone myocardial perfusion SPECT (SPECT) and hybrid SPECT/CCTA in patients with conclusive SPECT studies (n = 87). Using a fractional flow reserve <0.80 as a reference standard. PPV, positive predictive value; NPV, negative predictive value.

Figure 3

The diagnostic performance of standalone myocardial perfusion SPECT (SPECT) and hybrid SPECT/CCTA in patients with conclusive SPECT studies (n = 87). Using a fractional flow reserve <0.80 as a reference standard. PPV, positive predictive value; NPV, negative predictive value.

SPECT had a sensitivity of 62% (95% CI: 52–70), a specificity of 84% (95% CI: 77–88), a PPV of 70% (95% CI: 60–78), and a NPV of 78% (95% CI: 72–83) on a per-vessel basis in all patients.

Coronary computed tomography angiography

Characteristics of CCTA scans are presented in Table 2. The diagnostic accuracy of CCTA in all patients is presented in Figure 2. For this analysis, non-conclusive scans (n = 23) were regarded abnormal. The majority of these patients (n = 17, 74%) suffered from significant CAD.

Seventy-five patients (77%) had a conclusive CCTA, 40 (53%) of these patients suffered from significant CAD. The diagnostic performance of CCTA in patients with conclusive results is presented in Figure 4.

Figure 4

The diagnostic performance of standalone CT coronary angiography (CCTA) and hybrid SPECT/CCTA in patients with conclusive CCTA studies (n = 75). Using a fractional flow reserve <0.80 as a reference standard. PPV, positive predictive value; NPV, negative predictive value.

Figure 4

The diagnostic performance of standalone CT coronary angiography (CCTA) and hybrid SPECT/CCTA in patients with conclusive CCTA studies (n = 75). Using a fractional flow reserve <0.80 as a reference standard. PPV, positive predictive value; NPV, negative predictive value.

CCTA had a sensitivity of 86% (95% CI: 79–91), a specificity of 81% (95% CI: 76–81), a PPV of 67% (95% CI: 59–74), and a NPV of 93% (95% CI: 89–93) on a per vessel basis in all patients.

Hybrid SPECT/CCTA imaging

Hybrid SPECT/CCTA in all patients resulted in an improved diagnostic performance vs. SPECT and CCTA as standalone imaging procedures. PPV of both SPECT (85%) and CCTA (77%) significantly improved to 96% (95% CI: 88–99) for hybrid imaging analysis. NPV of SPECT (89%) improved to 95% (95% CI: 84–99) if hybrid SPECT/CCTA was applied (Figure 2). Hybrid imaging analysis of four patients still demonstrated false positive or false negative results. Both patients with false negative results had a largely un-evaluable CCTA as a result of high CCS (>1500), in combination with a normal (false negative) SPECT. Both patients with false positive results had an un-evaluable RCA with a small perfusion defect (SDS = 2) in the myocardial territory subtended by this vessel. An example of the added value of hybrid imaging analysis is given in Figure 5.

Figure 5

Example of a discordant hybrid finding with definitely abnormal CCTA and balanced ischaemia on SPECT. A 61-year-old male with dypnoea during exercise. Hybrid imaging with myocardial perfusion SPECT (SPECT) showing normal perfusion (A and B hybrid stress- and C and D hybrid rest imaging; orange and white colours resemble normal perfusion, purple and blue colours resemble abnormal perfusion) CT coronary angiography (CCTA) showed significant left main stenosis (LM). With mild stenoses in the RCA and RCx. An intermediate lesion was visible in the proximal LAD. The coronary calcium score was 245. Conventional coronary angiography confirmed the significant LM stenosis, FFR 0.73. And mild stenosis of RCA, LAD, and RCx (E and F).

Figure 5

Example of a discordant hybrid finding with definitely abnormal CCTA and balanced ischaemia on SPECT. A 61-year-old male with dypnoea during exercise. Hybrid imaging with myocardial perfusion SPECT (SPECT) showing normal perfusion (A and B hybrid stress- and C and D hybrid rest imaging; orange and white colours resemble normal perfusion, purple and blue colours resemble abnormal perfusion) CT coronary angiography (CCTA) showed significant left main stenosis (LM). With mild stenoses in the RCA and RCx. An intermediate lesion was visible in the proximal LAD. The coronary calcium score was 245. Conventional coronary angiography confirmed the significant LM stenosis, FFR 0.73. And mild stenosis of RCA, LAD, and RCx (E and F).

In patients with conclusive SPECT results hybrid imaging analysis mainly resulted in improved NPV (85%, 95% CI: 71–93 vs. 95%, 95% CI: 82–98) (Figure 3). A significant improvement of PPV (99%, 95% CI: 91–100) was shown when hybrid imaging analysis was compared with conclusive CCTA results (PPV 81%, 95% CI: 68–90) (Figure 4).

Hybrid SPECT/CCTA had reliable results in patients with non-conclusive SPECT or CCTA results; PPV 91% (95% CI: 72–98) and NPV 90% (95% CI: 60–98) (Figure 6).

Figure 6

The diagnostic performance of hybrid myocardial perfusion SPECT (SPECT) and CT coronary angiography (CCTA) in patients with non-conclusive SPECT or CCTA studies (n = 32). Using a fractional flow reserve <0.80 as a reference standard. PPV, positive predictive value; NPV, negative predictive value.

Figure 6

The diagnostic performance of hybrid myocardial perfusion SPECT (SPECT) and CT coronary angiography (CCTA) in patients with non-conclusive SPECT or CCTA studies (n = 32). Using a fractional flow reserve <0.80 as a reference standard. PPV, positive predictive value; NPV, negative predictive value.

Hybrid SPECT/CCTA had a sensitivity of 67% (95% CI: 58–75), a specificity of 95% (95% CI: 91–97), a PPV of 84% (95% CI: 76–90), and a NPV of 87% (95% CI: 82–90) on a per-vessel basis in all patients.

Radiation dose analysis

The effective dose of the CT studies was quantified with a dose–length product conversion factor of 0.014 mSv/(mGy × cm) as described.29 An average effective dose of the complete CT studies was 4.3 ± 1.1 mSv. For SPECT, the effective dose was calculated using a conversion factor of 7.9e-3 mSv/MBq for stress and 9.0e-3 mSv/MBq for rest acquisition.30 An average effective dose of SPECT per patient was 6.8 ± 2.4 mSv. The calculated average effective dose of CA was 10.8 ± 5.2 mSv, using a conversion factor of k = 0.22 for the registered dose area products. The mean total effective dose was 21.9 ± 6.6 mSv per patient.

Discussion

The main finding of our study is that hybrid SPECT/CCTA has an excellent diagnostic performance vs. a reference standard of FFR measurements. In a patient population with a high pre-test likelihood of CAD and high rates of non-conclusive results on either SPECT or CCTA, hybrid imaging analysis results in an improved PPV of 96% (vs. PPV of 85 and 77% of SPECT and CCTA, respectively) and a NPV of 95% (vs. NPV of 89 and 96% of SPECT and CCTA, respectively) on a patient level. Even in patients with either non-conclusive SPECT or non-conclusive CCTA hybrid imaging analysis results in a NPV and PPV of 91 and 90%, respectively.

Current guidelines on hybrid SPECT/CCTA describe its main role in patients with an intermediate to high risk of CAD and a non-conclusive result of either modality.2 Five studies described the increased diagnostic performance of hybrid SPECT/CCTA, with reported sensitivities and specificities ranging from 89–99% to 67–95%, respectively, for the hybrid technique.15,18,31–33 Besides the fact that the reference standard in all studies was CA as assessed by visual interpretation of the angiogram, these patient populations were limited in several other respects. Rispler et al.15 evaluated 44 patients suspected to have CAD and scheduled for CA. Patients with unevaluable segments on CCTA, however, were excluded. Gaemperli et al.32 evaluated 38 patients with at least one fixed or reversible perfusion defect by hybrid SPECT/CCTA. Their population resembled a high-risk population due to the presence of perfusion defects as a mandatory inclusion criterion. CA was not available from all patients in this study. Santana et al.31 performed hybrid SPECT/CCTA imaging in 50 patients evaluating its performance in a population with low to intermediate pre-test likelihood of CAD. Performance of standalone CCTA in this population was not reported. Slomka et al.33 retrospectively evaluated automated co-registration, visualization, and combined quantification of CCTA and SPECT from standalone scanners in 35 patients.

We evaluated the performance of hybrid SPECT/CCTA vs. a reference standard of FFR measurements in the largest available patient cohort so far. Pre-test likelihood and diagnostic performance of each non-invasive modality vs. the reference standard of FFR measurements were prospectively acquired and available from all patients. CCS was high in patients with CAD, median 497.5, resembling a true high-risk population. At least one unevaluable coronary segment on CCTA was present in 23.5% of the patients. Including non-conclusive SPECT results (11.2%), 33% of patients had either a non-conclusive SPECT or CCTA. Obviously, hybrid imaging was most complimentary in patients with a non-conclusive test, a false positive result of CCTA and a false negative result of SPECT imaging. As demonstrated in this manuscript, the strong features of each test as standalone procedure compensate for the weaknesses of the other in a hybrid imaging setting. This results in an almost perfect diagnosis of the presence or absence of significant CAD.

The current study is limited by the fact that FFR was not measured in vessels with <50 or >95% obstructive disease. The measurement of these vessels could have resulted in improved results. However, based on available literature, it is safe to assume that vessels with very mild (<50%) and very severe (>95%) obstructive disease, respectively, have normal and positive FFR measurements.25,28 The study population is relatively small. However, hybrid SPECT/CCTA also had a high diagnostic accuracy in the excluded patients with only CA as a reference standard (n = 45). Hybrid SPECT/CCTA had a PPV 94% (95% CI: 73–99) and NPV 93% (95% CI 77–98) vs. a reference standard of >50% stenosis on CA. The fact that more patients had a non-conclusive CCTA (23%) compared with the number of patients with a non-conclusive SPECT (11%) could be exemplary for the fact that CCTA is more prone to non-conclusive results due to higher CCS in patients with an intermediate to high pre-test likelihood of disease. Hybrid imaging analysis of SPECT and CCTA is performed in several directions; both SPECT and CCTA were used as an adjunct to the other modality in conclusive and non-conclusive studies. The patient presented in Figure 5 could serve as an example in which CCTA proved to be complementary to a conclusive SPECT study. An equally compelling example could be found for a conclusive CCTA study. This leaves neither anatomical nor functional imaging to trump the other modality and hybrid imaging without a categorical guideline for image interpretation. For each patient, we chose the optimal stress protocol, either adenosine or exercise. However, adenosine stress has a known limited diagnostic performance compared with exercise stress. Despite the fact that almost a quarter of the patients received adenosine stress, the diagnostic performance of SPECT alone in this population is reasonable, and comparable with what has been reported in the past.5–7 CCTA has a higher number of unevaluable segments and lower diagnostic performance compared with previous reports. This may be explained by the fact that patients were not excluded from further CT angiography based on the height of their CCS, which led to a high number of unevaluable segments (5.1%).17 Also, to limit the overall radiation dose an axial CT scan protocol without availability of multiple cardiac phases was employed, which may have contributed to the lower performance of CCTA.10–12,17

The advantage of hybrid imaging lies in the compensation for the weak properties of CCTA and SPECT, and the dissolution of non-conclusive results of both as standalone imaging procedures. This advantage is best reflected in a group of patients with intermediate to high risk of CAD, as is demonstrated in this study. In over 40% of this category of patients, CAD can be reliably excluded due to the complementary nature of hybrid SPECT/CCTA.

Conflict of interest: none declared.

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