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Coronary artery disease
Original research
Dobutamine stress echocardiography after positive CCTA: diagnostic performance using fractional flow reserve and instantaneous wave-free ratio as reference standards
  1. Anders Tjellaug Bråten1,
  2. Espen Holte1,2,
  3. Rune Wiseth1,2 and
  4. Svend Aakhus1,2
  1. 1Clinic of Cardiology, St Olavs University Hospital, Trondheim, Norway
  2. 2Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
  1. Correspondence to Dr Anders Tjellaug Bråten; anders.tjellaug.braten{at}stolav.no

Abstract

Aims To assess the diagnostic accuracy of dobutamine stress echocardiography (DSE) in symptomatic patients with a low to intermediate pretest probability of obstructive coronary artery disease (CAD) and a positive coronary CT angiography (CCTA).

Methods We prospectively enrolled 104 consecutive patients undergoing coronary angiography for symptoms of stable CAD and a CCTA indicative of obstructive CAD. The diagnostic performance of DSE was evaluated against two intracoronary pressure indices: (a) fractional flow reserve (FFR) with a cut-off of ≤0.80 and (b) instantaneous wave-free ratio (iFR) with a cut-off of ≤0.89, indicating haemodynamically significant stenoses.

Results Of 102 patients, 46 (45%) had at least one significant lesion as defined by FFR, as did 37 (36%) as defined by iFR. DSE showed positive results in 33% (34/102) of cases. The discriminative power of DSE for detecting significant CAD was moderate, with areas under the curve of 0.63 (p=0.024) compared with FFR and 0.64 (p=0.025) compared with iFR. The accuracy, sensitivity and specificity of DSE were, respectively, 61%, 43%, and 75% against FFR, and 64%, 46% and 74% against iFR. The diagnostic accuracy of DSE did not differ significantly between FFR and iFR as a reference (p=0.549).

Conclusion In patients with positive CCTA, DSE has a moderate ability to identify haemodynamically significant CAD, with low sensitivity and moderate specificity. When assessed against FFR and iFR criteria, its additive diagnostic value is limited in patients with low to intermediate pretest probability of obstructive CAD.

Trial registration number NCT03045601.

  • FRACTIONAL FLOW RESERVE
  • CORONARY ARTERY DISEASE
  • Echocardiography
  • Computed Tomography Angiography
  • Angina Pectoris

Data availability statement

Data are available on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/openhrt-2024-002899

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Current guidelines recommend non-invasive functional testing to evaluate the ischaemic potential of angiographic stenoses detected by coronary CT angiography (CCTA). However, both perfusion scans with cardiac MR and myocardial perfusion scintigraphy have demonstrated limited accuracy in identifying haemodynamically significant coronary artery disease (CAD) when compared against fractional flow reserve (FFR) in this population.

    WHAT THIS STUDY ADDS

    • Dobutamine stress echocardiography shows limited diagnostic performance with low sensitivity and moderate specificity for detecting haemodynamically significant CAD when assessed against FFR and instantaneous wave-free ratio criteria.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • There is a discrepancy between dobutamine stress echocardiography and invasive pressure indices in identifying myocardial ischaemia following CCTA. The usefulness of dobutamine stress echocardiography in selecting patients for invasive coronary angiography in this population warrants further studies.

    Introduction

    Coronary CT angiography (CCTA) is increasingly used to investigate patients with suspected stable coronary artery disease (CAD) and has been highlighted in recent international guidelines.1 Because CCTA is an anatomical and not a physiological evaluation of coronary stenoses, its use in selecting patients for subsequent invasive coronary angiography (ICA) has not been well defined. The anatomical presence of stenosis often does not correlate with the physiological impacts and may lead to overestimation of its functional significance.2 3 To avoid excess use of ICA, guidelines recommend non-invasive functional testing to determine the presence and extent of myocardial ischaemia.1 Perfusion scans with cardiac MR or myocardial perfusion scintigraphy, however, show limited accuracy in characterising the physiological significance of coronary stenoses identified by CCTA.4 5

    In several randomised trials, fractional flow reserve (FFR)-guided revascularisation has proved superior to angiography-guided revascularisation with respect to clinical results and cost-effectiveness, establishing FFR as the gold standard for evaluating the haemodynamic significance of coronary stenoses.6–8 Recently, the instantaneous wave-free ratio (iFR) proved non-inferior to FFR as a novel diastolic pressure index without the need to induce hyperaemia. Consequently, iFR also has been established in contemporary guidelines as a class IA recommendation for determining the haemodynamic relevance of coronary stenoses.9–11

    How dobutamine stress echocardiography (DSE) performs in this clinical setting is not well known. In multiple studies, DSE has shown high predictive value and diagnostic performance for identifying ischaemia in high-risk populations when compared with ICA as the gold standard.12 13 Studies of DSE with FFR and iFR as the reference standard, however, are limited.

    The aim of the present study thus was to assess the diagnostic ability of DSE in identifying haemodynamically significant CAD following positive CCTA results, using FFR and iFR as reference standards.

    Methods

    During March 2017–March 2021, we prospectively enrolled 104 consecutive, stable outpatients with a low to intermediate pretest likelihood of CAD and a positive CCTA, referred for subsequent ICA. Exclusion criteria included age >75 years, body mass index >40, previous coronary revascularisation, chronic total occlusions, clinically significant arrhythmia, congenital coronary anomaly, cardiomyopathy and significant valvular heart disease. Additionally, patients hospitalised for unstable CAD after CCTA were deemed ineligible. Participants were enrolled as part of an ongoing clinical trial for developing a novel CT-FFR algorithm at St. Olavs Hospital in Trondheim, Norway.14 All of the 182 individuals recruited for this project were invited to participate in the DSE study, but 79 prospective participants ultimately were not included for the following reasons: declined to participate (n=13), administrative reasons (n=43), poor image quality (n=4), arrhythmia (n=6), unstable coronary disease or left main disease (n=6), total occlusions (n=3), cardiomyopathy (n=3) and coronary anomaly (n=1). Flowchart of recruitement is included in the online supplemental file 1.

    Coronary CT angiography

    CCTA was performed at St.Olavs University Hospital and five collaborating hospitals in the same health region in Norway. All CT examinations were conducted using prospective ECG gating. Nine CT scanners from three suppliers were used (General Electric Healthcare, Waukesha, Wisconsin, USA; Siemens Healthineers, Erlangen, Germany; Philips Healthcare, Best, Netherlands). Four were GE Revolution DE 256-slice scanner with a 160 mm detector width, one was a Discovery 64-slice scanner with a 40 mm detector width, two were Somatom Flash DE 2×128 slice scanners with a 2×38 mm detector width, one was a Drive 2×128 slice scanner with a 2×38 mm detector width and one was a Philips ICT 256-slice scanner with an 80 mm detector width. Image acquisition and postprocessing followed current guidelines.15 Sublingual nitroglycerin was administered to all patients immediately before scanning. To achieve a heart rate of <60 bpm, beta-blockers were administered orally and, if necessary, intravenously. Local radiologists experienced in cardiac imaging evaluated all images according to guidelines. In accordance with established clinical routines, patients were referred for subsequent ICA in case of symptoms and with the presence of at least one significant stenosis on CCTA.16 Diameter stenosis (DS%) ≥50% was considered significant in both CCTA and ICA.

    ICA and quantitative coronary angiography

    Experienced interventional cardiologists conducted ICA using standard techniques within 3 months after CCTA. Invasive FFR and iFR measurements were performed in every CCTA-documented stenosis except in arteries showing minimal angiographic lesions during ICA and considered non-obstructive (DS%≤25%). Additional FFR and iFR measurements were performed during ICA if intermediate stenoses with potential haemodynamic relevance not acknowledged on CCTA were identified. The angiographic severity of the coronary stenoses was retrospectively graded by quantitative coronary angiography using the CAAS workstation 8.2 system.

    Intracoronary pressure measurements

    Intracoronary pressure measurements were obtained using Verrata Plus (Philips Volcano, San Diego, USA) pressure wires according to standard practice. Following pressure equalisation, intracoronary nitroglycerin (0.2 mg) was given to all patients before the pressure wire was advanced into the coronary artery, followed by time for blood pressure to stabilise. iFR measurements were performed under resting conditions with subsequent FFR measurements taken during hyperaemia induced by continuous intravenous infusion of adenosine at a rate of 140 µg/kg/min. FFR was defined as the lowest recorded ratio. Following measurements, the pressure wire was pulled back to the equalisation point at the tip of the guiding catheter to ensure no drift. Acceptable drift was defined as ±0.02. A positive FFR was defined as ≤0.80, indicating a haemodynamically significant stenosis and a positive iFR was defined as ≤0.89.

    Stress echocardiography

    DSE was conducted at a European Association of Cardiovascular Imaging (EACVI)-accredited echocardiographic laboratory centre by four experienced cardiologists using a state-of-the-art scanner (GE Vivid E95, GE Vingmed Ultrasound, Horten, Norway), following a predefined protocol in accordance with current guidelines.17 Beta-blockers were withdrawn at least 24 hours before examination. Dobutamine infusion was delivered in 3 min increments starting at a dose of 10 µg/kg/min, to a maximum dose of 40 µg/kg/min, and if necessary, supplied with atropine up to 1 mg×2 to obtain a target heart rate response, defined as 85% of the age-predicted maximum. Ultrasound contrast (Sonovue) 0.2–0.5 mL was administered as an intravenous bolus at baseline and peak dobutamine when two or more segments were inadequately visualised.17 A cardiologist with >30 years of stress echocardiography experience and unaware of CCTA and ICA pressure measurement results analysed the test using a 16-segment model of the left ventricle.18 Regional wall motion was graded as recommended at each segment, as follows: normal wall motion=1, hypokinesia=2, severe hypokinesia or akinesia=3, dyskinesia=4 and aneurysmal=5. A new wall motion abnormality appearing in at least one segment during dobutamine infusion was considered an ischaemic response and positive result.

    Statistics

    Data analysis was performed by using SPSS V.28.0.1.0 (IBM) and MedCalc statistical software V.20.110 (MedCalc Software, Ostend, Belgium). Categorical variables are reported as numbers and percentages and continuous variables as means±SD or medians with IQRs. Diagnostic accuracy was assessed with the receiver operating characteristic curve with the calculation of the area under the curve (AUC) presented with 95% CIs. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy also were calculated with 95% CIs, using FFR with a cut-off of 0.80 and iFR with a cut-off of 0.89. In patients with multiple stenoses, the stenosis with the lowest FFR and iFR value was used in calculations. Accuracy, specificity and sensitivity were compared using McNemar’s test, with p<0.05 considered statistically significant.

    Results

    Study population

    The study included 104 patients with positive CCTA, all of whom underwent DSE before invasive angiography (figure 1). One participant was excluded from the analysis because of inadequate image quality, and one examination was terminated prematurely because of intolerable supraventricular arrhythmia. Intracoronary pressure measurements were successfully performed in 90% of enrolled patients. Nine patients did not undergo FFR and iFR measurements because of angiographically non-obstructive lesions (DS ≤25%), dichotomously defined as negative. One patient underwent only iFR measurement because of a total AV block during adenosine infusion.

    Figure 1
    Figure 1

    Case example. A patient with an intermediate pretest probability of obstructive CAD; hypertension, typical angina and exertional dyspnoea over the last year; and CCTA showing a significant stenosis in the proximal left anterior descending artery (A, green arrow). ICA confirmed an intermediate stenosis (B, orange arrow). FFR was 0.66 and iFR 0.85 (C, blue arrow), both of functional significance (C, E, F). DSE showed a biphasic response to dobutamine with improved contractile response at low dose and worsening wall motion abnormalities in the septal and anteroseptal wall during peak dobutamine infusion (D, red arrow). CAD, coronary artery disease; CCTA, coronary CT angiography; DSE, dobutamine stress echocardiography; FFR, fractional flow reserve; ICA, invasive coronary angiography; iFR, instantaneous wave-free ratio.

    Clinical characteristics are summarised in table 1. Mean age was 60 years, and 66% were men. The clinical pretest probability according to 2019 guidelines was low, with a mean of 23%.1 Typical angina was present in 35% of patients. 10 patients had a history of cardiovascular ischaemic events. Two patients experienced a procedure-related infarction during DSE with mildly raised troponins (troponin T<70 ng/L). Both were admitted to the hospital, where they underwent percutaneous coronary intervention (PCI). One patient suffered a cerebral infarction following ICA with pressure measurements.

    View this table:
    Table 1

    Baseline characteristics are given as n (%) or mean±SD

    Vessel characteristics

    Table 2 summarises the angiographic and functional vessel characteristics. A total of 46 patients (45%) were FFR positive (≤0.80) and 37 (36%) were iFR positive (≤0.89). The mean FFR was 0.76±0.16, and the mean iFR was 0.88±0.14. Median FFR was 0.81 (IQR 0.69–0.88), and median iFR was 0.92 (IQR 0.85–0.96), indicating that most lesions were of intermediate degree (figure 2). For DSE-positive patients, the mean FFR was 0.73±0.16, and the mean iFR was 0.84±0.17. Of 181 lesions that were successfully measured, 74 (41%) were FFR positive and 51 (28%) iFR positive.

    View this table:
    Table 2

    Patient (N=102) and vessel (N=181) characteristics according to DSE, FFR and iFR, given as n (%), mean±SD, or median (Q1, Q3)

    Figure 2
    Figure 2

    Distribution of (A) FFR and (B) IFR measurements. Outliers are indicated in red, defined as values below the lower quartile minus three times the IQR. FFR, fractional flow reserve; IFR, instantaneous wave-free ratio.

    Diagnostic performance of DSE

    A total of 34 (33%) DSE exams were positive for myocardial ischaemia. The patients were adequately stressed with a mean per cent of age-predicted heart rate of 89%±8% and an average heart rate at peak stress of 141±13 bpm. The mean dobutamine infusion dose was 39±4 µg/kg/min, and atropine was administered in 60 (63%) patients. The AUC for identifying haemodynamic significance was 0.63 (95% CI 0.52 to 0.72) for FFR ≤0.80 and 0.64 (95% CI 0.53 to 0.73) for iFR ≤0.89 (figure 3). Compared with intracoronary FFR as the reference standard, DSE sensitivity was 43% (95% CI 29% to 59%) and specificity was 75% (95% CI 62% to 86%; figure 4). Using iFR as a reference, DSE sensitivity was 46% (95% CI 29% to 63%) and specificity was 74% (95% CI 61% to 84%). The accuracy of DSE was 61% (95% CI 51% to 70%) compared with FFR and 64% (95% CI 54% to 73%) compared with iFR. DSE performance did not differ between the two coronary indices as reference standards in terms of diagnostic accuracy (p=0.549), sensitivity (p=0.344) or specificity (p=1.00). The positive likelihood ratio of DSE was 1.74 (95% CI 0.99 to 3.05) compared with FFR and 1.76 (95% CI 1.03 to 3.01) compared with iFR. The negative likelihood ratios were 0.75 (95% CI 0.56 to 1.01) and 0.73 (95% CI 0.53 to 1.02) compared with FFR and iFR, respectively.

    Figure 3
    Figure 3

    ROC curve analysis for stress echocardiography to detect haemodynamically significant CAD as defined by (A) FFR ≤0.80 and (B) iFR ≤0.89. ∆ WMSI represents the change in WMSI from baseline to peak stress. AUC, area under the curve; CAD, coronary artery disease; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; ROC, receiver operating characteristic; WMSI, Wall Motion Score Index.

    Figure 4
    Figure 4

    Diagnostic performance of stress echocardiography for detecting hemodynamically significant CAD as defined by FFR ≤0.80 and IFR ≤0.89. Results are presented with 95% CLs. FFR, fractional flow reserve; iFR, instantaneous wave-free ratio.

    With a pretest probability based on a 45% prevalence of FFR-positive patients, the post-test probability of significant CAD increased to 59% with a positive DSE and decreased to 38% with a negative DSE. Similarly, using a 36% iFR prevalence as the pretest probability, the post-test odds were 0.98 with a positive DSE and 0.41 with a negative DSE, translating to a post-test probability of 49% for the positive DSE and 29% for the negative DSE.

    Discussion

    Current guidelines recommend the use of non-invasive functional testing in CCTA-positive patients.2 We found, however, that DSE had only a moderate diagnostic ability to identify haemodynamically significant CAD in these patients when assessed against FFR and iFR criteria. Concordant with the results of the Dan-NICAD trial, which showed limited sensitivity and moderate specificity for cardiovascular magnetic resonance and myocardial perfusion scintigraphy as second-line tests following positive CCTA.4

    Although DSE has been validated extensively using ICA, relatively few studies have compared DSE in functionally significant CAD using FFR or iFR as a reference. Compared with anatomically significant CAD, in populations with intermediate and high prevalence, DSE has shown high sensitivity (85%) and specificity (82%).2 One meta-analysis showed a sensitivity of 77% and specificity of 75% for stress echocardiography compared with FFR.19 The sensitivity of DSE for identifying functionally significant CAD as defined by FFR and iFR after positive CCTA was considerably lower in our study.

    Several explanations for these discrepancies are possible. Many lesions in our study were close to the cut-offs defined for intracoronary pressure recordings, and several reports suggest that effects unrelated to ischaemia may affect FFR and iFR values. The importance of optimal measurement techniques and possible methodological inaccuracies must be acknowledged.20 Inaccurate calibration of the pressure wire, contrast in the guiding catheter and drifting can influence results. We focused on eliminating these factors in our study.

    In addition, atherosclerotic coronary disease is not a binary condition but rather a continuum from mild to severe, and DSE with ischaemic response is more likely with advanced disease compared with lesions near the cut-off threshold. This distinction is particularly relevant in current practice as high-risk patients often proceed directly to invasive evaluation and those with completely normal vessels are identified and excluded by CCTA. Bartunek et al compared DSE and FFR and reported a sensitivity of 76% and specificity of 97% for DSE in predicting FFR ≤0.75. The prevalence of DSE-positive patients in this study was 56% (42/75), with a mean FFR as low as 0.47±0.12 in the DSE-positive group vs 0.77±0.15 in the DSE-negative group.21 The mean FFR in our study was just below this value, at 0.76±0.15, and in the grey zone for FFR. Similarly, in the physiology-stratified analysis of the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), the mean FFR with normal stress echocardiography was 0.76±0.17, whereas it was 0.65±0.17 in patients with two or more affected segments on DSE.22 In our study, the mean FFR value for DSE-positive patients was 0.73±0.16.

    With CCTA, patients with smaller areas of ischaemia from anatomical stenosis in side branches or distally in main vessels may be diagnosed with CAD. Intracoronary pressure indices are flow-dependent but give no direct indication of the size of the subtended mass or area at risk for myocardial ischaemia. In this context, we note that in our study, 13 lesions with positive intracoronary pressure readings were located distally in a main vessel (segment 3, 4, 8 or 13), and 4 were located in side branches (marginal/diagonal branches). The sensitivity of DSE is reduced in patients with single-vessel disease, which was present in 63% of our patients.12

    In the original FFR validation study, the optimal cut-off for demonstrating myocardial ischaemia was established as ≤0.75.23 This threshold also was used in the DEFER trial, indicating that revascularisation of intermediate stenosis with FFR ≥0.75 could safely be deferred in favour of optimal medical therapy.24 A subset of patients exhibited myocardial ischaemia on non-invasive testing even in lesions with FFR values >0.75, however, resulting in a threshold of 0.80 being adopted in the subsequent clinical trials.6 7 This decision was taken despite a lack of validation studies supporting ≤0.80 as the optimal threshold and left a grey zone of FFR 0.75–0.80 in which myocardial ischaemia is likely absent but cannot be completely excluded. When the cut-off of FFR was raised to 0.80, the sensitivity of non-invasive functional tests decreased for lesions with lower FFR.

    iFR is a pressure measurement performed under resting conditions and shown to be non-inferior to FFR in guiding coronary revascularisation, although it is discordant in 20% of cases.9 10 25 Here, we found no statistically significant difference in the diagnostic performance of DSE with iFR versus FFR as the reference standard.

    The low sensitivity of DSE is somewhat discouraging, but its prognostic value is beyond doubt and risk stratification with DSE is highly predictive of cardiac events.26 27 Although FFR and iFR are valuable in guiding PCI treatment, these indices should not necessarily be considered as definitive diagnostic gold standards for myocardial ischaemia, as this may result from several and complex pathophysiological mechanisms, including microvascular and endothelial dysfunction. Whether DSE is falsely negative or FFR and iFR measurements are falsely positive remains an intriguing question. Originally developed to quantify the relative contribution of epicardial stenoses on transstenotic blood flow, FFR indicates the potential for flow to increase after revascularisation.28 In contrast, a positive DSE reflects myocardial ischaemia of several etiologies, including epicardial atherosclerosis with or without focal stenosis or microvascular dysfunction. In cases of high flow, that is, with minimal diffuse coronary atherosclerosis or microvascular dysfunction, the trans-stenotic gradient may be significant and ≤0.80, yet the maximum achievable flow may still suffice to avoid myocardial ischaemia. Conversely, with a high burden of diffuse CAD or microvascular disease, trans-stenotic flow may be low, resulting in a non-significant pressure gradient with myocardial ischaemia still present.29 Both scenarios could contribute to discrepancies between the intracoronary pressure indices and DSE.

    Non-invasive diagnostics have the potential to reduce unnecessary invasive procedures, thereby lowering the risk of procedural complications and exposure to potentially harmful radiation during invasive procedures. The median effective radiation dose during ICA in our study was 5.0 mSv (conversion coefficient=0.002) for patients who underwent PCI and 2.7 mSv for those who had diagnostic angiography with intracoronary pressure measurements alone. These doses are low compared with recently published data.30 Similarly, CCTA had a median effective radiation dose of 2.2 mSv (conversion factor=0.014) and 4.1 mSv (conversion factor=0.026) which are also low compared with other studies.31

    In our study, two patients experienced procedural complications related to ICA and pressure measurements. One patient experienced adduction paresis and diplopia during the procedure, with an MRI revealing a small brain stem infarction. In another patient, transient third-degree AV block occurred during adenosine infusion. These incidents underline the low, but inherent risks associated with invasive procedures and the advantage of iFR as an adenosine-free alternative for intracoronary pressure measurement.

    Three patients experienced procedural complications during DSE. At peak dobutamine infusion (40 µg/kg/min), one patient experienced transient hypotension and chest pain. This episode was clinically assessed as a possible vagal episode, however, echocardiography indicated ischaemia, later confirmed during the blinded review. Another patient developed chest pain and inferior ST elevations during DSE. Echocardiography revealed ischaemia, also confirmed during the blinded review. The ECG normalised immediately after the dobutamine infusion was stopped, symptoms regressed and troponins were mildly elevated. Recent studies have shown a higher incidence of high-sensitive troponin elevations following stress echocardiography, particularly after DSE, in both patients with positive and negative tests.32 The clinical significance of such troponin rises remains not well defined and may primarily reflect the physiological effects of dobutamine and the temporary cardiac stress during stress echocardiography, rather than indicating more significant cardiac events. In the third patient, DSE was terminated prematurely due to supraventricular tachycardia (SVT), which resolved when dobutamine infusion was stopped and intravenous beta-blocker was administered. SVT has a reported incidence of 1.3% during DSE, consistent with our study.33

    Limitations

    There are several limitations to our study. The study cohort included patients characterised by a low prevalence of typical chest pain and a low pretest likelihood of obstructive CAD. However, this population is probably representative of patients referred for outpatient chest pain evaluation and reflects those undergoing CCTA in current practice. Scans were conducted at six hospitals using three different vendors, contributing to a somewhat heterogeneous cohort that may have influenced the moderate prevalence of significant CAD despite a positive CCTA. An experienced radiologist evaluated the scans to ensure acceptable image quality, and the prevalence of FFR-positive patients in our cohort is comparable to prevalences from similarly designed studies.34 To obtain valid FFR results, strict protocol adherence is required and experienced operators performed the FFR measurements in our study, using a predefined protocol to minimise procedural variability and ensure high accuracy and repeatability. Skilled cardiologists conducted the DSE exams at an EACVI-accredited laboratory using a predefined protocol and state-of-the-art equipment to ensure high image quality and adequately stressed patients. The assessment was performed by a cardiologist highly experienced in DSE and blinded to all patient data.

    Conclusion

    When applied to patients with a low to intermediate pretest probability of obstructive CAD and positive CCTA results, DSE has low sensitivity and moderate specificity for haemodynamically significant CAD as defined by current FFR and iFR criteria. This finding suggests limited additive value for DSE in ruling in or ruling out significant CAD. Graphical abstract is included in the online supplemental file 2.

    Data availability statement

    Data are available on reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by the Regional Ethics Committee of Central Norway (2016/1609). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    The authors would like to thank Bjørn Inge Våga, Matthias Heigert, Olav Magne Leiren and Ola Kleveland for their support in conducting the intracoronary pressure measurements.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors ATB: design of study, principal investigator, performed stress echocardiography, analysing data, drafting manuscript, corresponding author. EH: design of study, performed stress echocardiography, drafting manuscript, approved final version of manuscript. RW: design of study, performed invasive investigations, drafting manuscript, approved final version of manuscript. SA: design of study, analysed stress echo exams, analysing data, drafting manuscript, approved final version of manuscript. ATB serves as guarantor for this work, ensuring its accuracy.

    • Funding The Liaison Committee of education, research and innovation in Central Norway.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.