Petra Bijsterveld

Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial.

Summary Background In patients with suspected coronary heart disease, single-photon emission computed tomography (SPECT) is the most widely used test for the assessment of myocardial ischaemia, but its diagnostic accuracy is reported to be variable and it exposes patients to ionising radiation. The aim of this study was to establish the diagnostic accuracy of a multiparametric cardiovascular magnetic resonance (CMR) protocol with x-ray coronary angiography as the reference standard, and to compare CMR with SPECT, in patients with suspected coronary heart disease. Methods In this prospective trial patients with suspected angina pectoris and at least one cardiovascular risk factor were scheduled for CMR, SPECT, and invasive x-ray coronary angiography. CMR consisted of rest and adenosine stress perfusion, cine imaging, late gadolinium enhancement, and MR coronary angiography. Gated adenosine stress and rest SPECT used 99mTc tetrofosmin. The primary outcome was diagnostic accuracy of CMR. This trial is registered at controlled-trials.com, number ISRCTN77246133. Findings In the 752 recruited patients, 39% had significant CHD as identified by x-ray angiography. For multiparametric CMR the sensitivity was 86·5% (95% CI 81·8–90·1), specificity 83·4% (79·5–86·7), positive predictive value 77·2%, (72·1–81·6) and negative predictive value 90·5% (87·1–93·0). The sensitivity of SPECT was 66·5% (95% CI 60·4–72·1), specificity 82·6% (78·5–86·1), positive predictive value 71·4% (65·3–76·9), and negative predictive value 79·1% (74·8–82·8). The sensitivity and negative predictive value of CMR and SPECT differed significantly (p<0·0001 for both) but specificity and positive predictive value did not (p=0·916 and p=0·061, respectively). Interpretation CE-MARC is the largest, prospective, real world evaluation of CMR and has established CMRs high diagnostic accuracy in coronary heart disease and CMRs superiority over SPECT. It should be adopted more widely than at present for the investigation of coronary heart disease. Funding British Heart Foundation.

Diffusion-weighted MRI determined cerebral embolic infarction following transcatheter aortic valve implantation: assessment of predictive risk factors and the relationship to subsequent health status

Background ‘Silent’ cerebral infarction and stroke are complications of transcatheter aortic valve implantation (TAVI). Objective To assess the occurrence of cerebral infarction, identify predictive risk factors and examine the impact on patient health-related quality of life (HRQoL). Methods Cerebral diffusion weighted MRI of 31 patients with aortic stenosis undergoing CoreValve TAVI was carried out. HRQoL was assessed at baseline and at 30 days by SF-12v2 and EQ5D questionnaires. Results New cerebral infarcts occurred in 24/31 patients (77%) and stroke in 2 (6%). Stroke was associated with a greater number and volume of cerebral infarcts. Age (r=0.37, p=0.042), severity of atheroma (arch and descending aorta; r=0.91, p<0.001, r=0.69, p=0.001, respectively) and catheterisation time (r=0.45, p=0.02) were predictors of the number of new cerebral infarcts. HRQoL improved overall: SF-12v2 physical component summary increased significantly (32.4±6.2 vs 36.5±7.2; p=0.03) with no significant change in mental component summary (43.5±11.7 vs 43.1±14.3; p=0.85). The EQ5D score and Visual Analogue Scale showed no significant change (0.56±0.26 vs 0.59±0.31; p=0.70, and 54.2±19 vs 58.2±24; p=0.43). Conclusion Multiple small cerebral infarcts occurred in 77% of patients with TAVI. The majority of infarcts were ‘silent’ with clinical stroke being associated with a both higher infarct number and volume. Increased age and the severity of aortic arch atheroma were independent risk factors for the development of new cerebral infarcts. Overall HRQoL improved and there was no association between the number of new cerebral infarcts and altered health status.

Comparison of Cardiovascular Magnetic Resonance and Single-Photon Emission Computed Tomography in Women With Suspected Coronary Artery Disease From the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) Trial

Background— Coronary artery disease is the leading cause of death in women, and underdiagnosis contributes to the high mortality. This study compared the sex-specific diagnostic performance of cardiovascular magnetic resonance (CMR) and single-photon emission computed tomography (SPECT). Methods and Results— A total of 235 women and 393 men with suspected angina underwent CMR, SPECT, and x-ray angiography as part of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease (CE-MARC) study. CMR comprised adenosine stress/rest perfusion, cine imaging, late gadolinium enhancement, and magnetic resonance coronary angiography. Gated adenosine stress/rest SPECT was performed with 99mTc-tetrofosmin. For CMR, the sensitivity in women and men was similar (88.7% versus 85.6%; P=0.57), as was the specificity (83.5% versus 82.8%; P=0.86). For SPECT, the sensitivity was significantly worse in women than in men (50.9% versus 70.8%; P=0.007), but the specificities were similar (84.1% versus 81.3%; P=0.48). The sensitivity in both the female and male groups was significantly higher with CMR than SPECT (P<0.0001 for both), but the specificity was similar (P=0.77 and P=1.00, respectively). For perfusion-only components, CMR outperformed SPECT in women (area under the curve, 0.90 versus 0.67; P<0.0001) and in men (area under the curve, 0.89 versus 0.74; P<0.0001). Diagnostic accuracy was similar in both sexes with perfusion CMR (P=1.00) but was significantly worse in women with SPECT (P<0.0001). Conclusions— In both sexes, CMR has greater sensitivity than SPECT. Unlike SPECT, there are no significant sex differences in the diagnostic performance of CMR. These findings, plus an absence of ionizing radiation exposure, mean that CMR should be more widely adopted in women with suspected coronary artery disease. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN77246133.

Effect of Care Guided by Cardiovascular Magnetic Resonance, Myocardial Perfusion Scintigraphy, or NICE Guidelines on Subsequent Unnecessary Angiography Rates: The CE-MARC 2 Randomized Clinical Trial

IMPORTANCE Among patients with suspected coronary heart disease (CHD), rates of invasive angiography are considered too high. OBJECTIVE To test the hypothesis that among patients with suspected CHD, cardiovascular magnetic resonance (CMR)-guided care is superior to National Institute for Health and Care Excellence (NICE) guidelines-directed care and myocardial perfusion scintigraphy (MPS)-guided care in reducing unnecessary angiography. DESIGN, SETTING, AND PARTICIPANTS Multicenter, 3-parallel group, randomized clinical trial using a pragmatic comparative effectiveness design. From 6 UK hospitals, 1202 symptomatic patients with suspected CHD and a CHD pretest likelihood of 10% to 90% were recruited. First randomization was November 23, 2012; last 12-month follow-up was March 12, 2016. INTERVENTIONS Patients were randomly assigned (240:481:481) to management according to UK NICE guidelines or to guided care based on the results of CMR or MPS testing. MAIN OUTCOMES AND MEASURES The primary end point was protocol-defined unnecessary coronary angiography (normal fractional flow reserve >0.8 or quantitative coronary angiography [QCA] showing no percentage diameter stenosis ≥70% in 1 view or ≥50% in 2 orthogonal views in all coronary vessels ≥2.5 mm diameter) within 12 months. Secondary end points included positive angiography, major adverse cardiovascular events (MACEs), and procedural complications. RESULTS Among 1202 symptomatic patients (mean age, 56.3 years [SD, 9.0]; women, 564 [46.9%] ; mean CHD pretest likelihood, 49.5% [SD, 23.8%]), number of patients with invasive coronary angiography after 12 months was 102 in the NICE guidelines group (42.5% [95% CI, 36.2%-49.0%])], 85 in the CMR group (17.7% [95% CI, 14.4%-21.4%]); and 78 in the MPS group (16.2% [95% CI, 13.0%-19.8%]). Study-defined unnecessary angiography occurred in 69 (28.8%) in the NICE guidelines group, 36 (7.5%) in the CMR group, and 34 (7.1%) in the MPS group; adjusted odds ratio of unnecessary angiography: CMR group vs NICE guidelines group, 0.21 (95% CI, 0.12-0.34, P < .001); CMR group vs the MPS group, 1.27 (95% CI, 0.79-2.03, P = .32). Positive angiography proportions were 12.1% (95% CI, 8.2%-16.9%; 29/240 patients) for the NICE guidelines group, 9.8% (95% CI, 7.3%-12.8%; 47/481 patients) for the CMR group, and 8.7% (95% CI, 6.4%-11.6%; 42/481 patients) for the MPS group. A MACE was reported at a minimum of 12 months in 1.7% of patients in the NICE guidelines group, 2.5% in the CMR group, and 2.5% in the MPS group (adjusted hazard ratios: CMR group vs NICE guidelines group, 1.37 [95% CI, 0.52-3.57]; CMR group vs MPS group, 0.95 [95% CI, 0.46-1.95]). CONCLUSIONS AND RELEVANCE In patients with suspected angina, investigation by CMR resulted in a lower probability of unnecessary angiography within 12 months than NICE guideline-directed care, with no statistically significant difference between CMR and MPS strategies. There were no statistically significant differences in MACE rates. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT01664858.

Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): A prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease

Background A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large-scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance. Trial Design CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance–guided care, single-photon emission computed tomography–guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines–based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed. Conclusions The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation.

Prognostic value of CMR and SPECT in suspected coronary heart disease: long term follow-up of the CE-MARC study

Background CE-MARC established the comparative diagnostic performance of cardiovascular magnetic resonance (CMR) and single photon emission computed tomography (SPECT) in patients with suspected coronary heart disease. However, there are no prospective, prognostic data comparing the two modalities in the same patient population. Our objective was to establish the comparative ability of CMR and SPECT to predict major adverse cardiovascular events.

Diagnostic accuracy of the core components of a multi-parametric cardiovascular magnetic resonance imaging protocol: a CE-MARC sub-study

Background The CE-MARC study was the largest prospective evaluation of the diagnostic accuracy of cardiovascular magnetic resonance (CMR) in coronary artery disease (CAD), demonstrating its superiority over single-photon emission computed tomography [1]. The trial adopted a multi-parametric protocol assessing ventricular function, myocardial perfusion, viability (with late gadolinium enhancement (LGE)) and coronary artery anatomy. There have been a number of previous studies analysing the diagnostic accuracy of different components of the CMR examination with contrasting results. We assessed the diagnostic accuracy of the individual components and selected combinations of the multi-parametric CMR examination from the CE-MARC study. Methods All patients from the CE-MARC population were studied. Visual CMR analyses were from the original, blinded read. Pre-specified sub-analysis of the four individual core components of the CMR protocol was performed in isolation, as a paired component (perfusion and LGE) and as a triplet (perfusion, LGE and ventricular function) and compared to the full multi-parametric protocol. Results Both CMR and X-ray angiography were available in 676 patients. The sensitivity of the combined CMR protocol was 86.5%, specificity 83.4%, PPV 77.2% and NPV 90.5%. The diagnostic accuracy of the individual components and paired and triplet combinations compared to the full multi-parametric protocol are presented in Table 1 and Figure 1. The maximum sensitivity for the detection of significant CAD by CMR was achieved when all four components were used. No individual component; paired perfusion with LGE; or perfusion with LGE and function significantly outperformed the multi-parametric protocol in terms of sensitivity. However in terms specificity, the individual components of perfusion, ventricular function and late gadolinium enhancement (LGE) all performed significantly better than the multi-parametric protocol (P < 0.0001). In addition, combining LGE with perfusion or with perfusion and ventricular function significantly improved the test specificity compared to the multi-parametric protocol (P < 0.0001 for each). In terms of PPV and NPV, the multi-parametric protocol performed significantly better than all individual components, paired or triplet combination. Conclusions A combined multi-parametric CMR protocol has higher sensitivity, PPV and NPV that the individual components however the specificity of the individual components of perfusion, ventricular function and late gadolinium enhancement (LGE) all performed significantly better than the multi-parametric protocol.

The role of cardiovascular magnetic resonance in women with suspected CAD: a CE-MARC substudy

The CE-MARC study is the largest, prospective evaluation of cardiovascular magnetic resonance (CMR) in patients with suspected coronary artery disease (CAD). This predefined CE-MARC substudy compared the diagnostic performance of CMR and single-photon emission computed tomography (SPECT) in the female cohort.

89 Development and external validation of a multivariable model of pre-test likelihood of coronary artery disease based on a contemporary uk population, with comparison to existing risk models

Introduction Pre-test likelihood models recommended in current UK and US guidelines have been shown to overestimate the probability of coronary artery disease(CAD). We aimed to develop a UK population-based multivariable risk model from CE-MARC(a contemporary study of stable CAD where all patients underwent X-ray coronary angiography) and validate it prospectively in the CE-MARC 2 trial population. Methods CE-MARC (development population) enrolled patients between 2006–9 with suspected angina. Multivariable logistic regression modelled presence of significant stenosis (QCA≥70% in epicardial arteries or ≥50% in Left Main Stem) as a function of baseline demographic and clinical characteristics. The validation population were from the CE-MARC 2 trial (2012–16) that underwent angiography, plus additional low and high-risk patients from Leeds General Infirmary (2014–2016) to ensure adequate numbers across the full risk spectrum. Discrimination and calibration were assessed and compared to existing CAD consortium models(ESC 2013 guidelines) and the Duke Score(NICE CG95 2010 and US 2012 guidelines). Results There were 675 patients in the development population, and 369 patients in the validation population(Table 1). A multivariable model was developed that included age, sex, angina type, smoking, diabetes, dyslipidaemia, hypertension, ECG Q-waves and ST segment abnormalities.The validation population had a similar CV risk profile. The new CE-MARC model discriminated well (c-statistic: 0.78 (95%CI 0.73–0.82)) and was well-calibrated (Table 2, Figure 1). In comparison, the Duke clinical model was very poorly calibrated (−1.016; −1.265 to −0.766; p<0.001) indicating substantial overestimation of pre-test likelihood compared to the average in the two populations (Figure 2, Table 2). The models used in the ESC 2013 guidelines under-estimated risk (0.74, 95% CI 0.51–0.97; p<0.001), but performed well once adjusted for different baseline risk levels (Table 2).Abstract 89 Figure 1 Calibration plot showing relation between predicted PTL of CAD and observed rates of CAD by decile in validation population for CEMARC modelAbstract 89 Figure 2 Calibration plot showing the relation between predicted PTL of CAD and observed rates of CAD by decile in validation population for Duke model Conclusion The CE-MARC risk model, developed from a large contemporary UK population undergoing angiography, performed very well in the independent validation sample, without needing any adjustment for different risk prevalence or for miscalibration. In contrast, the earlier Duke risk score substantially over-predicted CAD risk, and remained poorly-calibrated even when this was corrected. The CAD consortium model (ESC 2013 guidelines), slightly under-estimated average CAD risk, but performed well once this was accounted for lower margin presents histogram of number of patients with each predicted risk scoreAbstract 89 Table 2 Model performance statistics Model Discrimination (c-statistic) Calibration in the large (alpha) Logistic miscalibration (beta) Development population Duke model (1993) 0.763 (0.725–0.800) −1.108 (-1.305, 0.911); p<0.001 −0.298 (-0.416,–0.180); p<0.001 Genders et al (2012) Basic 0.770 (0.733–0.806) 0.713 (0.532, 0.893); p<0.001 −0.015 (-0.131, 0.101); p=0.803 Genders et al (2012) Clinical 0.762 (0.725–0.7995) 0.822 (0.639, 1.005); p<0.001 −0.051 (-0.159, 0.057); p=0.354 Validation population CEMARC 0.777 (0.731–0.824) 0.045 (-0.190, 0.280); p=0.709 0.028 (-0.214, 0.269); p=0.823 Pryor et al (1993) 0.752 (0.704–0.801) −1.016 (-1.265,–0.766); p<0.001 −0.207 (-0.363,–0.050); p=0.010 Genders et al (2012) Basic 0.755 (0.706–0.803) 0.738 (0.507, 0.969); p<0.001 −0.007 (-0.182, 0.169); p=0.940 Genders et al (2012) Clinical 0.752 (0.703–0.800) 0.866 (0.629, 1.103); p<0.001 −0.054 (-0.121, 0.105); p=0.507 Abstract 89 Table 1 Demographics Development population (n=675) Validation population (n=369) Age/years (mean/SD) 59.4 (9.66) 59.6 (10.10) Male (n/%) 417 (61.8) 160 (43.4) Typical pain (n/%) 145 (21.5) 182 (49.3) Atypical pain (n/%) 497 (73.6) 154 (41.7) Non-anginal pain (n/%) 32 (4.7) 33 (8.9) Hypertension (n/%) 354 (52.4) 165 (44.7) Current Smoker (n/%) 126 (18.7) 77 (20.9) Dyslipidaemia (n/%) 358 (53.0) 170 (46.1) Diabetes Mellitus (n/%) 76 (11.3) 61 (16.5)

104 A service review and comparison of resource?utilisation with the change in recommendations from nice 2010 cg95 to the nice 2016update (chest pain of recent onset: assessment and diagnosis)

Background NICE 2010 guidelines (CG95) proposed investigation according to pre-test likelihood (PTL) of coronary artery disease (CAD) in patients presenting with stable chest pain; low risk patients are referred for CT coronary angiography (CTCA), intermediate risk should have a functional test (stress echocardiography, MPS, CMR) with invasive angiography reserved for high risk patients and those with a PTL>90% having no investigation and treated prospectively as angina. The 2016 update to CG95 now recommends referral for CTCA in all patients with typical or atypical chest pain and in those with non-anginal pain but with ECG changes, with functional imaging reserved for those who have previously documented coronary disease or revascularisation. Our aim was to compare imaging resource utilisation between the 2010 and 2016 guideline recommendations to highlight the potential service implications if followed explicitly. Methods Consecutive patients referred over 4 weeks to the Leeds General Infirmary rapid access chest pain clinic (RACPC) with stable chest pain symptoms were prospectively evaluated. Non identifiable data was collected on demographics, typicality of chest pain symptoms and ECG findings and subsequently requested 1st line investigation. Patient notes were reviewed and PTL for patients was calculated in accordance with CG95 and hypothetical investigative strategies calculated according to both 2010 and 2016 guidelines. Results 157 consecutive patients were evaluated between 17th October and 17th November 2016. Patient demographics are displayed in table 1. 37 (23.5%) patients had typical angina, 55 (35.0%) had atypical angina, 65 (41.4%) had non-anginal symptoms. 16 (10.2%) patients had previous infarction/revascularisation. 25 (15.9%) patients had a PTL<10%, 36 (22.9%) had a PTL of 10%–29%, 30 (19.1%) had a PTL of 30%–60%, 41 (26.1%) had a PTL of 61%–90% and 25 (15.9%) had a PTL of >90%. Table 2 shows diagnostic tests requested and hypothetical investigative strategies according to NICE 2010 CG95 and the 2016 update. Conclusion/Implications Our results show that if implemented in proposed 2016 form there will be a significant increase in the referral rate for CTCA with a corresponding decrease in referral for functional imaging and angiography. Furthermore the number of patients that are not investigated would more than double following the introduction of the proposed NICE 2016 guidelines. CTCA has high sensitivity for the diagnosis of CAD but more limited specificity and concerns are that increased usage in intermediate/high risk patients may lead to increased rates of unnecessary angiography due to the overestimation of severity of CAD. The change in guidelines would lead to a significant shift in practice that has implications for both workforce planning and provision of resources. Abstract 104 Table 1 Patient demographics Patient Characteristics Number (n=157) Age/years (mean/SD) 60.4 (13.0) Male n/% 83 (52.8) Hypertension n/% 62 (39.5) Dyslipidaemia n/% 50 (33.8) Diabetes mellitus n/% 30 (19.1) Smoking n/% 27 (17.2) Family History n/% 61 (38.9) ECG Q-waves n/% 8 (5.0) ECG ST segment change n/% 8 (5.0)Abstract 104 Table 2 Investigative strategy according to CG95 guidelines and per clinician request Actual investigation requested 2010 recommended investigation 2016 recommended investigation P-value (difference between 2010 and 2016) No test 22 25 62 <0.001 CTCA 14 36 79 <0.001 Functional imaging 111 30 16 0.031 X-ray Angiogram 10 41 0 <0.001 Treat as angina 0 25 0 <0.001