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Background: There are only few data about the predictive value of atherosclerosis imaging beyond traditional risk calculators in younger subjects. Methods: We assessed cardiovascular risk prediction with the PROCAM (the Prospective Cardiovascular Munster Study) risk equation and with carotid plaque imaging (determination of total plaque area (TPA) and the maximum plaque thickness with ultrasound) in subjects without known cardiovascular diseases. The follow-up was generated during follow-up examinations as part of preventive medical examinations or by telephone calls. Results: In 2,508 subjects aged 35 - 64 years (50 ± 8 years, 34% women), 132 (5.3%) cardiovascular events occurred (42 myocardial infarction, 17 bypass surgery, 31 stent implantation, 42 coronary artery disease defined by invasive angiography) during a mean follow-up period of 5.4 (1 - 12) years. TPA in combination with the maximum plaque thickness (type III - IV b plaques ) tended to be superior compared to TPA, and both plaque imaging methods were superior to PROCAM: area under the curve (AUC) 0.9 (95% confidence interval (CI): 0.91 - 0.89) vs. 0.89 (95% CI: 0.90 - 0.88), P = 0.2 vs. 0.82 (95% CI: 0.84 - 0.81), P = 0.001; positive predictive value (PPV) 27% (95% CI: 0.31 - 0.22) vs. 19% (95% CI: 0.22 - 0.16) vs.19% (95% CI: 0.27 - 0.13). Conclusions: Amount of carotid plaque assessed by carotid plaque imaging significantly improves cardiovascular risk prediction beyond the PROCAM risk equation. Cardiol Res. 2020;11(4):233-238 doi: https://doi.org/10.14740/cr1067

Background Advanced atherosclerosis of the carotid artery is associated with a high risk of cardiovascular disease. The aim of the study was to investigate whether treatment with statins improved the prognosis. Methods Sum of all plaque areas (total plaque area (TPA)) and the maximum plaque thickness were determined in healthy subjects using ultrasound. We compared the outcome in subjects with advanced atherosclerosis of the carotid artery (type III-IV b finding) with and without statin treatment. The follow-up was recorded during follow-up examinations as part of preventive occupational health examinations or by personal communication. Results In 7,106 subjects aged 35 - 65 years (50 ± 8 years, 43% women), we found 669 subjects with advanced atherosclerosis of the carotid artery (type III-IV b finding). A follow-up was available for 640 (95.4%) subjects. In these subjects (54 ± 8 years, 20.4% women), 94 (88 men) had cardiovascular events (35 myocardial infarctions, 13 bypass operations, 32 stent implantations, and 14 strokes) with a mean follow-up time of 3.9 (1 - 12) years. Two hundred sixty subjects were treated with a statin, while 339 received no statin. Fourteen cardiovascular events occurred in the treated group (eight stent implantations, two heart attacks, two bypass operations, and two strokes). In the untreated group, 80 cardiovascular events occurred (12 strokes, 11 bypass operations, 33 heart attacks, and 24 stent implantations). The event rate was 5.4% for the subjects treated with a statin and 23.6% for the untreated subjects. Both groups were well matched for the baseline presence of cardiovascular risk factors. Conclusion Statin treatment in subjects with advanced atherosclerosis of the carotid artery (type III-IV b finding on ultrasound) significantly improves the prognosis in a non-randomized observational cohort study.

BACKGROUND The Swiss Federal Office of Public Health performed a health technology assessment regarding statins in primary care. The chosen models may lead to a situation where a clinically indicated statin therapy is estimated not to be cost effective. METHODS We performed a cohort study regarding cardiovascular events, comparing SCORE and AGLA risk categories with tertiles of carotid plaque burden and used two models for cost-effectiveness analysis of high-potency statins. RESULTS Subjects (n = 2842) were followed up for 5.9 ± 2.9 years with the occurrence of 154 cardiovascular events (extrapolated 10-year risk was 9.2%). Carotid plaque imaging (total plaque area, TPA) significantly improved cardiovascular risk prediction compared with AGLA and SCORE for event-free survival prediction, test accuracy (discrimination) and calibration. Discrimination was significantly improved by about 4% with the inclusion of TPA. Cost-effectiveness analysis using quality-adjusted life years (QALYs) and sensitivity analyses (based on 16 models) ranged between CHF 144,496 and −128,328 per QALY. Cost-effectiveness analysis using direct and indirect costs showed that a treat-them-all strategy in the Swiss population would be cost effective with a return-on-investment per patient in 10 years of between CHF 4442 and 19,059, and the use of carotid imaging was also cost effective (incremental cost-efficiency ratio −2.97 to −7.86). CONCLUSIONS Carotid ultrasound significantly improved cardiovascular risk stratification and is cost effective. The Swiss Medical Board QALY model presents several drawbacks, which are shown in our sensitivity analysis, where results vary considerably and are not useful for clinical decision making. A “treat them all” strategy with statins in the Swiss population aged 30–65 years may be cost effective, when indirect costs of avoidable cardiovascular events are included, even at an unacceptably low value of a statistical life year.

The quality of cardiovascular risk assessment and subsequent medical treatment for those at elevated risk is dependent on the precision of resource allocation. Several confounders may lead to unnecessary treatments, while those at elevated risk may remain untreated. Confounders occur both in calibration and discrimination. While calibration defines the threshold for individuals, which labels them as low, intermediate, high or very high subjects, discrimination describes the diagnostic accuracy of a test to detect those with future disease (Romanens et al., 2010). Once a test for cardiovascular risk assessment, such as the Framingham algorithm, has been derived from a population over decades, accuracy in different populations and continents still has to be undertaken (external validation). External validation is however difficult to obtain because contemporary performance can be assessed only after decades of observation of the outcome variable. Substitutions are however possible, e.g. with atherosclerosis imaging of carotid or coronary arteries (Romanens et al., 2017) or by measuring cardiovascular risk at the time of a cardiovascular event (Mortensen and Falk, 2017). Other important issues are the demographic or ethnic background of individuals assessed with such risk tools or the type of occupation. The working group on lipids and atherosclerosis (AGLA) recommends the use of cardiac or cardiovascular risk derived from PROCAM and SCORE respectively in Switzerland (Eckardstein, 2014). Based on predefined risk thresholds, a primary care subject is categorized into low, intermediate or high risk. For PROCAM, the categories are 0–9%, 10–19% and 20% or more; for SCORE, the categories are 0.0–0.9%, 1.0–4.9% and 5% or more (Piepoli et al., 2016). A major limitation to calculate global cardiovascular risk is present when single cardiovascular risk factors are high. Therefore, subjects with LDL above 5.0 mmol/l or systolic blood pressure above 160 mmHg are by definition high risk in Switzerland (for SCORE, the high-risk cutoffs are 8.0 mmol/l for total cholesterol and systolic blood pressure of 180 mmHg or more). The SCORE model based the risk algorithm on observations of fatal cardiovascular events in 12 European cohorts undergoing baseline examination between 1967 and 1991 (Conroy et al., 2003). In contrast, PROCAM was derived from working men, later extended to women using observations for myocardial infarction only (Assmann et al., 2007). Therefore, the accuracy of these risk assessment tools may be different in various populations. For the purpose of this study, we assess the agreement for a statin indication in German and Swiss subjects using the PROCAM/AGLA and the SCORE algorithm at various calibration thresholds.

A large number of cardiovascular events occur in seemingly healthy individuals. Atherosclerosis imaging can improve the outcome and treatment regime of such subjects. We aim to assess the predictive value of atherosclerosis imaging beyond traditional risk calculators in subjects aged 40-65 years. We compared PROCAM, SCORE and FRAM with carotid ultrasound (total plaque area, TPA) and arterial age (AA) was calculated in subjects without known cardiovascular diseases. Follow-up was obtained by phone or mail. In 2842 subjects (age 50 ± 8, 38% women) 154 (5.4%) cardiovascular events occurred (ASCVD: 41 myocardial infarctions, 16 strokes or TIA, 21 CABG, 41 PTCA, 35 coronary artery disease defined by invasive angiography) during a mean follow-up time of 5.9 (1-12) years. PROCAM risk was 5 ± 6%, SCORE risk 1.3 ± 1.6% and FRAM 10 ± 6%. Both for the primary outcome (AMI, STROKE/TIA, CABG) and the secondary outcome (adding CAD and PTCA) hazards increased significantly for TPA tertiles and AA groups between 1.4 (0.1-16.1) and 21.4 (2.8-163.6) after adjustment for risk factors (age, smoke, sex, systolic BP, lipids, BMI, medication in Model 1) and after adjustment for results from PROCAM, SCORE and FRAM (Model 2). Model performance was statistically improved regarding model fit in all models using TPA and AA. Net reclassification improvement (NRI) for PROCAM and SCORE using TPA tertiles or AA age groups increased significantly between 30% to 48%. TPA and AA added prognostic information to conventional risk equations, supporting the assessment of ASCVD risk with carotid ultrasound in subjects aged 40-65 years.

Carotid ultrasound allows rapid and reliable quantification of atherosclerosis in humans. Although the definition of carotid plaque is not uniform, intimal thickening of at least 1.5 mm is currently defined as plaque. Plaque can be easily quantified by tracing the plaque area, a software-independent low-cost technique. More sophisticated quantifications involve 3D volume acquisitions, which is software-dependent and not widely available. Carotid plaque has a higher prognostic impact than intimal thickening, and carotid plaque volume showed comparable prognostic power to coronary calcifications. According to the latest European Joint ESC guidelines, carotid artery scanning should be considered for adjusting the level of risk especially in intermediate-risk subjects. There are various methods to incorporate results from imaging into clinical decision making, such as using arterial age instead of chronological age in risk equations or post-test risk calculations using the sensitivity and the specificity of the results from a given carotid plaque burden. In subjects with low or intermediate cardiovascular risk, the search for atherosclerosis may be appropriate and ultrasound of the carotid or the femoral arteries could be the primary method applied (depending on local expertise). Assessment of carotid total plaque presence, progression, stability and regression over time may be a valuable clinical tool for optimising the intensity of preventive therapies.

A large number of cardiovascular events occur in seemingly healthy individuals. Atherosclerosis imaging can improve the outcome and treatment regime of such subjects. We aim to assess the predictive value of atherosclerosis imaging beyond traditional risk calculators in subjects aged 40–65 years. We compared PROCAM, SCORE and FRAM with carotid ultrasound (total plaque area, TPA) and arterial age (AA) was calculated in subjects without known cardiovascular diseases. Follow-up was obtained by phone or mail. In 2842 subjects (age 50 ± 8, 38% women) 154 (5.4%) cardiovascular events occurred (ASCVD: 41 myocardial infarctions, 16 strokes or TIA, 21 CABG, 41 PTCA, 35 coronary artery disease defined by invasive angiography) during a mean follow-up time of 5.9 (1−12) years. PROCAM risk was 5 ± 6%, SCORE risk 1.3 ± 1.6% and FRAM 10 ± 6%. Both for the primary outcome (AMI, STROKE/TIA, CABG) and the secondary outcome (adding CAD and PTCA) hazards increased significantly for TPA tertiles and AA groups between 1.4 (0.1–16.1) and 21.4 (2.8–163.6) after adjustment for risk factors (age, smoke, sex, systolic BP, lipids, BMI, medication in Model 1) and after adjustment for results from PROCAM, SCORE and FRAM (Model 2). Model performance was statistically improved regarding model fit in all models using TPA and AA. Net reclassification improvement (NRI) for PROCAM and SCORE using TPA tertiles or AA age groups increased significantly between 30% to 48%. TPA and AA added prognostic information to conventional risk equations, supporting the assessment of ASCVD risk with carotid ultrasound in subjects aged 40–65 years.

Objective About 50% of acute coronary syndromes occur in patients classified as being at low coronary risk. We aimed to assess the potential preventive benefit of carotid plaque imaging with ultrasound. Methods We assessed the prevalence of loldr arteries (vascular age g70 years; VA70) in 3248 healthy subjects aged 40n65 years from the Swiss region of Olten and the German region of Koblenz. We compared sensitivity, specificity and discriminatory performance of SCORE, PROCAM and AGLA coronary risk calculators to detect VA70 for various decision thresholds and performed reclassification and cost-efficiency analysis. Results VA70 was found in one out of eight subjects. Sensitivity for VA70 was 6% at the 10% AGLA threshold in women and 30% in men in the Olten area, which was confirmed for the Koblenz area with PROCAM (sensitivity 8% in women, 56% in men). Results were similar for SCORE. The discriminatory performance ranged between 0.69 and 0.82. Reclassification from low risk to a higher risk category occurred in 17n35% of patients. Analysis showed that carotid imaging for CHF 100 per person was highly cost efficient. Conclusions In subjects aged 40n65 years, the prevalence of old arteries is one out of eight and the detection rate of AGLA and SCORE is lower in women (6% for PROCAM) than for men (30%) at the 10% threshold. Carotid imaging may be used to reclassify subjects from low to intermediate or high cardiovascular risk. Our method is highly cost efficient at a price of CHF 100 per examination.

Preventive therapy in primary care is guided by risk thresholds for future cardiovascular events. We aimed to assess whether the sensitivity of various risk calculators for the detection of subclinical carotid atherosclerosis (TPA80) could be improved by lowering risk thresholds in younger age groups. We compared sensitivity, specificity, and discriminatory performance of SCORE, SCORE-HDL, PROCAM, AGLA, FRAM and PCE coronary risk calculators to detect total plaque area > 80 mm2 (TPA80), a coronary risk equivalent, in age groups 40–55, 56–65, 66–75 from Germany (DE, N = 2942) and Switzerland (CH, N = 2202) during the years 2002 to 2016. All calculators showed good to moderate discriminatory performance to detect TPA80 with AUC ranging from 0.74 (CH-AGLA) to 0.87 (DE- SCORE), but the sensitivity of high risk risk thresholds varied widely from 39% for DE-FRAM-CVD to 5% for CH-AGLA. Lowering of the risk threshold increased sensitivity substantially at the expense of minor losses in specificity, but the sensitivity generally remained, Highlights • Low sensitivity of European and American risk calculators in two independent populations • Relatively high prevalence of advanced carotid atherosclerosis in people aged 40–65 • New thresholds for intermediate or high risk in younger subjects

Background Takotsubo syndrome (TTS) is an acute cardiomyopathy associated with intense physical or emotional stress. The precise mechanisms of the disease remain unclear. The aim of this study was to study alterations in endothelial function, vascular compliance and structure and muscle sympathetic activity in the stable phase of the disease. Methods In this prospective observational study, patients with TTS and controls matched for age, sex, cardiovascular risk factors and medications were recruited. Flow-mediated vasodilatation (FMD) as a measure of endothelial dysfunction was the primary endpoint. Secondary endpoints included measurements of arterial stiffness, carotid atherosclerosis, quality of life and laboratory parameters. In a subset of patients, muscle sympathetic activity was measured before and after stress tests. Results The study included 22 TTS patients and 21 matched controls. A significant increase in endothelial dysfunction was seen in TTS compared to controls (FMD 3.4±2.4% vs. 4.8±1.9%, p =0.016). No significant differences in arterial stiffness, intima-media thickness, quality of life and laboratory markers including endothelin-1 were noted. TTS patients showed a reduced carotid total plaque area compared to controls (TPA 17.3±15.1 vs 24.7±12.8mm 2 , p =0.02). A trend of increased muscle sympathetic activity at rest was observed in TTS patients vs. controls (53.5±28.4 vs. 29.4±16.5 bursts/100 heart beats, p =0.09) with no significant differences in muscle sympathetic activity in response to stress. Conclusions Our findings underscore the importance of endothelial dysfunction in patients with TTS which may be involved in the pathophysiology of this syndrome. ClinicalTrials.gov identifier NCT01249599

Der Autor beurteilt die Qualitat von Public-Health-Studien der Schweiz als mangelhaft. Dies habe gravierende Folgen fur grundlegende Entscheidungen des Gesundheitswesens. Die Verfasser der von ihm exemplarisch ausgewahlten Studie nehmen im Anschluss zu den Vorwurfen Stellung.

Summary Aim: To determine population-attributable predicted coronary risk for major coronary risk factors and derive potential for reduction of global coronary risk. Methods: We obtained images of carotid atherosclerosis in practice-based subjects from self-referred CORDICARE (COR) and physician-referred KARDIOLAB (KAR) patients and calculated 10-year predicted coronary risk according to Swiss guidelines (AGLA) and via reclassification by post-test risk derived from ultrasound-measured total plaque area of the left and right carotid artery. We calculated predicted coronary risk reduction attributable to achievement of all AGLA goals, and for individual risk factors: smokers became nonsmokers, diabetic patients became nondiabetic patients, HDL level, if not already attained, was increased to 1.5 mmol/l, similarly, LDL level was lowered to 1.8 mmol/l, systolic blood pressure (BP) was lowered to 130 and then 10-year risk was recalculated for every subject. Results: COR included N = 900 (48% female), mean age 59 ± 9 years, KAR included N = 600 (35% female), mean age 58 ± 9 years. COR vs KAR: fewer smokers (12% vs 28%), fewer diabetic patients (3% vs 9%), higher systolic BP (133 ± 15 vs 128 ± 19) and higher HDL (1.6 ± 0.4 vs 1.4 ± 0.4 mmol/l), lower AGLA coronary risk (6.6 ± 7.0 vs 8.1 ± 8.6%), lower post-test risk (13.4 ± 14.1 vs 16.2 ± 16.4%). Predicted percent risk reductions for COR and KAR were: all AGLA treatment goals reached (–46% vs –51%), AGLA LDL goals met (–29% vs –29%), LDL ≤1.8 mmol/l (–52% vs –49%), no smokers (–7% vs –12%), HDL 1.50 mmol/l (–13% vs –21%), blood pressure ≤130 (–7% vs –6%), no diabetes (–1% vs –3%).

Cardiovascular risk assessment might be improved with the addition of emerging, new tests derived from atherosclerosis imaging, laboratory tests or functional tests. This article reviews relative risk, odds ratios, receiver-operating curves, posttest risk calculations based on likelihood ratios, the net reclassification improvement and integrated discrimination. This serves to determine whether a new test has an added clinical value on top of conventional risk testing and how this can be verified statistically. Two clinically meaningful examples serve to illustrate novel approaches. This work serves as a review and basic work for the development of new guidelines on cardiovascular risk prediction, taking into account emerging tests, to be proposed by members of the 'Taskforce on Vascular Risk Prediction' under the auspices of the Working Group 'Swiss Atherosclerosis' of the Swiss Society of Cardiology in the future.

Summary Purpose: We investigated whether the additional knowledge of lung uptake (lung-heart-ratio, LHR), transient ischaemic dilation (TID) and ungated left ventricular volumes (VOL) on top of perfusion defects (summed stress score [SSS]) derived from a single day rest-stress-technetium-99m SestaMIBI imaging protocol (sd-MPS) improves prediction of major cardiac events (MACE) in the long-term. SSS together with exercise SestaMIBI measurements provide important prognostic information. However, little is known about the incremental prognostic value of LHR, TID, and VOL. Methods: In a primary care outpatient setting, 519 patients underwent a supine bicycle electrocardiogram stress test (EST) as specified by an sd-MPS protocol. SSS, TID, and VOL were quantified with AutoQUANT (version 4.3). LHR was measured from a planar anterior image 4–6 minutes after peak exercise. The mean follow-up period was 6.1 ± 1.5 years. Results: The mean patient age was 59 ± 11 years. Of the 519 patients, 363 (70%) were male and 236 (45%) had known coronary artery disease. There were 44 major cardiac events, thereof 32 cardiac deaths and 12 nonfatal myocardial infarctions. Using Cox analysis for EST and scintigraphic variables, the independent predictors of MACE were male gender, the cardiac workload level reached during testing, and VOL. When a Cox-proportional Hazard model was used, LHR (X2 = 26.83, p = 0.04) and VOL (X2 = 69.55, p