Prognostic impact of carotid plaque imaging using total plaque area added to SCORE2 in middle-aged subjects: the ARteris Cardiovascular Outcome (ARCO) cohort study.

AIMS: Many cardiovascular events occur in seemingly healthy individuals.We set out to assess the predictive value of atherosclerosis imaging in combination with cardiovascular risk calculators in subjects aged 40-65 years. METHODS: We compared PROCAM (PROspective CArdiovascular Münster study), SCORE (Systematic COronary Risk Evaluation) and SCORE2 with carotid ultrasound (total plaque area, TPA) in subjects without cardiovascular disease. In this prospective cohort study, follow-up was obtained by phone or mail from patients; or from clinical records, if needed. RESULTS: In 2842 subjects (mean age 50±8 years; 38% women), cardiovascular events occurred in 154 (5.4%) of them over an mean follow-up period of 5.9 (range 1-12) years, specifically: 41 cases of AMI (myocardial infarction), 16 strokes, 21 CABG (coronary artery bypass grafting), 41 PTCA (percutaneous transluminal coronary angioplasty) and 35 CAD (coronary artery disease). Mean PROCAM risk was 5±6%, mean SCORE risk was 1.3±1.6% and mean SCORE2 risk was 5±3%. Both for the primary outcome (major adverse cardiovascular events, MACEs, i.e. AMI + strokes) and the secondary outcome (atherosclerotic cardiovascular disease, ASCVD, i.e. MACEs + CABG + CAD + PTCA), hazards increased significantly for TPA tertiles and SCORE2 post-test risk between 6.7 to 12.8 after adjustment for risk factors (age, smoke, sex, systolic blood pressure, lipids, medication) and after adjustment for results from PROCAM, SCORE and SCORE2. Model performance was statistically improved regarding model fit in all models using TPA. Net reclassification improvement for SCORE2 with TPA post-test risk increased significantly by 24% for MACEs (p = 0.01) and 39% for ASCVD (p <0.0001). CONCLUSIONS: Integration of TPA post-test risk into SCORE2 adds prognostic information, supporting the use of carotid ultrasound when assessing ASCVD risk in subjects aged 40-65 years.

[Ultrasound examination of the carotid artery for improved prediction of cardiovascular events and the effect of statin treatment in advanced atherosclerosis : An observational study]. / Ultraschalluntersuchung der A. carotis zur verbesserten Vorhersage kardiovaskulärer Ereignisse und der Wirkung einer Statinbehandlung bei fortgeschrittener Atherosklerose : Eine Beobachtungsstudie.

BACKGROUND: Advanced atherosclerosis of the carotid artery is associated with a high risk of cardiovascular diseases. It was investigated whether ultrasound provides a better prediction of cardiovascular events compared to the prospective cardiovascular Münster study (PROCAM) score and whether treatment of subjects with advanced atherosclerosis with statins improves the prognosis. METHOD: Between 2009 and 2016 a total of 4482 subjects (41% women) aged 35-65 years with no signs of cardiovascular disease underwent carotid artery ultrasound examination. Total plaque area (TPA) and maximum plaque thickness were measured. The PROCAM score was used to determine the cardiovascular risk. RESULTS: The median follow-up time was 77 months (6.4 years) for the men and 74 months (6.2 years) for the women. Events, such as myocardial infarction, ischemic stroke, coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA), occurred in 131 (3.4%) of the 3833 subjects with complete follow-up data. The prediction of cardiovascular events was better with ultrasound than with the PROCAM score. Ultrasound predicted 79.4% of 131 events and the PROCAM score predicted 22.9%. Treatment of subjects with advanced atherosclerosis (types III, IV b) with a statin significantly improved the prognosis. The event rate was 12.6% in men and women in the treated group vs. 31.5% (p < 0.0001) in the untreated group. Mortality (from any cause) was significantly lower in men treated with statins (p = 0.0148). CONCLUSION: The prediction of cardiovascular events was better with plaque burden measurements than with the PROCAM score. Treatment with statins in subjects with advanced carotid atherosclerosis (types III-IV b findings on ultrasound) significantly improved the prognosis in a nonrandomized observational study.

PROCAM based myocardial infarction risk in relation to global vascular disease risk: observations from the ARCO cohort study.

BACKGROUND: In Switzerland, risk for acute myocardial infarction (AMI) has been considered as equivalent to risk for atherosclerotic cardiovascular disease (ASCVD). This may lead to an underestimation of ASCVD risk and prevent adequate preventive measures. METHODS: We calculated correction factors for AMI risk to obtain ASCVD risk, tested predicting abilities of PROCAM/AGLA, SCORE, HerzCheck® and carotid plaque imaging (TPA) for ASCVD events in this cohort study and calculated survival curves, calibration and discrimination for ASCVD outcomes derived from PROCAM/AGLA, SCORE and TPA. RESULTS: In 2842 subjects (age 50 ± 8, 38% women), 154 (5.4%) cardiovascular events occurred (ASCVD: 41 myocardial infarctions, 16 strokes or TIAs, 21 CABG, 41 PTCA, 35 coronary artery disease [CAD]defined by invasive angiography) during a mean follow-up time of 5.9 (1-12) years. AGLA-AMI risk was well calibrated for AMI (15% underreported risk for the risk of AMI), but was poorly calibrated for ASCVD (stroke, CABG, PTCA or CAD, which contributed to the secondary outcome variables) with underreported risk resulting in a correction factor of 3.45. Discrimination was comparable for all risk calculators, but TPA outperformed risk calculators for survival using Cox proportional survival functions. Net reclassification improvement for PROCAM and SCORE using TPA tertiles groups increased significantly between 30% to 48%. CONCLUSIONS: PROCAM-derived risk calculators are well calibrated for the risk of AMI. PROCAM-AMI should be multiplied by a factor of 4 to obtain ASCVD. PROCAM-AMI does not represent global cardiovascular risk. Corresponding adjustments in the AGLA communication of risk appear necessary.

Effect of Statin Treatment in Patients With Advanced Carotid Atherosclerosis: An Observational Outcome Study.

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.

Cost-effectiveness analysis of statins in primary care: results from the Arteris 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.

Prediction of cardiovascular events with traditional risk equations and total plaque area of carotid atherosclerosis: The Arteris Cardiovascular Outcome (ARCO) cohort study.

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.

The Determination of the Plaque Burden on the Carotid Artery With Ultrasound Significantly Improves the Risk Prediction in Middle-Aged Subjects Compared to PROCAM: An Outcome Study.

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.

Sonographic assessment of carotid atherosclerosis: preferred risk indicator for future cardiovascular events?

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.

Advanced carotid atherosclerosis in middle-aged subjects: comparison with PROCAM and SCORE risk categories, the potential for reclassification and cost-efficiency of carotid ultrasound in the setting of primary care.

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 “old” arteries (vascular age ≥70 years; VA70) in 3248 healthy subjects aged 40–65 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 17–35% of patients. Analysis showed that carotid imaging for CHF 100 per person was highly cost efficient. CONCLUSIONS: In subjects aged 40–65 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.

Extensive carotid atherosclerosis and the diagnostic accuracy of coronary risk calculators.

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 < 45% at the 90% specificity threshold. Current risk thresholds of American and European coronary risk calculators have a low sensitivity to detect TPA80 in younger individuals.

Arterial age as a substitute for chronological age in the AGLA risk function could improve coronary risk prediction.

PRINCIPLES: As a result of the relatively low sensitivity of coronary risk charts, such as the Swiss coronary risk calculator (Arbeitsgruppe Lipide und Atherosklerose, AGLA), for detecting subjects with future myocardial infarction, the performance of arterial age (aa) as a surrogate marker for chronological age (ca) was tested. METHODS: In a practice based sample, burden of carotid plaque was obtained with ultrasound, using total plaque area (TPA). In this derivation cohort, sex-specific 5-year groups of mean TPA were calculated in subjects aged between 35 and 79 years. The arterial age formula was found by fitting an exponential function on these data. AGLAca and AGLAaa were tested externally for their ability to detect 13 myocardial infarctions in 684 subjects (validation cohort). RESULTS: The derivation cohort included 1,500 subjects (mean age 59 ± 9 years, mean TPA 54 ± 52 mm2, 5% diabetics, 43% women). Arterial age was found to be y = 5.4175e0.0426x in men and y = 4.1942e0.0392x in women. Mean 10-year AGLAca coronary risk was comparable to AGLAaa (8% ± 9% vs 9% ± 15%). Receiver operating characteristic (ROC) analysis of AGLAca and AGLAaa results showed areas under the curve of 0.65 (p = 0.041) and 0.78 (p <0.0001), respectively, (p = 0.041 for the difference = 0.13). This finding was also confirmed by a Cox proportional hazards regression model on patients' event-free survival (p = not significant for AGLAca, p = 0.0003 for AGLAaa). CONCLUSIONS: Arterial age derived from TPA could be used instead of chronological age in the AGLA coronary risk function. Further studies on the external validity and cost effectiveness of the additional ultrasound imaging study are necessary.

Antiplatelet resistance in outpatients with monitored adherence.

Antiplatelet resistance with aspirin and clopidogrel has been associated with clinical, cellular and pharmacogenetic factors; and non-adherence has been considered as a major contributor to resistance in outpatients. We aimed at assessing factors to resistance when adherence to the antiplatelet drugs and all other oral solid drugs was controlled for. In a pilot study, we tested arachidonic acid and/or ADP-induced in vitro platelet aggregation of 82 outpatients with chronic aspirin and/or clopidogrel treatment before and after a one-week period of measuring the patient's adherence with the polymedication electronic monitoring system (POEMS). Resistance was found in 20% (aspirin; n = 69) and 25% (clopidogrel; n = 32) of the patients after monitored adherence. Mean platelet aggregation was not (aspirin) or non-significantly (clopidogrel) lowered when compared to baseline. Diabetes mellitus and inflammation were consistently associated with resistance to both drugs, but CYP2C19 polymorphisms could not be confirmed as predictors of clopidogrel response. Electronically compiled multidrug dosing histories allowed the concomitant intake of high-dose lipophilic statins to be identified as a risk factor of impaired response to clopidogrel and revealed that exposure to further potential drug-drug interactions (DDIs) was too low for analysis. Multidrug adherence monitoring allowed thus dismissing non-adherence as a major contributor to resistance and inter-individual response variability in an outpatient setting. Additionally, it allowed analysing the impact of DDIs according to the actual exposure to the potentially interfering drugs. Further studies based on this methodology are essential to prevent misleading results due to incomplete adherence and gain additional insight into the impact of timing adherence on antiplatelet drug response.

Pattern of timing adherence could guide recommendations for personalized intake schedules.

Deviations in execution from the prescribed drug intake schedules (timing non adherence) are frequent and may pose a substantial risk for therapeutic failure. Simple methods to monitor timing adherence with multiple drugs are missing. A new technology, i.e., the polymedication electronic monitoring system (POEMS) attached to a multidrug punch card, was used in a clinical trial on outpatients with prescribed medicines for vascular risk reduction. The complete delineation of timing adherence allows for the calculation of objective adherence parameters and the linking of exposure with drug-drug interactions. A sub-analysis was performed on 68 patients, who were prescribed lipid lowering therapy. A smaller intake time variability of the lipid lowering drug was significantly associated with better levels of LDL-cholesterol, independently of the time of day. This finding may challenge current general recommendations for the timing of lipid lowering drugs' intake and substantiate that inter-individual differences in timing adherence may contribute to response variability. Thus, objective parameters based on multidrug adherence monitoring should be considered as independent variables in personalized medicine. In clinical practice, personalized intake recommendations according to patients' pattern of timing adherence may help to optimize the effectiveness of lipid lowering agents.

Improvement of cardiovascular risk prediction: time to review current knowledge, debates, and fundamentals on how to assess test characteristics.

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.