[The hidden risks of screening]. / De verhulde risico's van screening.

With screening the natural course of disease should be altered to reduce mortality from that disease. Screening offers very little benefit but has many disadvantages like false-positives, overdiagnosis and psychological distress. The advocates of screening overestimate the importance of the disease and the effects of screening but neglect the disadvantages. But also potential participants and medical doctors overestimate the effects of screening. Although considered important the still valuable criteria by Wilson and Jungner are neglected by researchers and committees that approve screening. Even in the situation that doctors disapprove screening healthy people are willing to undergo body-scans although nobody knows how to deal with the many abnormalities that are detected. Screening programmes should be evaluated against other interventions and not simply by making models with a lot of unproven assumptions. And most of all the potential participants have to informed about the potential disadvantages and the small effects on health.

Prediction of individualized lifetime benefit from cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people.

AIMS: The benefit an individual can expect from preventive therapy varies based on risk-factor burden, competing risks, and treatment duration. We developed and validated the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model for the estimation of individual-level 10 years and lifetime treatment-effects of cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people. METHODS AND RESULTS: Model development was conducted in the Multi-Ethnic Study of Atherosclerosis (n = 6715) using clinical predictors. The model consists of two complementary Fine and Gray competing-risk adjusted left-truncated subdistribution hazard functions: one for hard cardiovascular disease (CVD)-events, and one for non-CVD mortality. Therapy-effects were estimated by combining the functions with hazard ratios from preventive therapy trials. External validation was performed in the Atherosclerosis Risk in Communities (n = 9250), Heinz Nixdorf Recall (n = 4177), and the European Prospective Investigation into Cancer and Nutrition-Netherlands (n = 25 833), and Norfolk (n = 23 548) studies. Calibration of the LIFE-CVD model was good and c-statistics were 0.67-0.76. The output enables the comparison of short-term vs. long-term therapy-benefit. In two people aged 45 and 70 with otherwise identical risk-factors, the older patient has a greater 10-year absolute risk reduction (11.3% vs. 1.0%) but a smaller gain in life-years free of CVD (3.4 vs. 4.5 years) from the same therapy. The model was developed into an interactive online calculator available via www.U-Prevent.com. CONCLUSION: The model can accurately estimate individual-level prognosis and treatment-effects in terms of improved 10-year risk, lifetime risk, and life-expectancy free of CVD. The model is easily accessible and can be used to facilitate personalized-medicine and doctor-patient communication.

Prediction of Lifetime and 10-Year Risk of Cancer in Individual Patients With Established Cardiovascular Disease.

BACKGROUND: Cardiovascular disease (CVD) and cancer share many common risk factors; patients with CVD also may be at risk of developing cancer. OBJECTIVES: The aim of this study was to derive and externally validate prediction models for the estimation of lifetime and 10-year risk for total, colorectal, and lung cancer in patients with established CVD. METHODS: Data from patients with established CVD from the UCC-SMART cohort (N = 7,280) were used for model development, and from the CANTOS trial (N = 9,322) for model validation. Predictors were selected based on previously published cancer risk scores, clinical availability, and presence in the derivation dataset. Fine and Gray competing risk-adjusted lifetime models were developed for the outcomes total, colorectal, and lung cancer. RESULTS: Selected predictors were age, sex, smoking, weight, height, alcohol use, antiplatelet use, diabetes, and C-reactive protein. External calibration for the 4-year risk of lung, colorectal, and total cancer was reasonable in our models, as was discrimination with C-statistics of 0.74, 0.64, and 0.63, respectively. Median predicted lifetime and 10-year risks in CANTOS were 26% (range 1% to 52%) and 13% (range 1% to 31%) for total cancer; 4% (range 0% to 13%) and 2% (range 0% to 6%) for colorectal cancer; and 5% (range 0% to 37%) and 2% (range 0% to 24%) for lung cancer. CONCLUSIONS: Lifetime and 10-year risk of total, colorectal, and lung cancer can be estimated reasonably well in patients with established CVD with readily available clinical predictors. With additional study, these tools could be used in clinical practice to further aid in the emphasis of healthy lifestyle changes and to guide thresholds for targeted diagnostics and screening.

The relation between systemic inflammation and incident cancer in patients with stable cardiovascular disease: a cohort study.

AIMS: Low-grade inflammation, measured by elevated plasma concentrations of high-sensitive C-reactive protein (CRP), is a risk factor for cardiovascular disease (CVD). There is evidence that low-grade inflammation is also related to a higher risk of cancer. The present prospective cohort study evaluates the relation between low-grade systemic inflammation and risk of cancer in patients with stable CVD. METHODS AND RESULTS: In total, 7178 patients with stable CVD and plasma CRP levels ≤10 mg/L were included. Data were linked to the Dutch national cancer registry. Cox regression models were fitted to study the relation between CRP and incident CVD and cancer. After a median follow-up time of 8.3 years (interquartile range 4.6-12.3) 1072 incident cancer diagnoses were observed. C-reactive protein concentration was related to total cancer [hazard ratio (HR) 1.35; 95% confidence interval (CI) 1.10-1.65] comparing last quintile to first quintile of CRP. Especially lung cancer, independent of histopathological subtype, was related to CRP (HR 3.39; 95% CI 2.02-5.69 comparing last to first quintile of CRP). Incidence of epithelial neoplasms and especially squamous cell neoplasms were related to CRP concentration, irrespective of anatomical location. Sensitivity analyses after excluding patients with a cancer diagnosis within 1, 2, and 5 years of follow-up showed similar results. No effect modification was observed by smoking status or time since smoking cessation (P-values for interaction > 0.05). CONCLUSION: Chronic systemic low-grade inflammation, measured by CRP levels ≤10 mg/L, is a risk factor for incident cancer, markedly lung cancer, in patients with stable CVD. The relation between inflammation and incident cancer is seen in former and current smokers and is uncertain in never smokers.

Smoking cessation and risk of recurrent cardiovascular events and mortality after a first manifestation of arterial disease.

AIMS: To quantify the relation between smoking cessation after a first cardiovascular (CV) event and risk of recurrent CV events and mortality. METHODS: Data were available from 4,673 patients aged 61 ± 8.7 years, with a recent (≤1 year) first manifestation of arterial disease participating in the SMART-cohort. Cox models were used to quantify the relation between smoking status and risk of recurrent major atherosclerotic cardiovascular events (MACE including stroke, MI and vascular mortality) and mortality. In addition, survival according to smoking status was plotted, taking competing risk of non-vascular mortality into account. RESULTS: A third of the smokers stopped after their first CV event. During a median of 7.4 (3.7-10.8) years of follow-up, 794 patients died and 692 MACE occurred. Compared to patients who continued to smoke, patients who quit had a lower risk of recurrent MACE (adjusted HR 0.66, 95% CI 0.49-0.88) and all-cause mortality (adjusted HR 0.63, 95% CI 0.48-0.82). Patients who reported smoking cessation on average lived 5 life years longer and recurrent MACE occurred 10 years later. In patients with a first CV event >70 years, cessation of smoking had improved survival which on average was comparable to former or never smokers. CONCLUSIONS: Irrespective of age at first CV event, cessation of smoking after a first CV event is related to a substantial lower risk of recurrent vascular events and all-cause mortality. Since smoking cessation is more effective in reducing CV risk than any pharmaceutical treatment of major risk factors, it should be a key objective for patients with vascular disease.

Individual Treatment Effect Estimation of 2 Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation.

BACKGROUND: We aimed to estimate absolute benefit and harm from treatment with dabigatran in individual patients with atrial fibrillation, and to select the optimal dose for each individual. METHODS: We derived and validated a prediction model for ischemic stroke/systemic embolism and major bleeding in patients with atrial fibrillation from the 3 treatment arms of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy With Dabigatran Etexilate) (n=11 955 in derivation cohort, n=6158 in validation cohort). Readily available patient characteristics were included in Fine and Gray competing risk models (sex, age, smoking, antiplatelet drugs, previous vascular disease, diabetes mellitus, blood pressure, estimated glomerular filtration rate, and hemoglobin). Five-year risks for ischemic stroke/systemic embolism and major bleeding were estimated without anticoagulation therapy, and compared with high- and low-dose dabigatran. RESULTS: Model calibration was good, and discrimination was adequate with a c-statistic of 0.65 (95% CI, 0.62-0.70) for ischemic stroke/systemic embolism and 0.69 (95% CI, 0.66-0.71) for major bleeding. The 5-year absolute risk reduction for ischemic stroke/systemic embolism with dabigatran 150 mg twice daily ranged from <10% in 20% of patients to >25% in 14% of patients, and the 5-year absolute risk increase for major bleeding ranged from <5% in 53% of patients to 15% to 20% in 1% of patients. Comparing high-dose to low-dose dabigatran, the net benefit (absolute risk reduction minus absolute risk increase) was positive for 46% of patients. CONCLUSIONS: The absolute treatment benefits and harms of dabigatran in atrial fibrillation can be estimated based on readily available patient characteristics. Such treatment effect estimations can be used for shared decision making before starting dabigatran treatment and to determine the optimal dose. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Prediction of individual life-years gained without cardiovascular events from lipid, blood pressure, glucose, and aspirin treatment based on data of more than 500 000 patients with Type 2 diabetes mellitus.

AIMS: Although group-level effectiveness of lipid, blood pressure, glucose, and aspirin treatment for prevention of cardiovascular disease (CVD) has been proven by trials, important differences in absolute effectiveness exist between individuals. We aim to develop and validate a prediction tool for individualizing lifelong CVD prevention in people with Type 2 diabetes mellitus (T2DM) predicting life-years gained without myocardial infarction or stroke. METHODS AND RESULTS: We developed and validated the Diabetes Lifetime-perspective prediction (DIAL) model, consisting of two complementary competing risk adjusted Cox proportional hazards functions using data from people with T2DM registered in the Swedish National Diabetes Registry (n = 389 366). Competing outcomes were (i) CVD events (vascular mortality, myocardial infarction, or stroke) and (ii) non-vascular mortality. Predictors were age, sex, smoking, systolic blood pressure, body mass index, haemoglobin A1c, estimated glomerular filtration rate, non- high-density lipoprotein cholesterol, albuminuria, T2DM duration, insulin treatment, and history of CVD. External validation was performed using data from the ADVANCE, ACCORD, ASCOT and ALLHAT-LLT-trials, the SMART and EPIC-NL cohorts, and the Scottish diabetes register (total n = 197 785). Predicted and observed CVD-free survival showed good agreement in all validation sets. C-statistics for prediction of CVD were 0.83 (95% confidence interval: 0.83-0.84) and 0.64-0.65 for internal and external validation, respectively. We provide an interactive calculator at www.U-Prevent.com that combines model predictions with relative treatment effects from trials to predict individual benefit from preventive treatment. CONCLUSION: Cardiovascular disease-free life expectancy and effects of lifelong prevention in terms of CVD-free life-years gained can be estimated for people with T2DM using readily available clinical characteristics. Predictions of individual-level treatment effects facilitate translation of trial results to individual patients.

Intracranial Vessel Wall Lesions on 7T MRI (Magnetic Resonance Imaging).

Background and Purpose- Intracranial vessel wall lesions are a novel imaging marker of intracranial atherosclerosis (ICAS), but data on their occurrence and risk factors are lacking. Our aim was to study the frequency, distribution, and risk factors of intracranial vessel wall lesions on 7T magnetic resonance imaging in patients with a history of vascular disease. Methods- Within the SMART-MR study (Second Manifestations of Arterial Disease-Magnetic Resonance), cross-sectional analyses were performed in 130 patients (68±9 years) with assessable 7T intracranial vessel wall-magnetic resonance imaging data. Associations between vascular risk factors and ICAS burden, defined as the total number of vessel wall lesions, were estimated using linear regression analyses with ICAS burden as the dependent variable, adjusted for age and sex. Results- Ninety-six percent of patients had ≥1 vessel wall lesion. The mean±SD (range) ICAS burden was 8.5±5.7 (0-32) lesions. Significant associations were found between ICAS burden and age ( b=2.0 per +10 years; 95% CI, 0.81- 3.10), systolic blood pressure ( b=0.9 per +10 mm Hg; 95% CI, 0.27-1.42), diabetes mellitus ( b=3.2 for presence of diabetes mellitus; 95% CI, 0.79-5.72), hemoglobin A1c level ( b=1.2 per +1%; 95% CI, 0.19-2.26), apoB (apolipoprotein-B) ( b=4.7 per +1 g/L; 95% CI, 0.07-9.35), and hs-CRP (high-sensitivity C-reactive protein) level ( b=2.7 for hs-CRP >3 mg/L; 95% CI, 0.22-5.11). No significant associations were found with sex, smoking, and other lipid-factors. Conclusions- Vessel wall lesions are a novel and direct magnetic resonance imaging marker of ICAS. In this cohort, 96% of patients had at least 1 lesion on 7T vessel wall-magnetic resonance imaging. More lesions were found with older age, higher systolic blood pressure, diabetes mellitus, and higher levels of hemoglobin A1c, apoB, and hs-CRP.

Estimated Life Expectancy Without Recurrent Cardiovascular Events in Patients With Vascular Disease: The SMART-REACH Model.

Background In patients with vascular disease, risk models may support decision making on novel risk reducing interventions, such as proprotein convertase subtilisin/kexin type 9 inhibitors or anti-inflammatory agents. We developed and validated an innovative model to estimate life expectancy without recurrent cardiovascular events for individuals with coronary, cerebrovascular, and/or peripheral artery disease that enables estimation of preventive treatment effect in lifetime gained. Methods and Results Study participants originated from prospective cohort studies: the SMART (Secondary Manifestations of Arterial Disease) cohort and REACH (Reduction of Atherothrombosis for Continued Health) cohorts of 14 259 ( REACH Western Europe), 19 170 ( REACH North America) and 6959 ( SMART , The Netherlands) patients with cardiovascular disease. The SMART-REACH model to estimate life expectancy without recurrent events was developed in REACH Western Europe as a Fine and Gray competing risk model incorporating cardiovascular risk factors. Validation was performed in REACH North America and SMART . Outcomes were (1) cardiovascular events (myocardial infarction, stroke, cardiovascular death) and (2) noncardiovascular death. Predictors were sex, smoking, diabetes mellitus, systolic blood pressure, total cholesterol, creatinine, number of cardiovascular disease locations, atrial fibrillation, and heart failure. Calibration plots showed high agreement between estimated and observed prognosis in SMART and REACH North America. C-statistics were 0.68 (95% confidence interval, 0.67-0.70) in SMART and 0.67 (95% confidence interval, 0.66-0.68) in REACH North America. Performance of the SMART-REACH model was better compared with existing risk scores and adds the possibility of estimating lifetime gained by novel therapies. Conclusions The externally validated SMART-REACH model could be used for estimation of anticipated improvements in life expectancy without recurrent cardiovascular events in individual patients with cardiovascular disease in Western Europe and North America.

Combined use of polypill components in patients with type 2 diabetes mellitus.

Objectives A polypill containing aspirin, a statin and blood pressure (BP)-lowering agents has been proposed for the prevention of cardiovascular disease. To increase adherence and reduce the gaps between indicated and used therapy, a polypill might be of interest for patients with type 2 diabetes (T2DM). Our aim was to assess the prevalence of the combined use of polypill components in patients with T2DM over time. Methods The combined use of polypill components was assessed between 1996 and 2015 in patients with T2DM in the prospective SMART cohort ( n = 1828). The results were dichotomized into patients without ( n = 568) and with ( n = 1260) vascular disease. The patient characteristics associated with the use of polypill components were evaluated. Results In total, 19% of patients with T2DM without vascular disease received a statin and ≥2 BP-lowering agents ('cardiovascular polypill') and 13% received additional oral glucose-lowering therapy ('diabetic polypill'). Of the patients with T2DM with vascular disease, 42% received the combination of an antiplatelet agent, a statin and ≥2 BP-lowering agents ('cardiovascular polypill') and 30% received additional glucose-lowering therapy ('diabetic polypill'). The prevalence of the use of the cardiovascular and diabetic polypill combination has substantially increased between 1996 and 2015 to 36 and 32% in patients without vascular disease and to 67 and 57% in patients with vascular disease. Conclusions Patients with T2DM frequently use polypill components, often together with oral glucose-lowering agents, and this rate of use has increased steadily between 1996 and 2015. Introducing a cardiovascular or diabetic polypill for patients with T2DM seems to be highly relevant.

Higher Plasma Methylglyoxal Levels Are Associated With Incident Cardiovascular Disease and Mortality in Individuals With Type 2 Diabetes.

OBJECTIVE: Methylglyoxal (MGO) is a reactive dicarbonyl compound and a potential key player in diabetic cardiovascular disease (CVD). Whether plasma MGO levels are associated with CVD in type 2 diabetes is unknown. RESEARCH DESIGN AND METHODS: We included 1,003 individuals (mean ± SD age 59.1 ± 10.5 years, 69.3% male, and 61.6% with prior CVD) with type 2 diabetes from the Second Manifestations of ARTerial disease cohort (SMART). We measured plasma MGO levels and two other dicarbonyls (glyoxal [GO] and 3-deoxyglucosone [3-DG]) at baseline with mass spectrometry. Median follow-up of CVD events was 8.6 years. Data were analyzed with Cox regression with adjustment for sex, age, smoking, systolic blood pressure, total cholesterol, HbA1c, BMI, prior CVD, and medication use. Hazard ratios are expressed per SD Ln-transformed dicarbonyl. RESULTS: A total of 287 individuals suffered from at least one CVD event (n = 194 fatal events, n = 146 myocardial infarctions, and n = 72 strokes); 346 individuals died, and 60 individuals underwent an amputation. Higher MGO levels were associated with total (hazard ratio 1.26 [95% CI 1.11-1.42]) and fatal (1.49 [1.30-1.71]) CVD and with all-cause mortality (1.25 [1.11-1.40]), myocardial infarction (1.22 [1.02-1.45]), and amputations (1.36 [1.05-1.76]). MGO levels were not apparently associated with stroke (1.03 [0.79-1.35]). Higher GO levels were significantly associated with fatal CVD (1.17 [1.00-1.37]) but not with other outcomes. 3-DG was not significantly associated with any of the outcomes. CONCLUSIONS: Plasma MGO and GO levels are associated with cardiovascular mortality in individuals with type 2 diabetes. Influencing dicaronyl levels may therefore be a target to reduce CVD in type 2 diabetes.

[What are the benefits of MRI scans for people without symptoms?] / Wat levert MRI-onderzoek op bij mensen zonder klachten?

Commercial enterprises are selling MRI scans with the promise of longer and happier lives. A recent paper summarises the literature on this claim. We notice that, despite decades of this practice, very little careful research can be found. However, it does seem that serious issues are discovered in about 4% of people. When examining the supplementary materials, most of these issues turn out not to be of a serious nature, despite having been classified as such. Finally, scant and low-quality follow-up shows that only 0.4% of people end up with a serious diagnosis and we remain in the dark about whether the scans had any impact on their clinical outcomes. The paper also does not address the myriad of downsides related to scanning healthy people, such as needless distress and interventions for false-positives. We propose to incentivise proper collection of data by transferring the cost of following up on false-negative findings from the healthcare system to the MRI companies.

Incidence of cardiovascular events and vascular interventions in patients with type 2 diabetes.

OBJECTIVE: Diabetes mellitus is associated with an increased risk for cardiovascular morbidity and mortality. The vascular burden in terms of incidence of cardiovascular events (CVE) and vascular interventions is however poorly quantified. In this study we evaluated the incidence rates of CVE and vascular interventions in patients with type 2 diabetes (T2DM) with and without cardiovascular disease (CVD) in comparison to patients without type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort of 9.808 high-risk patients with and without cardiovascular disease and type 2 diabetes originated from the ongoing, single-center prospective SMART (Second Manifestations of ARTerial disease) cohort, the number and incidence rates of CVE and interventions were calculated. The incidence rates were adjusted for confounders using Poisson regression models. CVE were defined as vascular death, stroke and myocardial infarction (MI). Interventions were defined as percutaneous coronary intervention, coronary artery bypass grafting, percutaneous transluminal angioplasty or stenting of the peripheral arteries and amputation. RESULTS: Patients with T2DM and CVD had a 4-fold higher incidence rate of CVE and a 8-fold higher incidence rate of vascular interventions compared to high-risk patients without T2DM and CVD after adjusting for confounders. The incidence rate for the composite of non-fatal MI, non-fatal stroke and vascular death was 5.8 per 1000person-years in patients without T2DM or CVD at baseline, 15.2 per 1000person-years in patients with T2DM but without CVD at baseline, 26.0 per 1000person-years in patients without T2DM but with CVD and 40.7 per 1000person-years in patients with both T2DM and CVD at baseline. A similar increasing incidence rate was seen for all vascular interventions from patients without T2DM or CVD to patients with both T2DM and CVD. CONCLUSIONS: Patients with type 2 diabetes or CVD are subject to an increased incidence of cardiovascular events and interventions compared to high-risk patients without type 2 diabetes or vascular disease. Patients with type 2 diabetes and CVD have the highest incidence of new cardiovascular diseases and vascular interventions when compared to patients without type 2 diabetes and CVD. These results underline the need for optimal risk factor treatment as well as the need for new prevention and treatment strategies in this very high risk population.

Risk Factors for Recurrent Cardiovascular Events Before Age 65 Years or Within 2.5 Years of a Recent First Cardiovascular Event.

The aim of this study was to quantify the relation between classical risk factors (smoking, diabetes, BMI, waist circumference, blood pressure, and lipids), risk factor targets, and risk of recurrent major atherosclerotic cardiovascular events (MACE). This was first done for recurrent MACE ≤65 years in patients aged <60 years and second for recurrent MACE ≤2.5 years after a first cardiovascular event. Data were used from the Second Manifestations of Arterial Disease study (n = 5,115), a prospective cohort of patients with a recent (≤1 year) first cardiovascular event. During follow-up, 746 recurrent MACE occurred. Smoking (hazard ratio [HR] 1.43, 95% CI 1.11 to 1.84), diabetes (HR 1.83, 95% CI 1.11 to 1.84), diastolic blood pressure (>90 vs 70 to 90 mm Hg, HR 1.54, 95% CI 1.15 to 2.07), and high-density lipoprotein cholesterol (≤1.0 vs >1.0 mmol/L, HR 1.34, 95% CI 1.03 to 1.76) were related to increased risk of recurrent MACE ≤65 years in patients aged <60 years. Smoking (HR 1.65, 95% CI 1.23 to 2.22), physical inactivity (highest vs lowest tertile, HR 1.48, 95% CI 1.05 to 2.09), body mass index (per kg/m2, HR 1.04, 95% CI 1.00 to 1.08), diastolic blood pressure (>90 vs 70 to 90 mm Hg, HR 1.61, 95% CI 1.17 to 2.21), low-density lipoprotein cholesterol (per mmol/L, HR 1.18, 95% CI 1.02 to 1.37), and non-high-density lipoprotein cholesterol (per mmol/L, HR 1.15, 95% CI 1.03 to 1.28) were related to recurrent MACE ≤2.5 years of follow-up. In conclusion, in patients with a recent cardiovascular event, smoking, blood pressure, and lipids are related to increased risk of recurrent cardiovascular events at young age or within a short time span, and intensive treatment of modifiable risk factors may contribute to prevent recurrent MACE in these patients.

Identification of vascular patients at very high risk for recurrent cardiovascular events: validation of the current ACC/AHA very high risk criteria.

AIMS: To validate and assess performance of the current ACC/AHA very high risk criteria in patients with clinically manifest arterial disease. METHODS AND RESULTS: Data were used from the SMART study (n = 7216) and REACH Registry (n = 48 322), two prospective cohorts of patients with manifest atherosclerotic arterial disease. Prevalence and incidence rates of recurrent major adverse cardiovascular events (MACE) were calculated, according to the ACC/AHA VHR criteria (cardiovascular disease combined with diabetes, smoking, dyslipidaemia, and/or recent recurrent coronary events). Performance of the ACC/AHA criteria was compared with single very high risk factors in terms of C-statistics and Net Reclassification Index. All patients were at VHR according to the ESC guidelines (incidence of recurrent MACE in SMART was 2.4/100PY, with 95% CI 2.3-2.5/100PY and in REACH 5.1/100PY with 95% CI 5.0-5.3/100PY). In SMART 57% of the patients were at VHR according to the ACC/AHA criteria (incidence of recurrent MACE 2.7/100PY, 95% CI 2.5-2.9/100PY) and in REACH this was 64% (5.9/100PY, 95% CI 5.7-6.1/100PY). The C-statistic for the ACC/AHA VHR criteria was 0.53 in REACH and 0.54 in SMART. Very high risk factors with comparable or slightly better performance were eGFR < 45, polyvascular disease and age >70 years. Around two third of the patients meeting the ACC/AHA VHR criteria had a predicted 10-year risk of recurrent MACE <30%. CONCLUSION: The ACC/AHA VHR criteria have limited discriminative power. Identifying patients with clinically manifest arterial disease at VHR for recurrent vascular events using eGFR <45, polyvascular disease, or age >70 years performs as well as the ACC/AHA VHR criteria.

Do Lacunar Infarcts Have Different Aetiologies? Risk Factor Profiles of Lacunar Infarcts in Deep White Matter and Basal Ganglia: The Second Manifestations of ARTerial Disease-Magnetic Resonance Study.

BACKGROUND: Evidence suggests that lacunar infarcts have different etiologies, possibly related to their anatomical location and vascular territory. We investigated the risk factor profiles of patients with new lacunar infarcts in the basal ganglia and deep white matter. METHODS: Within the Second Manifestations of ARTerial disease-Magnetic Resonance study, a prospective cohort on brain changes on MRI in patients with symptomatic atherosclerotic disease, 679 patients (57 ± 9 years) had vascular screening and MRI at baseline and after a mean follow-up of 3.9 years. We investigated the association between vascular risk factors at baseline and appearance of new lacunar infarcts in the basal ganglia and deep white matter at follow-up. RESULTS: New lacunar infarcts appeared in 44 patients in the basal ganglia and in 37 patients in the deep white matter. In multivariable analysis, older age, history of cerebrovascular disease, and baseline white matter hyperintensity (WMH) volume were associated with increased risk of new lacunar infarcts in both locations. Hyperhomocysteinemia was associated with increased risk of lacunar infarcts in the basal ganglia (relative risk [RR] 2.0; 95% CI 1.0-4.2), whereas carotid stenosis >70% (RR 2.5; 95% CI 1.2-5.0), smoking (per 10 pack-year: RR 1.1; 95% CI 1.0-1.3), hypertension (RR 3.4; 95% CI 1.2-9.7), and progression of WMH volume (RR 2.4; 95% CI 1.1-5.2) were associated with increased risk of lacunar infarcts in the deep white matter. CONCLUSIONS: The different risk factor profiles for new lacunar infarcts in basal ganglia and deep white matter indicate different etiologies. The independent association between progression of WMH and new deep white matter lacunar infarcts suggest a common etiology for these radiological abnormalities.

Automatic Coronary Artery Calcium Scoring on Radiotherapy Planning CT Scans of Breast Cancer Patients: Reproducibility and Association with Traditional Cardiovascular Risk Factors.

OBJECTIVES: Coronary artery calcium (CAC) is a strong and independent predictor of cardiovascular disease (CVD) risk. This study assesses reproducibility of automatic CAC scoring on radiotherapy planning computed tomography (CT) scans of breast cancer patients, and examines its association with traditional cardiovascular risk factors. METHODS: This study included 561 breast cancer patients undergoing radiotherapy between 2013 and 2015. CAC was automatically scored with an algorithm using supervised pattern recognition, expressed as Agatston scores and categorized into five categories (0, 1-10, 11-100, 101-400, >400). Reproducibility between automatic and manual expert scoring was assessed in 79 patients with automatically determined CAC above zero and 84 randomly selected patients without automatically determined CAC. Interscan reproducibility of automatic scoring was assessed in 294 patients having received two scans (82% on the same day). Association between CAC and CVD risk factors was assessed in 36 patients with CAC scores >100, 72 randomly selected patients with scores 1-100, and 72 randomly selected patients without CAC. Reliability was assessed with linearly weighted kappa and agreement with proportional agreement. RESULTS: 134 out of 561 (24%) patients had a CAC score above zero. Reliability of CVD risk categorization between automatic and manual scoring was 0.80 (95% Confidence Interval (CI): 0.74-0.87), and slightly higher for scans with breath-hold. Agreement was 0.79 (95% CI: 0.72-0.85). Interscan reliability was 0.61 (95% CI: 0.50-0.72) with an agreement of 0.84 (95% CI: 0.80-0.89). Ten out of 36 (27.8%) patients with CAC scores above 100 did not have other cardiovascular risk factors. CONCLUSIONS: Automatic CAC scoring on radiotherapy planning CT scans is a reliable method to assess CVD risk based on Agatston scores. One in four breast cancer patients planned for radiotherapy have elevated CAC score. One in three patients with high CAC scores don't have other CVD risk factors and wouldn't have been identified as high risk.

Distribution of Estimated 10-Year Risk of Recurrent Vascular Events and Residual Risk in a Secondary Prevention Population.

BACKGROUND: Among patients with clinically manifest vascular disease, the risk of recurrent vascular events is likely to vary. We assessed the distribution of estimated 10-year risk of recurrent vascular events in a secondary prevention population. We also estimated the potential risk reduction and residual risk that can be achieved if patients reach guideline-recommended risk factor targets. METHODS: The SMART score (Second Manifestations of Arterial Disease) for 10-year risk of myocardial infarction, stroke, or vascular death was applied to 6904 patients with vascular disease. The risk score was externally validated in 18 436 patients with various manifestations of vascular disease from the TNT (Treating to New Targets), IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), and CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trials. The residual risk at guideline-recommended targets was estimated by applying relative risk reductions from meta-analyses to the estimated risk for targets for systolic blood pressure, low-density lipoprotein cholesterol, smoking, physical activity, and use of antithrombotic agents. RESULTS: The external performance of the SMART risk score was reasonable, apart from overestimation of risk in patients with 10-year risk >40%. In patients with various manifestations of vascular disease, median 10-year risk of a recurrent major vascular event was 17% (interquartile range, 11%-28%), varying from <10% in 18% to >30% in 22% of the patients. If risk factors were at guideline-recommended targets, the residual 10-year risk would be <10% in 47% and >30% in 9% of the patients (median, 11%; interquartile range, 7%-17%). CONCLUSIONS: Among patients with vascular disease, there is very substantial variation in estimated 10-year risk of recurrent vascular events. If all modifiable risk factors were at guideline-recommended targets, half of the patients would have a 10-year risk <10%. These data suggest that even with optimal treatment, many patients with vascular disease will remain at >20% and even >30% 10-year risk, clearly delineating an area of substantial unmet medical need.

Novel Biomarkers to Improve the Prediction of Cardiovascular Event Risk in Type 2 Diabetes Mellitus.

BACKGROUND: We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors. METHODS AND RESULTS: We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition-NL (EPIC-NL). The associations of 23 biomarkers (adiponectin, C-reactive protein, epidermal-type fatty acid binding protein, heart-type fatty acid binding protein, basic fibroblast growth factor, soluble FMS-like tyrosine kinase-1, soluble intercellular adhesion molecule-1 and -3, matrix metalloproteinase [MMP]-1, MMP-3, MMP-9, N-terminal prohormone of B-type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E-selectin, P-selectin, tissue inhibitor of MMP-1, thrombomodulin, soluble vascular cell adhesion molecule-1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c-statistic and net reclassification index (NRI; continuous and based on 10-year risk strata 0-10%, 10-20%, 20-30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N-terminal prohormone of B-type natriuretic peptide, osteopontin, and MMP-3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c-statistic with 0.03 (95% CI 0.01-0.05), and the continuous NRI was 0.37 (95% CI 0.21-0.52). In EPIC-NL, the multimarker model increased the c-statistic with 0.03 (95% CI 0.00-0.03), and the continuous NRI was 0.44 (95% CI 0.23-0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03-0.21) in SMART and 0.07 (95% CI -0.04-0.17) in EPIC-NL. CONCLUSIONS: Of the 23 evaluated biomarkers from different pathophysiological pathways, N-terminal prohormone of B-type natriuretic peptide, osteopontin, MMP-3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited.