[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.

Population median imputation was noninferior to complex approaches for imputing missing values in cardiovascular prediction models in clinical practice.

OBJECTIVES: To compare the validity and robustness of five methods for handling missing characteristics when using cardiovascular disease risk prediction models for individual patients in a real-world clinical setting. STUDY DESIGN AND SETTING: The performance of the missing data methods was assessed using data from the Swedish National Diabetes Registry (n = 419,533) with external validation using the Scottish Care Information - diabetes database (n = 226,953). Five methods for handling missing data were compared. Two methods using submodels for each combination of available data, two imputation methods: conditional imputation and median imputation, and one alternative modeling method, called the naïve approach, based on hazard ratios and populations statistics of known risk factors only. The validity was compared using calibration plots and c-statistics. RESULTS: C-statistics were similar across methods in both development and validation data sets, that is, 0.82 (95% CI 0.82-0.83) in the Swedish National Diabetes Registry and 0.74 (95% CI 0.74-0.75) in Scottish Care Information-diabetes database. Differences were only observed after random introduction of missing data in the most important predictor variable (i.e., age). CONCLUSION: Validity and robustness of median imputation was not dissimilar to more complex methods for handling missing values, provided that the most important predictor variables, such as age, are not missing.

Impact of a Patient's Baseline Risk on the Relative Benefit and Harm of a Preventive Treatment Strategy: Applying Trial Results in Clinical Decision Making.

Background For translating an overall trial result into an individual patient's expected absolute treatment effect, differences in relative treatment effect between patients need to be taken into account. The aim of this study was to evaluate whether relative treatment effects of medication in 2 large contemporary trials are influenced by multivariable baseline risk of an individual patient. Methods and Results In 9361 patients from SPRINT (Systolic Blood Pressure Intervention Trial), risk of major adverse cardiovascular events was assessed using a newly derived risk model. In 18 133 patients from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial, risk of stroke or systemic embolism and major bleeding was assessed using the Global Anticoagulant Registry in the Field-Atrial Fibrillation risk model. Heterogeneity of trial treatment effect was assessed using Cox models of trial allocation, model linear predictor, and their interaction. There was no significant interaction between baseline risk and relative treatment effect from intensive blood pressure lowering in SPRINT (P=0.92) or from dabigatran compared with warfarin for stroke or systemic embolism in the RE-LY trial (P=0.71). There was significant interaction between baseline risk and treatment effect from dabigatran versus warfarin in the RE-LY trial (P<0.001) for major bleeding. Quartile-specific hazard ratios for bleeding ranged from 0.40 (95% CI, 0.26-0.61) to 1.04 (95% CI, 0.83-1.03) for dabigatran, 110 mg, and from 0.61 (95% CI, 0.42-0.88) to 1.20 (95% CI, 0.97-1.50) for dabigatran, 150 mg, compared with warfarin. Conclusions Effect modification of relative treatment effect by individual baseline event risk should be assessed systematically in randomized clinical trials using multivariate risk prediction, not only in terms of treatment efficacy but also for important treatment harms, as a prespecified analysis. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01206062.

Communicating personalised statin therapy-effects as 10-year CVD-risk or CVD-free life-expectancy: does it improve decisional conflict? Three-armed, blinded, randomised controlled trial.

OBJECTIVE: To determine whether communicating personalised statin therapy-effects obtained by prognostic algorithm leads to lower decisional conflict associated with statin use in patients with stable cardiovascular disease (CVD) compared with standard (non-personalised) therapy-effects. DESIGN: Hypothesis-blinded, three-armed randomised controlled trial SETTING AND PARTICIPANTS: 303 statin users with stable CVD enrolled in a cohort INTERVENTION: Participants were randomised in a 1:1:1 ratio to standard practice (control-group) or one of two intervention arms. Intervention arms received standard practice plus (1) a personalised health profile, (2) educational videos and (3) a structured telephone consultation. Intervention arms received personalised estimates of prognostic changes associated with both discontinuation of current statin and intensification to the most potent statin type and dose (ie, atorvastatin 80 mg). Intervention arms differed in how these changes were expressed: either change in individual 10-year absolute CVD risk (iAR-group) or CVD-free life-expectancy (iLE-group) calculated with the SMART-REACH model (http://U-Prevent.com). OUTCOME: Primary outcome was patient decisional conflict score (DCS) after 1 month. The score varies from 0 (no conflict) to 100 (high conflict). Secondary outcomes were collected at 1 or 6 months: DCS, quality of life, illness perception, patient activation, patient perception of statin efficacy and shared decision-making, self-reported statin adherence, understanding of statin-therapy, post-randomisation low-density lipoprotein cholesterol level and physician opinion of the intervention. Outcomes are reported as median (25th- 75th percentile). RESULTS: Decisional conflict differed between the intervention arms: median control 27 (20-43), iAR-group 22 (11-30; p-value vs control 0.001) and iLE-group 25 (10-31; p-value vs control 0.021). No differences in secondary outcomes were observed. CONCLUSION: In patients with clinically manifest CVD, providing personalised estimations of treatment-effects resulted in a small but significant decrease in decisional conflict after 1 month. The results support the use of personalised predictions for supporting decision-making. TRIAL REGISTRATION: NTR6227/NL6080.

Added value of cardiovascular calcifications for prediction of recurrent cardiovascular events and cardiovascular interventions in patients with established cardiovascular disease.

The purpose is to investigate the added prognostic value of coronary artery calcium (CAC), thoracic aortic calcium (TAC), and heart valve calcium scores for prediction of a combined endpoint of recurrent major cardiovascular events and cardiovascular interventions (MACE +) in patients with established cardiovascular disease (CVD). In total, 567 patients with established CVD enrolled in a substudy of the UCC-SMART cohort, entailing cardiovascular CT imaging and calcium scoring, were studied. Five Cox proportional hazards models for prediction of 4-year risk of MACE + were developed; traditional CVD risk predictors only (model I), with addition of CAC (model II), TAC (model III), heart valve calcium (model IV), and all calcium scores (model V). Bootstrapping was performed to account for optimism. During a median follow-up of 3.43 years (IQR 2.28-4.74) 77 events occurred (MACE+). Calibration of predicted versus observed 4-year risk for model I without calcium scores was good, and the c-statistic was 0.65 (95%CI 0.59-0.72). Calibration for models II-V was similar to model I, and c-statistics were 0.67, 0.65, 0.65, and 0.68 for model II, III, IV, and V, respectively. NRIs showed improvement in risk classification by model II (NRI 15.24% (95%CI 0.59-29.39)) and model V (NRI 20.00% (95%CI 5.59-34.92)), but no improvement for models III and IV. In patients with established CVD, addition of the CAC score improved performance of a risk prediction model with classical risk factors for the prediction of the combined endpoint MACE+ . Addition of the TAC or heart valve score did not improve risk predictions.

Intracranial atherosclerosis on 7T MRI and cognitive functioning: The SMART-MR study.

OBJECTIVE: To investigate the association between intracranial atherosclerosis (ICAS) and cognitive functioning in patients with a history of vascular disease. METHODS: Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed in 130 patients (mean ± SD age 68 ± 9 years) with 7T vessel wall MRI data. Vessel wall lesions were rated according to established criteria and summed into a circulatory and artery-specific ICAS burden. Associations between ICAS burden and Z scores of memory, executive functioning, working memory, and processing speed were estimated using linear regression analyses adjusted for age, sex, education, reading ability, and vascular risk factors. RESULTS: A total of 125 patients (96%) had ≥1 vessel wall lesion; the mean ICAS burden was 8.5 ± 5.7. A statistically nonsignificant association was found between total ICAS burden and memory (b = -0.03 per +1 lesion; 95% confidence interval [CI] -0.05 to 0.00). No associations were found for the other domains. A statistically significant association was found for ICAS burden of the posterior cerebral artery (PCA) and memory (b = -0.12 per +1 lesion; 95% CI -0.23 to -0.01) and executive functioning (b = -0.10 per +1 lesion; 95% CI -0.19 to -0.01). Statistically nonsignificant associations were found for the anterior cerebral artery (ACA) burden and memory (b = -0.13 per +1 lesion; 95% CI -0.26 to 0.01) and executive functioning (b = -0.11 per +1 lesion; 95% CI -0.22 to 0.01). Additional adjustments for large infarcts, white matter hyperintensities, lacunes, and ≥50% carotid stenosis produced similar results. CONCLUSIONS: Our results suggest an artery-specific vulnerability of memory and executive functioning to ICAS, possibly due to strategic brain regions involved with these cognitive domains, which are located in the arterial territory of the PCA and ACA.

Development of a clinical decision tool to reduce diagnostic testing for primary aldosteronism in patients with difficult-to-control hypertension.

BACKGROUND: Satisfactory tools to preclude low-risk patients from intensive diagnostic testing for primary aldosteronism (PA) are lacking. Therefore, we aimed to develop a decision tool to determine which patients with difficult-to-control hypertension have a low probability of PA, thereby limiting the exposure to invasive testing while at the same time increasing the efficiency of testing in the remaining patients. METHODS: Data from consecutive patients with difficult-to-control hypertension, analysed through a standardized diagnostic protocol between January 2010 and October 2017 (n = 824), were included in this cross-sectional study. PA was diagnosed by a combined approach: 1) elevated aldosterone-to-renin ratio (> 5.0 pmol/fmol/s), confirmed with 2) non-suppressible aldosterone after standardized saline infusion (≥280 pmol/L). Multivariable logistic regression analyses including seven pre-specified clinical variables (age, systolic blood pressure, serum potassium, potassium supplementation, serum sodium, eGFR and HbA1c) was performed. After correction for optimism, test reliability, discriminative performance and test characteristics were determined. RESULTS: PA was diagnosed in 40 (4.9%) of 824 patients. Predicted probabilities of PA agreed well with observed frequencies and the c-statistic was 0.77 (95% confidence interval (95%CI) 0.70-0.83). Predicted probability cut-off values of 1.0-2.5% prevented unnecessary testing in 8-32% of the patients with difficult-to-control hypertension, carrying sensitivities of 0.98 (95%CI 0.96-0.99) and 0.92 (0.83-0.97), and negative predictive values of 0.99 (0.98-1.00) and 0.99 (0.97-0.99). CONCLUSIONS: With a decision tool, based on seven easy-to-measure clinical variables, patients with a low probability of PA can be reliably selected and a considerable proportion of patients with difficult-to-control hypertension can be spared intensive diagnostic testing.

Would treatment decisions about secondary prevention of CVD based on estimated lifetime benefit rather than 10-year risk reduction be cost-effective?

OBJECTIVE: To test the hypothesis that treatment decisions (treatment with a PCSK9-mAb versus no treatment) are both more effective and more cost-effective when based on estimated lifetime benefit than when based on estimated risk reduction over 10 years. METHODS: A microsimulation model was constructed for 10,000 patients with stable cardiovascular disease (CVD). Costs and quality-adjusted life years (QALYs) due to recurrent cardiovascular events and (non)vascular death were estimated for lifetime benefit-based compared to 10-year risk-based treatment, with PCSK9 inhibition as an illustration example. Lifetime benefit in months gained and 10-year absolute risk reduction were estimated using the SMART-REACH model, including an individualized treatment effect of PCSK9 inhibitors based on baseline low-density lipoprotein cholesterol. For the different numbers of patients treated (i.e. the 5%, 10%, and 20% of patients with the highest estimated benefit of both strategies), cost-effectiveness was assessed using the incremental cost-effectiveness ratio (ICER), indicating additional costs per QALY gain. RESULTS: Lifetime benefit-based treatment of 5%, 10%, and 20% of patients with the highest estimated benefit resulted in an ICER of €36,440/QALY, €39,650/QALY, or €41,426/QALY. Ten-year risk-based treatment decisions of 5%, 10%, and 20% of patients with the highest estimated risk reduction resulted in an ICER of €48,187/QALY, €53,368/QALY, or €52,390/QALY. CONCLUSION: Treatment decisions (treatment with a PCSK9-mAb versus no treatment) are both more effective and more cost-effective when based on estimated lifetime benefit than when based on estimated risk reduction over 10 years.

Multifocal cardiovascular calcification in patients with established cardiovascular disease; prevalence, risk factors, and relation with recurrent cardiovascular disease.

AIMS: The aim is to investigate (multifocal) cardiovascular calcification in patients with established cardiovascular disease (CVD), regarding prevalence, risk factors, and relation with recurrent CVD or vascular interventions. Coronary artery calcification (CAC), thoracic aortic calcification (TAC) (including ascending aorta, aortic arch, descending aorta), mitral annular calcification (MAC), and aortic valve calcification (AVC) are studied. METHODS: The study concerned 568 patients with established CVD enrolled in the ORACLE cohort. All patients underwent computed tomography. Prevalence of site-specific and multifocal calcification was determined. Ordinal regression analyses were performed to quantify associations of risk factors with cardiovascular calcification, and Cox regression analyses to determine the relation between calcium scores and recurrent CVD or vascular interventions. RESULTS: Calcification was multifocal in 76% (N = 380) of patients with calcification. Age (per SD) was associated with calcification at all locations (lowest OR 2.17; 99%CI 1.54-3.11 for ascending aorta calcification). Diabetes mellitus and systolic blood pressure were associated with TAC, whereas male sex was a determinant of CAC. TAC and CAC were related to the combined endpoint CVD or vascular intervention (N = 68). In a model with all calcium scores combined, only CAC was related to the combined outcome (HR 1.39; 95%CI 1.15-1.68). CONCLUSION: Cardiovascular calcification is generally multifocal in patients with established CVD. Differences in associations between risk factors and calcification at various anatomical locations stress the divergence in pathophysiological pathways. CAC is most strongly related to recurrent CVD or vascular interventions independent of traditional risk factors, and independent of heart valve and thoracic aorta calcification.

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.

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.

MRI phenotypes of the brain are related to future stroke and mortality in patients with manifest arterial disease: The SMART-MR study.

Neurodegenerative and neurovascular diseases lead to heterogeneous brain abnormalities. A combined analysis of these abnormalities by phenotypes of the brain might give a more accurate representation of the underlying aetiology. We aimed to identify different MRI phenotypes of the brain and assessed the risk of future stroke and mortality within these subgroups. In 1003 patients (59 ± 10 years) from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, different quantitative 1.5T brain MRI markers were used in a hierarchical clustering analysis to identify 11 distinct subgroups with a different distribution in brain MRI markers and cardiovascular risk factors, and a different risk of stroke (Cox regression: from no increased risk compared to the reference group with relatively few brain abnormalities to HR = 10.34; 95% CI 3.80↔28.12 for the multi-burden subgroup) and mortality (from no increased risk compared to the reference group to HR = 4.00; 95% CI 2.50↔6.40 for the multi-burden subgroup). In conclusion, within a group of patients with manifest arterial disease, we showed that different MRI phenotypes of the brain can be identified and that these were associated with different risks of future stroke and mortality. These MRI phenotypes can possibly classify individual patients and assess their risk of future stroke and mortality.

Are there gender disparities in symptom presentation or triage of patients with chest discomfort at primary care out-of-hours services? An observational study.

OBJECTIVES: Previous hospital-based studies have suggested delayed recognition of acute coronary syndrome (ACS) in women. We wanted to assess differences in symptom presentation or triage among women and men who contacted primary care out-of-hours services (OHS) for chest discomfort. DESIGN: Retrospective observational study. SETTING: Primary care OHS. PARTICIPANTS: 276 women and 242 men with chest discomfort who contacted a primary care OHS in the Netherlands in 2013 and 2014. MAIN OUTCOME MEASURES: Differences between women and men regarding symptom presentation and urgency allocation. RESULTS: 8.4% women and 14.0% men had ACS. Differences in symptoms between patients with and without ACS were in general small, for both women and men. In women with ACS compared with women without ACS, mean duration of telephone calls was discriminative; 5.22 (SD 2.53) vs 7.26 (SD 3.11) min, p value=0.003. In men, radiation of pain (89.3% vs 54.9%, p value=0.011) was discriminative for ACS, and stabbing chest pain (3.7% vs 24.0%, p value=0.014) for absence of ACS . Women and men with chest discomfort received similar high urgency allocation (crude and adjusted OR after correction for ACS and age; 1.03 (95% CI 0.72 to 1.48) and 1.04 (95% CI 0.72 to 1.52), respectively). Women with ACS received a high urgency allocation in 22/23 (95.7%) and men with ACS in 30/34 (88.2%), p value=0.331. CONCLUSIONS: Discriminating ACS in patients with chest discomfort who contacted primary care OHS is difficult in both women and men. Women and men with chest discomfort received similar high urgency allocation.

Normal-range thyroid-stimulating hormone levels and cardiovascular events and mortality in type 2 diabetes.

AIMS: Thyroid dysfunction is a risk factor for cardiovascular disease. Whether thyroid function within the normal range is a risk factor for cardiovascular disease remains uncertain. The aim of this study is to evaluate whether plasma thyroid-stimulating hormone (TSH) levels in the normal range are a risk factor for cardiovascular disease and mortality in participants with type 2 diabetes mellitus with high cardiovascular risk. METHODS: We included 1265 participants with high cardiovascular risk, type 2 diabetes, and TSH within the normal range (0.35-5.00 mIU/L) from the Second Manifestations of ARTerial disease cohort. The primary outcome was major cardiovascular events (MACE; vascular death, stroke and myocardial infarction). Secondary outcomes of interest were the separate vascular outcomes and all-cause mortality. Cox proportional hazard models were used to evaluate the risk of plasma TSH levels on all outcomes. RESULTS: A total of 191 MACE occurred during a total follow-up of 8183 years. Plasma TSH levels were not associated with MACE (hazard ratio (HR) per mIU/L TSH increase 0.93; 95% confidence interval (95%CI) 0.80-1.08). With a total of 54 strokes during the study period, plasma TSH was associated with a lower risk of stroke (HR per mIU/L 0.64, 95% CI 0.45-0.89). There was no association between plasma TSH levels and risk of myocardial infarction, vascular death, or all-cause mortality. CONCLUSIONS: Higher TSH levels within the normal range are associated with a lower risk of stroke in high-risk patients with type 2 diabetes, but not associated with the risk of other cardiovascular events or mortality.

Estimating individual lifetime benefit and bleeding risk of adding rivaroxaban to aspirin for patients with stable cardiovascular disease: results from the COMPASS trial.

AIMS: Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease. METHODS AND RESULTS: Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months). CONCLUSION: There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.

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.

Subjective cognitive decline, brain imaging biomarkers, and cognitive functioning in patients with a history of vascular disease: the SMART-Medea study.

We estimated associations of subjective cognitive decline (SCD) with neuroimaging markers of dementia and cognitive functioning in patients with a history of vascular disease without objective cognitive impairment. Within the Second Manifestations of ARTerial disease-Memory, depression and aging study, 599 patients (62 ± 9 years) had 1.5 T brain magnetic resonance imaging and cognitive testing at the baseline and after 8 years of follow-up. Using multiple regression analyses, we estimated cross-sectional and longitudinal associations of SCD according to research criteria with volumes of total brain, hippocampus, white matter hyperintensities, and presence of lacunes and with memory, executive functioning, information processing speed, and working memory. SCD was associated with increased risk of lacunes at the baseline (relative risk = 1.48, 95% confidence interval: 1.03; 2.12) but not during follow-up. No significant associations with volumes of white matter hyperintensities, total brain, or hippocampus were observed. SCD was cross-sectionally associated with poorer executive functioning and speed but not during follow-up. More prospective studies are needed to further elucidate the relationship between SCD, brain imaging markers, and cognitive decline and the role of SCD in the preclinical stage of Alzheimer's disease.

Heterogeneity of Treatment Effects From an Intensive Lifestyle Weight Loss Intervention on Cardiovascular Events in Patients With Type 2 Diabetes: Data From the Look AHEAD Trial.

OBJECTIVE: To explore the presence of heterogeneity of treatment effect (HTE) of an intensive lifestyle intervention on the occurrence of major cardiovascular events (MACE) in overweight or obese patients with type 2 diabetes, and to identify patient characteristics associated with individual treatment effect. RESEARCH DESIGN AND METHODS: In 4,901 participants from the Action for Health in Diabetes (Look AHEAD) trial, a penalized Cox regression model to predict treatment effect of intensive lifestyle intervention for the risk of MACE was derived, including all possible treatment-by-covariate interaction terms. The ability of the model to predict HTE was confirmed by calculating hazard ratios (HRs) and absolute risk change in quartiles of predicted treatment effect, and baseline patient characteristics were compared between quartiles. RESULTS: In quartile 1 of predicted treatment effect, with the highest predicted risk reduction, there was a significant treatment benefit of intensive lifestyle intervention (HR 0.64 [95% CI 0.49-0.83]), whereas there was no effect from treatment in quartiles 2 and 3 (HR 0.81 [95% CI 0.58-1.14] and 1.13 [95% CI 0.80-1.60], respectively) and a detrimental effect in quartile 4 (HR 1.37 [95% CI 1.09-1.73]). Several patient characteristics in demographics, medical history, physical examination, and laboratory values were associated with the level of treatment effect. CONCLUSIONS: This post hoc analysis of the Look AHEAD trial showed that an intensive lifestyle intervention aimed at weight loss may reduce cardiovascular events in selected patients but may have a detrimental treatment effect in others.

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.

Mediation analysis of the relationship between type 2 diabetes and cardiovascular events and all-cause mortality: Findings from the SMART cohort.

AIM: To quantify the magnitude and specific contributions of known cardiovascular risk factors leading to higher cardiovascular risk and all-cause mortality caused by type 2 diabetes (T2D). METHODS: Mediation analysis was performed to assess the relative contributions of known classical risk factors for vascular disease in T2D (insulin resistance, systolic blood pressure, renal function, LDL-cholesterol, triglycerides and micro-albuminuria), and what proportion of the effect of T2D on cardiovascular events and all-cause mortality these factors mediate in the Second Manifestations of ARTerial disease (SMART) cohort consisting of 1910 T2D patients. RESULTS: Only 35% (95% CI 15-71%) of the excess cardiovascular risk caused by T2D is mediated by the classical cardiovascular risk factors. The largest mediated effect was through insulin resistance [proportion of mediated effect (PME) 18%, 95% CI 3-37%], followed by elevated triglycerides (PME 8%, 95% CI 4-14%) and micro-albuminuria (PME 7%, 95% CI 3-17%). Only 42% (95% CI 18-73%) of the excess mortality risk was mediated by the classical risk factors considered. The largest mediated effect was by micro-albuminuria (PME 18%, 95% CI 10-29%) followed by insulin resistance (PME 15%, 95% CI 1-33%). CONCLUSION: A substantial amount of the increased cardiovascular risk and all-cause mortality caused by T2D cannot be explained by traditional vascular risk factors. Future research should focus on identifying non-classical pathways that might further explain the increased cardiovascular and mortality risk caused by T2D.