User-defined outcomes of the Danish cardiovascular screening (DANCAVAS) trial: A post hoc analyses of a population-based, randomised controlled trial.

BACKGROUND: The Danish cardiovascular screening (DANCAVAS) trial, a nationwide trial designed to investigate the impact of cardiovascular screening in men, did not decrease all-cause mortality, an outcome decided by the investigators. However, the target group may have varied preferences. In this study, we aimed to evaluate whether men aged 65 to 74 years requested a CT-based cardiovascular screening examination and to assess its impact on outcomes determined by their preferences. METHODS AND FINDINGS: This is a post hoc study of the randomised DANCAVAS trial. All men 65 to 74 years of age residing in specific areas of Denmark were randomised (1:2) to invitation-to-screening (16,736 men, of which 10,471 underwent screening) or usual-care (29,790 men). The examination included among others a non-contrast CT scan (to assess the coronary artery calcium score and aortic aneurysms). Positive findings prompted preventive treatment with atorvastatin, aspirin, and surveillance/surgical evaluation. The usual-care group remained unaware of the trial and the assignments. The user-defined outcome was based on patient preferences and determined through a survey sent in January 2023 to a random sample of 9,095 men from the target group, with a 68.0% response rate (6,182 respondents). Safety outcomes included severe bleeding and mortality within 30 days after cardiovascular surgery. Analyses were performed on an intention-to-screen basis. Prevention of stroke and myocardial infarction was the primary motivation for participating in the screening examination. After a median follow-up of 6.4 years, 1,800 of 16,736 men (10.8%) in the invited-to-screening group and 3,420 of 29,790 (11.5%) in the usual-care group experienced an event (hazard ratio (HR), 0.93 (95% confidence interval (CI), 0.88 to 0.98; p = 0.010); number needed to invite at 6 years, 148 (95% CI, 80 to 986)). A total of 324 men (1.9%) in the invited-to-screening group and 491 (1.7%) in the usual-care group had an intracranial bleeding (HR, 1.17; 95% CI, 1.02 to 1.35; p = 0.029). Additionally, 994 (5.9%) in the invited-to-screening group and 1,722 (5.8%) in the usual-care group experienced severe gastrointestinal bleeding (HR, 1.02; 95% CI, 0.95 to 1.11; p = 0.583). No differences were found in mortality after cardiovascular surgery. The primary limitation of the study is that exclusive enrolment of men aged 65 to 74 renders the findings non-generalisable to women or men of other age groups. CONCLUSION: In this comprehensive population-based cardiovascular screening and intervention program, we observed a reduction in the user-defined outcome, stroke and myocardial infarction, but entail a small increased risk of intracranial bleeding. TRIAL REGISTRATION: ISRCTN Registry number, ISRCTN12157806 https://www.isrctn.com/ISRCTN12157806.

The association between diabetes and abdominal aortic aneurysms in men: results of two Danish screening studies, a systematic review, and a meta-analysis of population-based screening studies.

BACKGROUND: A paradoxical protective effect of diabetes on the development and progression of abdominal aortic aneurysms (AAA) has been known for years. This study aimed to investigate whether the protective role of diabetes on AAAs has evolved over the years. METHODS: A cross-sectional study, a systematic review and meta-analysis. This study was based on two large, population-based, randomised screening trials of men aged 65-74; VIVA (2008-2011) and DANCAVAS (2014-2018), including measurement of the abdominal aorta by ultrasound or CT, respectively. Analyses were performed using multiple logistic regressions to estimate the odds ratios (ORs) for AAAs in men with diabetes compared to those not having diabetes. Moreover, a systematic review and meta-analysis of population-based screening studies of AAAs to visualise a potential change of the association between diabetes and AAAs. Studies reporting only on women or Asian populations were excluded. RESULTS: In VIVA, the prevalence of AAA was 3.3%, crude OR for AAA in men with diabetes 1.04 (95% confidence interval, CI, 0.80-1.34), and adjusted OR 0.64 (CI 0.48-0.84). In DANCAVAS, the prevalence of AAA was 4.2%, crude OR 1.44 (CI 1.11-1.87), and adjusted OR 0.78 (CI 0.59-1.04). Twenty-three studies were identified for the meta-analysis (N = 224 766). The overall crude OR was 0.90 (CI 0.77-1.05) before 2000 and 1.16 (CI 1.03-1.30) after 1999. The overall adjusted OR was 0.63 (CI 0.59-0.69) before 2000 and 0.69 (CI 0.57-0.84) after 1999. CONCLUSION: Both the crude and adjusted OR showed a statistically non-significant trend towards an increased risk of AAA by the presence of diabetes. If this represents an actual trend, it could be due to a change in the diabetes population. TRIAL REGISTRATION: DANCAVAS: Current Controlled Trials: ISRCTN12157806. VIVA: ClinicalTrials.gov NCT00662480.

Five-Year Outcomes of the Danish Cardiovascular Screening (DANCAVAS) Trial.

BACKGROUND: Limited data suggest a benefit of population-based screening for cardiovascular disease with respect to the risk of death. METHODS: We performed a population-based, parallel-group, randomized, controlled trial involving men 65 to 74 years of age living in 15 Danish municipalities. The participants were randomly assigned in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. Randomization was based on computer-generated random numbers and stratified according to municipality. Only the control group was unaware of the trial-group assignments. Screening included noncontrast electrocardiography-gated computed tomography to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation, ankle-brachial blood-pressure measurements to detect peripheral artery disease and hypertension, and a blood sample to detect diabetes mellitus and hypercholesterolemia. The primary outcome was death from any cause. RESULTS: A total of 46,611 participants underwent randomization. After exclusion of 85 men who had died or emigrated before being invited to undergo screening, there were 16,736 men in the invited group and 29,790 men in the control group; 10,471 of the men in the invited group underwent screening (62.6%). In intention-to-treat analyses, after a median follow-up of 5.6 years, 2106 men (12.6%) in the invited group and 3915 men (13.1%) in the control group had died (hazard ratio, 0.95; 95% confidence interval [CI], 0.90 to 1.00; P = 0.06). The hazard ratio for stroke in the invited group, as compared with the control group, was 0.93 (95% CI, 0.86 to 0.99); for myocardial infarction, 0.91 (95% CI, 0.81 to 1.03); for aortic dissection, 0.95 (95% CI, 0.61 to 1.49); and for aortic rupture, 0.81 (95% CI, 0.49 to 1.35). There were no significant between-group differences in safety outcomes. CONCLUSIONS: After more than 5 years, the invitation to undergo comprehensive cardiovascular screening did not significantly reduce the incidence of death from any cause among men 65 to 74 years of age. (Funded by the Southern Region of Denmark and others; DANCAVAS ISRCTN Registry number, ISRCTN12157806.).

Cost effectiveness of population screening vs. no screening for cardiovascular disease: the Danish Cardiovascular Screening trial (DANCAVAS).

AIMS: A recent trial has shown that screening of men for cardiovascular disease (CVD) may reduce all-cause mortality. This study assesses the cost effectiveness of such screening vs. no screening from the perspective of European healthcare systems. METHODS AND RESULTS: Randomized controlled trial-based cost-effectiveness evaluation with a mean 5.7 years of follow-up. Screening was based on low-dose computed tomography to detect coronary artery calcification and aortic/iliac aneurysms, limb blood pressure measurement to detect peripheral artery disease and hypertension, telemetric assessment of the heart rhythm to detect atrial fibrillation, and measurements of the cholesterol and HgbA1c levels. Censoring-adjusted incremental costs, life years (LY), and quality-adjusted LY (QALY) were estimated and used for cost-effectiveness analysis. The incremental cost of screening for the entire health care sector was €207 [95% confidence interval (CI) -24; 438, P = 0.078] per invitee for which gains of 0.019 LY (95% CI -0.007; 0.045, P = 0.145) and 0.023 QALY (95% CI -0.001; 0.046, P = 0.051) were achieved. The corresponding incremental cost-effectiveness ratios were of €10 812 per LY and €9075 per QALY, which would be cost effective at probabilities of 0.73 and 0.83 for a willingness to pay of €20 000. Assessment of population heterogeneity showed that cost effectiveness could be more attractive for younger men without CVD at baseline. CONCLUSIONS: Comprehensive screening for CVD is overall cost effective at conventional thresholds for willingness to pay and also competitive to the cost effectiveness of common cancer screening programmes. The screening target group, however, needs to be settled.

Association of Left Atrial Size Measured by Non-Contrast Computed Tomography with Cardiovascular Risk Factors-The Danish Cardiovascular Screening Trial (DANCAVAS).

Left atrium (LA) size is associated with adverse cardiovascular events. The purpose of this study was to investigate the association of LA enlargement measured by non-contrast CT (NCCT) with traditional cardiovascular risk factors. Individuals aged 60-75 years from the population-based multicentre Danish Cardiovascular Screening (DANCAVAS) trial were included in this cross-sectional study. The LA was manually traced on the NCCT scans, and the largest cross-section area was indexed to body surface area. All traditional risk factors were recorded, and a subgroup received an echocardiographic examination. We enrolled 14,987 individuals. Participants with known cardiovascular disease or lacking measurements of LA size or body surface area were excluded, resulting in 10,902 men for the main analysis and 616 women for a sensitivity analysis. Adjusted multivariable analysis showed a significantly increased indexed LA size by increasing age and pulse pressure, while smoking, HbA1c, and total cholesterol were associated with decreased indexed LA size. The findings were confirmed in a supplementary analysis including left ventricle ejection fraction and mass. In this population-based cohort of elderly men, an association was found between age and pulse pressure and increasing LA size. Surprisingly, smoking, HbA1c, and total cholesterol were associated with a decrease in LA size. This indicates that the pathophysiology behind atrial cardiomyopathy is not only reflected by enlargement, but also shrinking.

Cardiac rehabilitation for patients with heart failure: association with readmission and mortality risk.

AIMS: To examine the temporal trends and factors associated with national cardiac rehabilitation (CR) referral and compare the risk of hospital readmission and mortality in those referred for CR versus no referral. METHODS AND RESULTS: This cohort study includes all adult patients alive 120 days from incident heart failure (HF) identified by the Danish Heart Failure Registry (n = 33 257) between 2010 and 2018. Multivariable logistic regression models were used to assess the association between CR referral and patient factors and acute all-cause hospital readmission and mortality at 1 year following HF admission. Overall, 46.7% of HF patients were referred to CR, increasing from 31.7% in 2010 to 52.2% in 2018. Several factors were associated with lower odds of CR referral: male sex [odds ratio (OR): 0.85; 95% confidence interval: 0.80-0.89], older age, unemployment, retirement, living alone, non-Danish ethnic origin, low educational level, New York Heart Association (NYHA) class IV vs. I (OR: 0.75; 0.60-0.95), left ventricular ejection fraction >40%, and comorbidity (stroke, chronic kidney disease, atrial fibrillation/flutter, and diabetes). Myocardial infarction, arthritis, coronary artery bypass grafting, percutaneous coronary intervention, valvular surgery, NYHA class II, and use of angiotensin-converting enzyme inhibitors were associated with higher odds of CR referral. CR referral was associated with lower risk of acute all-cause readmission (OR: 0.92; 0.87-0.97) and all-cause mortality (OR: 0.65; 0.58-0.72). CONCLUSION: Although increased over time, only one in two HF patients in Denmark were referred to CR in 2018. Strategies are needed to reduce referral disparities, focusing on subgroups of patients at highest risk of non-referral.

Cross-sectional study of aortic valve calcification and cardiovascular risk factors in older Danish men.

OBJECTIVE: Aortic valve calcification (AVC) and coronary artery calcification (CAC) are predictors of cardiovascular disease (CVD), presumably sharing risk factors. Our objectives were to determine the prevalence and extent of AVC in a large population of men aged 60-74 years and to assess the association between AVC and cardiovascular risk factors including CAC and biomarkers. METHODS: Participants from the DANish CArdioVAscular Screening and intervention trial (DANCAVAS) with AVC and CAC scores and without previous valve replacement were included in the study. Calcification scores were calculated on non-contrast CT scans. Cardiovascular risk factors were self-reported, measured or both, and further explored using descriptive and regression analysis for AVC association. RESULTS: 14 073 men aged 60-74 years were included. The AVC scores ranged from 0 to 9067 AU, with a median AVC of 6 AU (IQR 0-82). In 8156 individuals (58.0%), the AVC score was >0 and 215 (1.5%) had an AVC score ≥1200. In the regression analysis, all cardiovascular risk factors were associated with AVC; however, after inclusion of CAC ≥400, only age (ratio of expected counts (REC) 1.07 (95% CI 1.06 to 1.09)), hypertension (REC 1.24 (95% CI 1.09 to 1.41)), obesity (REC 1.34 (95% CI 1.20 to 1.50)), known CVD (REC 1.16 (95% CI 1.03 to 1.31)) and serum phosphate (REC 2.25 (95% CI 1.66 to 3.10) remained significantly associated, while smoking, diabetes, hyperlipidaemia, estimated glomerular filtration rate and serum calcium were not. CONCLUSIONS: AVC was prevalent in the general population of men aged 60-74 years and was significantly associated with all modifiable cardiovascular risk factors, but only selectively after adjustment for CAC ≥400 AU. TRIAL REGISTRATION NUMBER: NCT03946410 and ISRCTN12157806.

High-risk coronary artery plaque in asymptomatic patients with type 2 diabetes: clinical risk factors and coronary artery calcium score.

BACKGROUND: High-risk coronary artery plaque (HRP) is associated with increased risk of acute coronary syndrome. We aimed to investigate the prevalence of HRP in asymptomatic patients with type 2 diabetes (T2D), and its relation to patient characteristics including cardiovascular risk factors, diabetes profile, and coronary artery calcium score (CACS). METHODS: Asymptomatic patients with T2D and no previous coronary artery disease (CAD) were studied using coronary computed tomography angiography (CCTA) in this descriptive study. Plaques with two or more high-risk features (HRP) defined by low attenuation, positive remodeling, spotty calcification, and napkin-ring sign were considered HRP. In addition, total atheroma volume (TAV), proportions of dense calcium, fibrous, fibrous-fatty and necrotic core volumes were assessed. The CACS was obtained from non-enhanced images by the Agatston method. Cardiovascular and diabetic profiles were assessed in all patients. RESULTS: In 230 patients CCTA was diagnostic and 161 HRP were detected in 86 patients (37%). Male gender (OR 4.19, 95% CI 1.99-8.87; p < 0.01), tobacco exposure in pack years (OR 1.02, 95% CI 1.00-1.03; p = 0.03), and glycated hemoglobin (HbA1c) (OR 1.04, 95% CI 1.02-1.07; p < 0.01) were independent predictors of HRP. No relationship was found to other risk factors. HRP was not associated with increased CACS, and 13 (23%) patients with zero CACS had at least one HRP. CONCLUSION: A high prevalence of HRP was detected in this population of asymptomatic T2D. The presence of HRP was associated with a particular patient profile, but was not ruled out by the absence of coronary artery calcium. CCTA provides important information on plaque morphology, which may be used to risk stratify this high-risk population. Trial registration This trial was retrospectively registered at clinical trials.gov January 11, 2017 trial identifier NCT03016910.

Population-Based Risk Factors for Ascending, Arch, Descending, and Abdominal Aortic Dilations for 60-74-Year-Old Individuals.

BACKGROUND: Aortic dilations (ectasias and aneurysms) may occur on any segment of the aorta. Pathogenesis varies between locations, suggesting that etiology and risk factors may differ. Despite this discrepancy, guidelines recommend screening of the whole aorta if 1 segmental dilation is discovered. OBJECTIVES: The purpose of this study was to determine the most dominant predictors for dilations at the ascending, arch, descending, and abdominal part of the aorta, and to establish comprehensive risk factor profiles for each aortic segment. METHODS: Individuals aged 60-74 years were randomly selected to participate in DANCAVAS I+II (Danish Cardiovascular Multicenter Screening Trials). Participants underwent cardiovascular risk assessments, including blood samples, blood pressure readings, medical records, and noncontrast computed tomography scans. Adjusted odds ratios for potential risk factors of dilations were estimated by multivariate logistic analyses. RESULTS: The study population consisted of 14,989 participants (14,235 men, 754 women) with an average age of 68 ± 4 years. The highest adjusted odd ratios for having any aortic dilation were observed when coexisting aortic dilations were present. Other noteworthy predictors included coexisting iliac dilations, hypertension, increasing body surface area, male sex, familial disposition, and atrial fibrillation, which were present in various combinations for the different aortic parts. Smoking and acute myocardial infarction were inversely associated with ascending and abdominal dilations. Diabetes was a shared protective factor. CONCLUSIONS: Risk factors differ for aortic dilations between locations. The most dominant predictor for having a dilation at any aortic segment is the presence of an aortic dilation elsewhere. This supports current guidelines when recommending a full screening of the aorta if a focal aortic dilation is discovered.

Survival, Prevalence, Progression and Repair of Abdominal Aortic Aneurysms: Results from Three Randomised Controlled Screening Trials Over Three Decades.

AIM: The prevalence and mortality of abdominal aortic aneurysms (AAA) has been reported to decline. The aim of this study is to compare survival, prevalence, and repair rate of AAA in Denmark in the 1990s, the 2000s and the 2010s - and to examine any change in factors known to influence the prevalence. METHODS: Baseline status and up to 5-year outcomes of 34,079 general population men aged 65-74 were obtained from three RCTs; the Viborg study (1994-1998, n=4,860), the Viborg Vascular (VIVA) trial (2008-2011, n=18,748), and the Danish Cardiovascular (DANCAVAS) trial (2015-2018, n=10,471). After the millennium (VIVA and DANCAVAS) men with AAA were further offered low dose aspirin and statins. Follow-up data were not available for the DANCAVAS trial yet. RESULTS: Across the three decades, the AAA prevalence was 3.8% (Reference), 3.3% (p<0.001) and 4.2% (p=0.882), the proportion of smokers were 62%, 42% and 34% (p<0.001) amongst men with AAA, but AAA risk associations with smoking increased during the decades suggesting increased tobacco consumption of smokers. In addition, the proportions of attenders with ischemic heart disease or stroke increased significantly. The aneurysmal progression rate in the 1990s was 2.90 vs 2.98 mm/year in the 2000s (p=0.91). The need for preventive AAA repair increased insignificantly in the 2000s (Age adj. HR= 1.29, 95% C.I.: 0.95; 1.71, p=0.10), and mortality of men with screen-detected AAA was lower in the 2000s compared to the 1990s (Age-adj. HR= 0.28, 95% C.I.: 0.22; 0.36, p<0.001). CONCLUSION: The Danish prevalence of AAA today compares to the nineties. Unchanged aneurysmal progression rates combined with improved survival of men at risk of AAA leave them in longer time to develop an AAA, be diagnosed and to need later aneurysmal repair or experience rupture. CLINICAL TRIAL REGISTRATIONS: Viborg study: No possibility of registration in the nineties. VIVA: NCT00662480, URL: https://clinicaltrials.gov/show/NCT00662480, DANCAVAS: ISRCTN12157806, URL: http://www.isrctn.com/ISRCTN12157806.

A novel alignment procedure to assess calcified coronary plaques in histopathology, post-mortem computed tomography angiography and optical coherence tomography.

PURPOSE: Improve mapping and registration of longitudinal view on histopathology vessels in a three-dimensional alignment procedure for postmortem quantitative coronary plaque analyses. This new procedure is applied and results shown using calcified coronary plaque analyses within post-mortem computed tomography angiography (PMCTA), optical coherence tomography (OCT) and the gold standard of histopathology. RESULTS: In total, 338 annotated histopathology images were included, 166 PMCTA transversal images and 285 OCT images were aligned in the comparison. The results from the comparison using the alignment procedure showed overall that the calcified plaques seem to be overestimated by PMCTA and underestimated by OCT. CONCLUSIONS: The 3D fusion approach, aligning the images of PMCTA, OCT and histopathology as gold standard allowed for a slice-based comparison of the different modalities. The results showed that PMCTA overestimates the calcified plaques while OCT underestimates these, compared to histopathology.

Image quality in coronary computed tomography angiography: influence of adaptive statistical iterative reconstruction at various radiation dose levels.

Background Computed tomography (CT) technology is rapidly evolving and software solution developed to optimize image quality and/or lower radiation dose. Purpose To investigate the influence of adaptive statistical iterative reconstruction (ASIR) at different radiation doses in coronary CT angiography (CCTA) in detailed image quality. Material and Methods A total of 160 CCTA were reconstructed as follows: 55 scans with filtered back projection (FBP) (650 mA), 51 scans (455 mA) with 30% ASIR (ASIR30), and 54 scans (295 mA) with 60% ASIR (ASIR60). For each reconstruction, subjective image quality was assessed by five independent certified cardiologists using a visual grading analysis (VGA) with five predefined image quality criteria consisting of a 5-point scale. Objective measures were contrast, noise, and contrast-to-noise ratio (CNR). Results The CTDIvol resulted in 10.3 mGy, 7.4 mGy, and 4.6 mGy for FBP, ASIR30, and ASIR60, respectively. Homogeneity of the left ventricular lumen was the sole aspect in which reconstruction algorithms differed with a decreasing effect for ASIR60 compared to FBP (estimated odds ratio [OR] = 0.49 [95% confidence interval (CI) = 0.32-0.76; P = 0.001]). Decreased sharpness and spatial- and low-contrast resolutions were observed when using ASIR instead of FBP, but differences were not statistically significant. Concerning objective measurements, noise increased significantly for ASIR30 (OR = 1.08; 95% CI = 1.02-1.14; P = 0.006) and ASIR60 (OR = 1.06; 95% CI = 1.01-1.12; P = 0.034) compared to FBP. Conclusion ASIR significantly decreased the subjectively assessed homogeneity of the left ventricular lumen and increased the objectively measured noise compared to FBP. Considering these results, ASIR at a reduced radiation dose should be implemented with caution.

Association Between Diverticular Disease and Abdominal Aortic Aneurysms: Pooled Analysis of Two Population Based Screening Cohorts.

BACKGROUND: The aetiology of abdominal aortic aneurysms (AAA) is multifactorial, and many risk factors are shared with diverticular disease. It is unknown whether an independent association exists between these conditions. METHODS: Individuals enrolled in two Danish population based randomised AAA screening trials and assigned to cross sectional screening and evaluation of cardiovascular risk factors were identified. Diagnoses of diverticular disease were interrogated from a national patient registry covering the period from 1977 to the screening date. Adjusted odds ratios (aOR) and hazard ratios (aHR) with 95% CI were calculated as risk measures. RESULTS: 24,632 individuals (median age, 69 years) were included. At screening, 687 patients had pre-existing diverticular disease. Patients with diverticular disease were more likely to have AAA at screening compared with those without diverticular disease (5.2% vs. 3.3%) (OR 1.61, 95% CI 1.14-2.27). This association persisted after adjusting for potential confounders (aOR 1.49, 95% CI 1.04-2.12) and on sensitivity analyses. The association was most pronounced for those with a diagnosis of diverticular disease for at least 10 years (aOR 2.56, 95% CI 1.49-4.38). Following screening, 6.2% of patients with diverticular disease and AAA experienced aneurysm rupture, compared with 2.2% of patients with AAA without diverticular disease (aHR 4.1, 95% CI 1.6-10.8). CONCLUSION: An association was found between diverticular disease and AAA in a large population based cohort. Biological causality remains to be established, and a potential impact of diverticular disease on the natural history of AAA needs to be explored further.

The Danish Heart Failure Registry.

AIM OF DATABASE: The aim of the Danish Heart Failure Registry (DHFR) is to monitor and improve the care of patients with incident heart failure (HF) in Denmark. STUDY POPULATION: The DHFR includes inpatients and outpatients (≥18 years) with incident HF. Reporting to the DHFR is mandatory for the Danish hospital departments treating patients with incident HF. Final decision to register a patient in the DHFR is made by a cardiologist to ensure the validity of the diagnosis. Approximately 42,400 patients with incident HF were registered in the DHFR in July 2015. MAIN VARIABLES AND DESCRIPTIVE DATA: The main variables recorded in the DHFR are related to the indicators for quality of care in patients with incident HF: performance of echocardiography, functional capacity (New York Heart Association functional classification), pharmacological therapy (angiotensin converting enzyme/angiotensin II antagonist inhibitors, beta-blockers, and mineralocorticoid receptor antagonist), nonpharmacological therapy (physical training, patient education), 4-week readmission rate, and 1-year mortality. Furthermore, basic patient characteristics and prognostic factors (eg, smoking and alcohol) are recorded. At the annual national audit in the DHFR, the indicators and standards for good clinical quality of care for patients with HF are discussed, and recommendations are reported back to clinicians to promote quality improvement initiatives. Furthermore, results and recommendations are communicated to the public in an annual report. All standards for the quality indicators have been met at a national level since 2014. Indicators for treatment status 1 year after diagnosis are under consideration (now prevalent HF). CONCLUSION: The DHFR is a valuable tool for continuous improvement of quality of care in patients with incident HF in Denmark. Furthermore, it is an important resource for the Danish registry-based HF research.

Mortality Risk Among Heart Failure Patients With Depression: A Nationwide Population-Based Cohort Study.

BACKGROUND: The prevalence of depression is 4- to 5-fold higher in heart failure patients than in the general population. We examined the influence of depression on all-cause mortality in patients with heart failure. METHODS AND RESULTS: Using Danish medical registries, this nationwide population-based cohort study included all patients with a first-time hospitalization for heart failure (1995-2014). All-cause mortality risks and 19-year mortality rate ratios were estimated based on Cox regression analysis, adjusting for age, sex, time period, comorbidity, and socioeconomic status. The analysis included 9636 patients with and 194 887 patients without a diagnosis of depression. Compared with patients without a history of depression, those with depression had higher 1-year (36% versus 33%) and 5-year (68% versus 63%) mortality risks. Overall, the adjusted mortality rate ratio was 1.03 (95% CI 1.01-1.06). Compared with no depression, the adjusted mortality rate ratios for mild, moderate, and severe depression, as defined by diagnostic codes, were 1.06 (95% CI 1.00-1.13), 1.03 (95% CI 0.99-1.08), and 1.02 (95% CI 0.96-1.09), respectively. In a subcohort of patients, the mortality rate ratios were modified by left ventricular ejection fraction, with adjusted mortality rate ratios of 1.17 (95% CI, 1.05-1.31) for ≤35%, 0.98 (95% CI 0.81-1.18) for 36% to 49%, and 0.96 (95% CI 0.74-1.25) for ≥50%. Results were consistent after adjustment for alcohol abuse and smoking. CONCLUSIONS: A history of depression was an adverse prognostic factor for all-cause mortality in heart failure patients with left ventricular ejection fraction ≤35% but not for other heart failure patients.

Coronary calcification among 3477 asymptomatic and symptomatic individuals.

BACKGROUND: Coronary artery calcification (CAC) can be detected by cardiac computed tomography (CT), is associated to cardiovascular risk, and common in asymptomatic individuals and patients referred for cardiac CT. DESIGN: CAC was evaluated in asymptomatic individuals and symptomatic patients referred for cardiac CT, to assess whether differences in CAC may be explained by symptoms or traditional cardiovascular risk factors. METHODS: The presence and extent of CAC, gender, family history of coronary artery disease, hypertension, hyperlipidaemia, diabetes and tobacco were compared in 1220 asymptomatic individuals aged 49-61 years and 2257 age-matched symptomatic patients referred for cardiac CT with suspected coronary artery disease. RESULTS: Symptomatic individuals had a higher frequency of a family history of coronary artery disease (46% vs. 23%, p < 0.001), hypertension (38% vs. 21%, p < 0.001), hyperlipidaemia (42% vs. 12%, p < 0.001), a trend for more diabetes (6% vs. 5%, p = 0.05), but no significant difference was observed for the presence of CAC (Agatston > 0; 45% vs. 45%, p = 0.94) or severe calcifications (Agatston > 400; 6% vs. 5%, p = 0.36). In multivariate analyses age (odds ratio (OR) 1.09-1.18), male gender (OR 3.5-6.43), hypertension (OR 1.42-1.79), hyperlipidaemia (OR 1.86-2.09) and tobacco use (OR 1.83-2.01) were predictors for the presence and extent of CAC, whereas symptoms were not predictive for the presence of (Agatston > 0, OR 0.70 (0.59-0.83)), mild (Agatston ≥ 10; OR 0.85 (0.71-1.02)), moderate (Agatston ≥ 100; OR 0.99 (0.79-1.24)) or severe calcifications (Agatston ≥ 400; OR 0.93 (0.65-1.33)). CONCLUSION: No difference in the presence or severity of coronary calcifications was observed between asymptomatic and symptomatic middle-aged individuals. After adjusting for cardiovascular risk factors, symptoms were not predictive for the presence or extent of CAC.

The Danish Cardiovascular Screening Trial (DANCAVAS): study protocol for a randomized controlled trial.

BACKGROUND: The significant increase in the average life expectancy has increased the societal challenge of managing serious age-related diseases, especially cancer and cardiovascular diseases. A routine check by a general practitioner is not sufficient to detect incipient cardiovascular disease. DESIGN: Population-based randomized clinically controlled screening trial. PARTICIPANTS: 45,000 Danish men aged 65-74 years living on the Island of Funen, or in the surrounding communities of Vejle and Silkeborg. No exclusion criteria are used. INTERVENTIONS: One-third will be invited to cardiovascular seven-faceted screening examinations at one of four locations. The screening will include: (1) low-dose non-contrast CT scan to detect coronary artery calcification and aortic/iliac aneurysms, (2) brachial and ankle blood pressure index to detect peripheral arterial disease and hypertension, (3) a telemetric assessment of the heart rhythm, and (4) a measurement of the cholesterol and plasma glucose levels. Up-to-date cardiovascular preventive treatment is recommended in case of positive findings. OBJECTIVE: To investigate whether advanced cardiovascular screening will prevent death and cardiovascular events, and whether the possible health benefits are cost effective. OUTCOME: Registry-based follow-up on all cause death (primary outcome), and costs after 3, 5 and 10 years (secondary outcome). RANDOMIZATION: Each of the 45,000 individuals is, by EPIDATA, given a random number from 1-100. Those numbered 67+ will be offered screening; the others will act as a control group. BLINDING: Only those randomized to the screening will be invited to the examination;the remaining participants will not. Numbers randomized: A total of 45,000 men will be randomized 1:2. Recruitment: Enrollment started October 2014. OUTCOME: A 5% reduction in overall mortality (HR=0.95), with the risk for a type 1 error=5% and the risk for a type II error=80%, is expected. We expect a 2-year enrollment, a 10-year follow-up, and a median survival of 15 years among the controls. The attendance to screening is assumed to be 70%. DISCUSSION: The primary aim of this so far stand-alone population-based, randomized trial will be to evaluate the health benefits and costeffectiveness of using non-contrast full truncus computer tomography (CT) scans (to measure coronary artery calcification (CAC) and identify aortic/iliac aneurysms) and measurements of the ankle brachial blood pressure index (ABI) as part of a multifocal screening and intervention program for CVD in men aged 65-74. Attendance rate and compliance to initiated preventive actions must be expected to become of major importance. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN12157806 (21 March 2015).

Incidence of cancer and mortality in patients from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial.

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) clinical trial, including 1,873 patients found an increased risk for cancer with lipid-lowering therapy with ezetimibe/simvastatin 10/40 mg/day, relative to placebo. In a registry-based follow-up study over 21 months from the conclusion of the SEAS trial, new incident cancer and total mortality were investigated in the SEAS study cohort from Denmark, Finland, Norway, Sweden, and the United Kingdom. Among 1,359 subjects eligible for follow-up (73% of the original total cohort), 1,194 had no history of cancer (primary follow-up cohort). New cancers and deaths were identified in the national cancer and mortality registries and classified by an Expert Review Committee. Data were analyzed using Cox proportional-hazards models of new cancers and mortality during follow-up according to treatment group assigned in the SEAS base study and with age, gender, smoking history, and previous cancers as covariates. The primary follow-up cohort had 12 patients with new cancers in the ezetimibe/simvastatin group and 22 in the placebo group (hazard ratio 0.55, 95% confidence interval 0.27 to 1.11), indicating no significant difference between the treatment groups. During follow-up, 43 patients assigned to ezetimibe/simvastatin and 33 assigned to placebo died (hazard ratio 1.29, 95% confidence interval 0.82 to 2.03). In conclusion, in this registry-based observational follow-up study of the original SEAS study patient population, treatment with ezetimibe/simvastatin was not associated with an increased risk for cancer or mortality in the 21-month period after the completion of the original SEAS study.

Stroke in patients with aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study.

BACKGROUND AND PURPOSE: There are limited data on risk stratification of stroke in aortic stenosis. This study examined predictors of stroke in aortic stenosis, the prognostic implications of stroke, and how aortic valve replacement (AVR) with or without concomitant coronary artery bypass grafting influenced the predicted outcomes. METHODS: Patients with mild-to-moderate aortic stenosis enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Diabetes mellitus, known atherosclerotic disease, and oral anticoagulation were exclusion criteria. Ischemic stroke was the primary end point, and poststroke survival a secondary outcome. Cox models treating AVR as a time-varying covariate were adjusted for atrial fibrillation and congestive heart failure, hypertension, age≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years and female sex (CHA2DS2-VASc) scores. RESULTS: One thousand five hundred nine patients were followed for 4.3±0.8 years (6529 patient-years). Rates of stroke were 5.6 versus 21.8 per 1000 patient-years pre- and post-AVR; 429 (28%) underwent AVR and 139 (9%) died. Atrial fibrillation (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.1-6.6), CHA2DS2-VASc score (HR 1.4 per unit; 95% CI, 1.1-1.8), diastolic blood pressure (HR, 1.4 per 10 mm Hg; 95% CI, 1.1-1.8), and AVR with concomitant coronary artery bypass grafting (HR, 3.2; 95% CI, 1.4-7.2, all P≤0.026) were independently associated with stroke. Incident stroke predicted death (HR, 8.1; 95% CI, 4.7-14.0; P<0.001). CONCLUSIONS: In patients with aortic stenosis not prescribed oral anticoagulation, atrial fibrillation, AVR with concomitant coronary artery bypass grafting, and CHA2DS2-VASc score were the major predictors of stroke. Incident stroke was strongly associated with mortality. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Microvascular dysfunction is associated with plasma osteoprotegerin levels in patients with acute myocardial infarction.

OBJECTIVE: Osteoprotegerin (OPG) is a glycoprotein that inhibits nuclear factor-κB's regulatory effects on inflammation, skeletal, and vascular systems, and is a potential biomarker of atherosclerosis and seems to be involved in vascular calcifications. The objective of this study was to assess the relationship between OPG, left ventricular function, and microvascular function in patients with acute myocardial infarction (AMI). PATIENTS AND METHODS: After successful revascularization, noninvasive assessment of coronary flow reserve (CFR) was performed in the distal part of the left anterior descending artery in 183 patients with first AMI. We performed low-dose dobutamine stress echocardiography to assess viability and finally we assessed the ventriculoarterial coupling (VAC). Plasma OPG was determined by ELISA. RESULTS: Plasma OPG concentrations were higher in patients with impaired microcirculation (CFR<2) than in patients without [median (first; third quartile), 1.939 (1.366; 2.724) vs. 1.451 (0.925; 2.164) ng/l; P=0.001]. OPG was associated with CFR both in linear regression single-variable analysis (P=0.001) and in multivariable analysis adjusting for possible confounders (P=0.024).Eighty-seven patients had resting wall motion abnormalities and 28 patients fulfilled the criteria for viability. In the group with low OPG 20 patients had viability, and in patients with high OPG only eight patients had viability (P=0.03).Both the E/A ratio (1.22±0.65 vs. 1.06±0.39; P=0.04) and the E/e' ratio (10.4±3.1 vs. 12.2±4.6; P=0.002) indicated worse diastolic function in patients with increased levels of OPG.Overall, an increase in the VAC point was observed in the population (1.11±0.6). The VAC point was higher in patients with increased OPG compared with low OPG (1.01±0.51 vs. 1.2±0.67; P=0.03). CONCLUSION: This is the first study to show an association between OPG levels and CFR, decreased diastolic function, and increased VAC in the setting of AMI. Our results indicate a relationship between OPG and the degree of microvascular dysfunction.