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.

Association between REDUCE-IT criteria, coronary artery disease severity, and cardiovascular events: the Western Denmark Heart Registry.

AIMS: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) trial demonstrated that icosapent ethyl lowered the risk of atherosclerotic cardiovascular disease (ASCVD) among patients with elevated triglycerides. However, how to appropriately implement its use in clinical practice is not well-defined. We aimed to determine whether plaque burden as assessed by coronary artery calcium (CAC) could stratify ASCVD risk among patients eligible for icosapent ethyl. METHODS AND RESULTS: Among 23 759 patients who underwent computed tomography angiography (CTA) in the Western Denmark Heart Registry, we identified eligibility for the REDUCE-IT trial. A total of 2146 participants (9%) met enrolment criteria for REDUCE-IT. During a median of 4.3 years of follow-up, 146 ASCVD events occurred. Overall, there was a stepwise increase in ASCVD event rates per 1000 person-years with increasing CAC (CAC = 0: 10.5, CAC 1-299: 18.7, CAC ≥300: 49.8). REDUCE-IT-eligible patients with CAC ≥300 had a multivariable-adjusted hazard ratio of 3.1 compared with CAC = 0 (95% confidence interval: 1.9-4.9). Coronary artery calcium differentiated risk similarly in patients with and without obstructive coronary artery disease (CAD). Overall, the 5-year estimated number needed to treat to prevent one event with icosapent ethyl was 45 and ranged from 87 in those with CAC = 0 to 17 in those with CAC ≥300. Some patients with non-obstructive CAD had lower estimated number needed to treat than patients with obstructive CAD when their plaque burden was higher. CONCLUSION: Atherosclerotic plaque burden as assessed by CAC can identify REDUCE-IT-eligible patients who are expected to derive most, and least, absolute benefit from treatment with icosapent ethyl regardless of obstructive versus non-obstructive CAD status.

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.

Association of Coronary Plaque With Low-Density Lipoprotein Cholesterol Levels and Rates of Cardiovascular Disease Events Among Symptomatic Adults.

Importance: Atherosclerosis burden and coronary artery calcium (CAC) are associated with the risk for atherosclerotic cardiovascular disease (ASCVD) events, with absence of plaque and CAC indicating low risk. Whether this is true in patients with elevated levels of low-density lipoprotein cholesterol (LDL-C) is not known. Specifically, a high prevalence of noncalcified plaque might signal high risk. Objective: To determine the prevalence of noncalcified and calcified plaque in symptomatic adults and assess its association with cardiovascular events across the LDL-C spectrum. Design, Setting, and Participants: This cohort study included symptomatic patients undergoing coronary computed tomographic angiography from January 1, 2008, to December 31, 2017, from the seminational Western Denmark Heart Registry. Follow-up was completed on July 6, 2018. Data were analyzed from April 2 to December 2, 2021. Exposures: Prevalence of calcified and noncalcified plaque according to LDL-C strata of less than 77, 77 to 112, 113 to 154, 155 to 189, and at least 190 mg/dL. Severity of coronary artery disease was categorized using CAC scores of 0, 1 to 99, and ≥100, where higher numbers indicate greater CAC burden. Main Outcomes and Measures: Atherosclerotic cardiovascular disease events (myocardial infarction and stroke) and death. Results: A total of 23 143 patients with a median age of 58 (IQR, 50-65) years (12 857 [55.6%] women) were included in the analysis. During median follow-up of 4.2 (IQR, 2.3-6.1) years, 1029 ASCVD and death events occurred. Across all LDL-C strata, absence of CAC was a prevalent finding (ranging from 438 of 948 [46.2%] in patients with LDL-C levels of at least 190 mg/dL to 4370 of 7964 [54.9%] in patients with LDL-C levels of 77-112 mg/dL) and associated with no detectable plaque in most patients, ranging from 338 of 438 (77.2%) in those with LDL-C levels of at least 190 mg/dL to 1067 of 1204 (88.6%) in those with LDL-C levels of less than 77 mg/dL. In all LDL-C groups, absence of CAC was associated with low rates of ASCVD and death (6.3 [95% CI, 5.6-7.0] per 1000 person-years), with increasing rates in patients with CAC scores of 1 to 99 (11.1 [95% CI, 10.0-12.5] per 1000 person-years) and CAC scores of at least 100 (21.9 [95% CI, 19.9-24.4] per 1000 person-years). Among those with CAC scores of 0, the event rate per 1000 person-years was 6.3 (95% CI, 5.6-7.0) in the overall population compared with 6.9 (95% CI, 4.0-11.9) in those with LDL-C levels of at least 190 mg/dL. Across all LDL-C strata, rates were similar and low in those with CAC scores of 0, regardless of whether they had no plaque or purely noncalcified plaque. Conclusions and Relevance: The findings of this cohort study suggest that in symptomatic patients with severely elevated LDL-C levels of at least 190 mg/dL who are universally considered to be at high risk by guidelines, absence of calcified and noncalcified plaque on coronary computed tomographic angiography was associated with low risk for ASCVD events. These results further suggest that atherosclerosis burden, including CAC, can be used to individualize treatment intensity in patients with severely elevated LDL-C levels.

Mitral Annulus Calcification and Cardiac Conduction Disturbances: A DANCAVAS Sub-study.

BACKGROUND: Due to its location very close to the bundle of His, mitral annulus calcification (MAC) might be associated with the development of atrioventricular (AV) conduction disturbances. This study assessed the association between MAC and AV conduction disturbances identified by cardiac implantable electronic device (CIED) use and electrocardiographic parameters. The association between MAC and traditional cardiovascular risk factors was also assessed. METHODS: This cross-sectional study analyzed 14,771 participants, predominantly men aged 60-75 years, from the population-based Danish Cardiovascular Screening trial. Traditional cardiovascular risk factors were obtained. Using cardiac non-contrast computed tomography imaging, MAC scores were measured using the Agatston method and divided into absent versus present and score categories. CIED implantation data were obtained from the Danish Pacemaker and Implantable Cardioverter Defibrillator Register. A 12-lead electrocardiogram was available for 2,107 participants. Associations between MAC scores and AV conduction disturbances were assessed using multivariate regression analyses. RESULTS: MAC was present in 22.4% of the study subjects. Participants with pacemakers for an AV conduction disturbance had significantly higher MAC scores (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.01-1.23) than participants without a CIED, whereas participants with a CIED for other reasons did not. Prolonged QRS-interval was significantly associated with the presence of MAC (OR, 1.45; 95% CI, 1.04-2.04), whereas prolonged PQ-interval was not. Female sex and most traditional cardiovascular risk factors were significantly associated with high MAC scores. CONCLUSIONS: MAC was associated with AV conduction disturbances, which could improve our understanding of the development of AV conduction disturbances.

Association of Age With the Diagnostic Value of Coronary Artery Calcium Score for Ruling Out Coronary Stenosis in Symptomatic Patients.

Importance: The diagnostic value is unclear of a 0 coronary artery calcium (CAC) score to rule out obstructive coronary artery disease (CAD) and near-term clinical events across different age groups. Objective: To assess the diagnostic value of a CAC score of 0 for reducing the likelihood of obstructive CAD and to assess the implications of such a CAC score and obstructive CAD across different age groups. Design, Setting, and Participants: This cohort study obtained data from the Western Denmark Heart Registry and had a median follow-up time of 4.3 years. Included patients were aged 18 years or older who underwent computed tomography angiography (CTA) between January 1, 2008, and December 31, 2017, because of symptoms that were suggestive of CAD. Data analysis was performed from April 5 to July 7, 2021. Exposures: Obstructive CAD, which was defined as 50% or more luminal stenosis. Main Outcomes and Measures: Proportion of individuals with obstructive CAD who had a CAC score of 0. Risk-adjusted diagnostic likelihood ratios were used to assess the diagnostic value of a CAC score of 0 for reducing the likelihood of obstructive CAD beyond clinical variables. Risk factors associated with myocardial infarction and death were estimated. Results: A total of 23 759 symptomatic patients, of whom 12 771 (54%) had a CAC score of 0, were included. This cohort had a median (IQR) age of 58 (49-65) years and was primarily composed of women (13 160 [55%]). Overall, the prevalence of obstructive CAD was relatively low across all age groups, ranging from 3% (39 of 1278 patients) in those who were younger than 40 years to 8% (52 of 619) among those who were 70 years or older. In patients with obstructive CAD, 14% (725 of 5043) had a CAC score of 0, and the prevalence varied across age groups from 58% (39 of 68) among those who were younger than 40 years, 34% (192 of 562) among those aged 40 to 49 years, 18% (268 of 1486) among those aged 50 to 59 years, 9% (174 of 1963) among those aged 60 to 69 years, to 5% (52 of 964) among those who were 70 years or older. The added diagnostic value of a CAC score of 0 decreased at a younger age, with a risk factor-adjusted diagnostic likelihood ratio of a CAC score of 0 ranging from 0.68 (approximately 32% lower likelihood of obstructive CAD than expected) in those who were younger than 40 years to 0.18 (approximately 82% lower likelihood than expected) in those who were 70 years or older. The presence of obstructive vs nonobstructive CAD among those with a CAC score of 0 was associated with a multivariable adjusted hazard ratio of 1.51 (95% CI, 0.98-2.33) for myocardial infarction and all-cause death; however, this hazard ratio varied from 1.80 (95% CI, 1.02-3.19) in those who were younger than 60 years to 1.24 (95% CI, 0.64-2.39) in those who were 60 years or older. Conclusions and Relevance: This cohort study found that the diagnostic value of a CAC score of 0 to rule out obstructive CAD beyond clinical variables was dependent on age, with the added diagnostic value being smaller for younger patients. In symptomatic patients who were younger than 60 years, a sizable proportion of obstructive CAD occurred among those without CAC and was associated with an increased risk of myocardial infarction and all-cause death.

Aortic valve calcification among elderly males from the general population, associated echocardiographic findings, and clinical implications.

AIMS: Aortic valve calcification (AVC) detected by non-contrast computed tomography (NCCT) associates with morbidity and mortality in patients with aortic valve stenosis. However, the importance of AVC in the general population is sparsely evaluated. We intend to describe the associations between AVC score on NCCT and echocardiographic findings as left atrial (LA) dilatation, left ventricular (LV) hypertrophy, aortic valve area (AVA), peak velocity, mean gradient, and aortic valve replacement (AVR) in a population with AVC scores ≥300 AU. METHODS AND RESULTS: Of 10 471 males aged 65-74 years from the Danish Cardiovascular Screening trial (DANCAVAS), participants with AVC score ≥300 AU were invited for transthoracic echocardiography and 828 (77%) of 1075 accepted the invitation. AVC scores were categorized (300-599, 600-799, 800-1199, and ≥1200 AU). AVR was obtained from registries. AVC was significantly associated with a steady increase in LA dilation (10.5%, 16.3%, 15.8%, 19.6%, P = 0.031), LV hypertrophy (3.9%, 6.6%, 8.9%, 10.1%, P = 0.021), peak velocity (1.7, 1.9, 2.1, 2.8 m/s, P = 0001), mean gradient (6, 8, 11, 19 mmHg, P = 0.0001), and a decrease in AVA (2.0, 1.9, 1.7, 1.3 cm2, P = 0.0001). The area under the curve was 0.79, 0.93, and 0.92 for AVA ≤1.5 cm2, peak velocity ≥3.0 m/s, and mean gradient ≥20 mmHg, respectively, and the associated optimal AVC score thresholds were 734, 1081, and 1019 AU. AVC > 1200 AU was associated with AVR (P < 0.0001). CONCLUSION: Among males from the background population, increasing AVC scores were associated with LA dilatation, LV hypertrophy, AVA, peak aortic velocity, mean aortic gradient, and AVR.

Prognostic value of myocardial perfusion imaging after first-line coronary computed tomography angiography: A multi-center cohort study.

PURPOSE: Further diagnostic testing may be required after a coronary computed tomography angiography (CTA) showing suspected coronary stenosis. Whether myocardial perfusion imaging (MPI) provides further prognostic information post-CTA remains debated. We evaluated the prognosis for patients completing CTA stratified for post-CTA diagnostic work-up using real-world data. METHODS: We identified all patients in our uptake area with angina symptoms undergoing first-time CTA over a 10-year period. Follow-up time was a median of 3.7 years [1.9-5.8]. The primary endpoint was a composite of myocardial infarction or death. The secondary endpoint was late revascularization. RESULTS: During the study period 53,351 patients underwent CTA. Of these, 24% were referred for further down-stream testing, 3,547 (7%) to MPI and 9,135 (17%) to invasive coronary angiography (ICA). The primary and secondary endpoints occurred in 2,026 (3.8%) and 954 (1.8%) patients. Patient-characteristic-adjusted hazard ratios for the primary and secondary endpoint using patients with a normal CTA as reference were 1.37 (1.21-1.55) and 2.50 (1.93-3.23) for patient treated medically, 1.68 (1.39-2.03) and 6.13 (4.58-8.21) for patients referred to MPI and 1.94 (1.69-2.23) and 9.18 (7.16-11.78) for patients referred for ICA, respectively. Adjusted analysis with stratification for disease severity at CTA showed similar hazard ratios for patients treated medically after CTA and patients referred for MPI and treated medically after the MPI. CONCLUSION: In patients completing coronary CTA, second-line MPI testing seems to identify patients at low risk of future events. MPI seems to have the potential to act as gatekeeper for ICA after coronary CTA.

Prevalence and extent of coronary artery calcification in the middle-aged and elderly population.

AIMS: Coronary artery calcification (CAC) measured on cardiac computed tomography (CT) is an important risk marker for cardiovascular disease (CVD) and has been included in the prevention guidelines. The aim of this study was to describe CAC score reference values in the middle-aged and elderly population and to develop a freely available CAC calculator. METHODS AND RESULTS: All participants from two population-based cardiac CT screening cohorts (DanRisk and DANCAVAS) were included. The CAC score was measured as a part of a screening session. Positive CAC scores were log-transformed and non-parametrically regressed on age for each gender, and percentile curves were transposed according to proportions of zero CAC scores. Men had higher CAC scores than women, and the prevalence and extend of CAC increased steadily with age. An online CAC calculator was developed, http://flscripts.dk/cacscore. After entering sex, age, and CAC score, the CAC score percentile and the coronary age are depicted including a figure with the specific CAC score and 25%, 50%, 75%, and 90% percentiles. The specific CAC score can be compared to the entire background population or only those without prior CVD. CONCLUSION: This study provides modern population-based reference values of CAC scores in men and woman and a freely accessible online CAC calculator. Physicians and patients are very familiar with blood pressure and lipids, but unfamiliar with CAC scores. Using the calculator makes it easy to see if a CAC value is low, moderate, or high, when a physician in the future communicate and discusses a CAC score with a patient.

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.

Interplay of Risk Factors and Coronary Artery Calcium for CHD Risk in Young Patients.

OBJECTIVES: The aim of this study was to examine prevalence, predictors, and impact of coronary artery calcium (CAC) across different risk factor burdens on the prevalence of obstructive coronary artery disease (CAD) and future coronary heart disease (CHD) risk in young patients. BACKGROUND: The interplay of risk factors and CAC for predicting CHD in young patients aged ≤45 years is not clear. METHODS: The study included 3,691 symptomatic patients (18-45 years of age) from the WDHR (Western Denmark Heart Registry) undergoing coronary computed tomographic angiography. CHD events were myocardial infarction and late revascularization. RESULTS: During a median of 4.1 years of follow-up, 57 first-time CHD events occurred. In total, 3,180 patients (86.1%) had CAC = 0 and 511 patients (13.9%) had CAC >0. Presence of CAC increased with number of risk factors (odds ratio: 4.5 [95% CI: 2.7-7.3] in patients with >3 vs 0 risk factors). The prevalence of obstructive CAD at baseline and the rate of future CHD events increased in a stepwise manner with both higher CAC and number of risk factors. The CHD event rate was lowest at 0.5 (95% CI: 0.1-3.6) per 1,000 person-years in patients with 0 risk factors and CAC = 0. Among patients with >3 risk factors, the event rate was 3.1 (95% CI: 1.0-9.7) in patients with CAC = 0 compared with 36.3 (95% CI: 17.3-76.1) in patients with CAC >10. CONCLUSIONS: In young patients, there is a strong interplay between CAC and risk factors for predicting the presence of obstructive CAD and for future CHD risk. In the presence of risk factors, even a low CAC score is a high-risk marker. These results demonstrate the importance of assessing risk factors and CAC simultaneously when assessing risk in young patients.

Prognostic importance of left atrial size measured by non-contrast cardiac computed tomography - A DANCAVAS study.

BACKGROUND: Enlargement of left atrium (LA) is a valuable marker of cardiovascular events, and LA size is readily available while performing non-contrast cardiac computed tomography (NCCT) for preventive purposes. We aimed to evaluate the predictive value of a single LA area from NCCT in a population-based cohort. METHOD: Mainly men aged 60-75 years from DANCAVAS were included. Traditional risk factors were recorded, and an NCCT scan performed at baseline. Coronary artery calcifications (CAC) score and the largest LA area were measured. LA was indexed to body surface area and categorised into four groups. Data on incident atrial fibrillation (AF), thromboembolic events, heart failure (HF) and death were obtained from Danish national registries. RESULTS: In total, 14,557 individuals were eligible, excluding those without LA measurement (N = 232) and with heart valve replacement (N = 197). Known AF or HF were respectively excluded from follow-up. Median follow-up time was 2.1 to 3.4 years. In total, 304 developed AF, 149 had thromboembolism, 129 developed HF and 482 died. In adjusted analysis, LA enlargement was associated with AF (HR (95% CI): large 1.99 (1.46-2.71) and very large LA 3.77 (2.31-6.14)) and HF (large 2.40 (1.50-3.85) and very large LA 6.54 (4.07-10.51)). A very large LA significantly increased mortality (HR: 2.01 (1.44-2.82)), and was associated with a two-fold increased risk of thromboembolism; however, not significantly in adjusted analysis (p = 0.09). CONCLUSION: We demonstrated that determination of LA area from NCCT was an important predictor of AF, HF and death. This knowledge could inform current risk assessment beyond CAC score.

Relation between Accumulated Air Pollution Exposure and Sub-Clinical Cardiovascular Disease in 33,723 Danish 60-74-Year-Old Males from the Background Population (AIR-CARD): A Method Article.

Cardiovascular disease is one of the main causes of death and disability in the Western world, and there is increasing evidence that air pollution is a risk factor for developing sub-clinical cardiovascular diseases. Previous studies have shown a correlation between cardiovascular disease and short-term exposure to elevated air pollution levels. However, the literature on the impact of long-term effect of air pollution is limited. We have a unique opportunity to evaluate this correlation. The DEHM/UBM/AirGIS model system calculates air pollution in a high temporal and spatial resolution and traces air pollution retrospectively to year 1979. The model calculates accumulated exposure using annual exposure from PM2.5 in relation to home and work addresses and takes into account working hours and holidays. We link the results from this model system to a population-based cardiovascular screening cohort of 33,723 individuals in the age of 60-74 to assess the contribution of the specific accumulated air pollution to the presence of sub-clinical arteriosclerosis in the coronary vessels, abdominal aortic aneurysms, and peripheral arterial disease. This correlation will be further analyzed in relation to specific air pollutants. This study will introduce more precise data for a longer period of time and incorporate participant's home and work addresses.

Heterogenous Distribution of Risk for Cardiovascular Disease Events in Patients With Stable Ischemic Heart Disease.

OBJECTIVES: The authors sought to assess the distribution of 5-year risk of cardiovascular disease (CVD) events (myocardial infarction, revascularizations, ischemic stroke) and death among symptomatic patients with varying degrees of coronary artery disease (CAD) ascertained from computed tomography angiography (CTA). BACKGROUND: CTA is used increasingly as the first-line test for evaluating patients with symptoms suggestive of CAD. This creates the daily clinical challenge of best using the information available from CTA to guide appropriate downstream allocation of preventive treatments. METHODS: Among 21,275 patients from the Western Denmark Heart Registry, the authors developed a model predicting 5-year risk for CVD and death based on traditional risk factors and CAD severity. Only events occurring >90 days after CTA were included. RESULTS: During a median follow-up of 4.2 years, 1,295 CVD events and deaths occurred. The median 5-year risk for events was 4% (interquartile range: 3% to 8%), and ranged from <5% to >50% in individual patients. The degree of CAD severity was the strongest risk factor; however, traditional risk factors also contributed significantly to risk. Thus, risk distributions in patients with varying degree of CAD overlapped considerably, and patients with extensive nonobstructive CAD could have higher estimated risk than patients with obstructive CAD (stenosis >50%). Among patients with obstructive CAD, 12% had 5-year risk <10% whereas 24% had risk >20%. A similar large overlap in risk was found when revascularizations were excluded from the endpoint. CONCLUSIONS: The 5-year risk for CVD events and death varies substantially in symptomatic patients undergoing CTA, even in the presence of obstructive CAD. These results provide support for individual risk assessment to improve potential benefit when allocating preventive therapies following CTA.

The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 × 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT).

OBJECTIVES: The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind, placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1500 HFrEF patients and test in a 2 × 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT). METHODS: Symptomatic, optimally treated HFrEF patients with LVEF ≤40% are randomized to active vs. placebo treatment. Patients can be randomized in either both H-HeFT and Met-HeFT or to only one of these study arms. In this event-driven study, it is anticipated that 1300 patients should be included in H-HeFT and 1100 in Met-HeFT and followed for an average of 4 years. RESULTS: As of May 2020, 296 patients have been randomized at 20 centers in Denmark. CONCLUSION: The H-HeFT and Met-HeFT studies will yield new knowledge about the potential benefit and safety of 2 commonly prescribed drugs with limited randomized data in patients with HFrEF.

Validation of the European Society of Cardiology pre-test probability model for obstructive coronary artery disease.

AIMS: Estimation of pre-test probability (PTP) of disease in patients with suspected coronary artery disease (CAD) is a common challenge. Due to decreasing prevalence of obstructive CAD in patients referred for diagnostic testing, the European Society of Cardiology suggested a new PTP (2019-ESC-PTP) model. The aim of this study was to validate that model. METHODS AND RESULTS: Symptomatic patients referred for coronary computed tomography angiography (CTA) due to suspected CAD in a geographical uptake area of 3.3 million inhabitants were included. The reference standard was a combined endpoint of CTA and invasive coronary angiography (ICA) with obstructive CAD defined at ICA as a ≥50% diameter stenosis or fractional flow reserve ≤0.80 when performed. The 2019-ESC-PTP, 2013-ESC-PTP, and CAD Consortium basic PTP scores were calculated based on age, sex, and symptoms. Of the 42 328 identified patients, coronary stenosis was detected in 8.8% using the combined endpoint. The 2019-ESC-PTP and CAD Consortium basic scores classified substantially more patients into the low PTP groups (PTP < 15%) than did the 2013-ESC-PTP (64% and 65% vs. 16%, P < 0.001). Using the combined endpoint as reference, calibration of the 2019-ESC-PTP model was superior to the 2013-ESC-PTP and CAD Consortium basic score. CONCLUSION: The new 2019-ESC-PTP model is well calibrated and superior to the previously recommended models in predicting obstructive stenosis detected by a combined endpoint of CTA and ICA.

Impact of Plaque Burden Versus Stenosis on Ischemic Events in Patients With Coronary Atherosclerosis.

BACKGROUND: Patients with obstructive coronary artery disease (CAD) are at high risk for cardiovascular disease (CVD) events. However, it remains unclear whether the high risk is due to high atherosclerotic disease burden or if presence of stenosis has independent predictive value. OBJECTIVES: The purpose of this study was to evaluate if obstructive CAD provides predictive value beyond its association with total calcified atherosclerotic plaque burden as assessed by coronary artery calcium (CAC). METHODS: Among 23,759 symptomatic patients from the Western Denmark Heart Registry who underwent diagnostic computed tomography angiography (CTA), we assessed the risk of major CVD (myocardial infarction, stroke, and all-cause death) stratified by CAC burden and number of vessels with obstructive disease. RESULTS: During a median follow-up of 4.3 years, 1,054 patients experienced a first major CVD event. The event rate increased stepwise with both higher CAC scores and number of vessels with obstructive disease (by CAC scores: 6.2 per 1,000 person-years (PY) for CAC = 0 to 42.3 per 1,000 PY for CAC >1,000; by number of vessels with obstructive disease: 6.1 per 1,000 PY for no CAD to 34.7 per 1,000 PY for 3-vessel disease). When stratified by 5 groups of CAC scores (0, 1 to 99, 100 to 399, 400 to 1,000, and >1,000), the presence of obstructive CAD was not associated with higher risk than presence of nonobstructive CAD. CONCLUSIONS: Plaque burden, not stenosis per se, is the main predictor of risk for CVD events and death. Thus, patients with a comparable calcified atherosclerosis burden generally carry a similar risk for CVD events regardless of whether they have nonobstructive or obstructive CAD.

CAD Severity on Cardiac CTA Identifies Patients With Most Benefit of Treating LDL-Cholesterol to ACC/AHA and ESC/EAS Targets.

OBJECTIVES: This study aimed to assess if information on CAD severity from coronary computed tomography angiography (CTA) can identify patients that benefit most from treating low-density lipoprotein-cholesterol (LDL-C) to American Heart Association/American College of Cardiology (ACC/AHA) and European Society of Cardiology (ESC) guidelines targets. BACKGROUND: Current treatment guidelines for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) disregard severity of coronary artery disease (CAD) for treatment choices. It is unclear whether severity of CAD should be considered in treatment recommendations. METHODS: Among 20,241 symptomatic patients undergoing diagnostic CTA from the Western Denmark Heart Registry, we assessed the number needed to treat (NNT) in 6 years to prevent 1 ASCVD event as well as the proportion of all events that could be prevented by treating LDL-C to targets. We assumed a 22% relative reduction of ASCVD events per 1 mmol/l reduction in LDL-C. RESULTS: In multivariable analysis with no CAD as the reference, the subdistribution hazard ratio for ASCVD events was 4.0 (95% confidence interval [CI]: 3.3 to 4.9) for 1-vessel disease, 4.6 (3.5 to 6.0) for 2-vessel disease, and 5.6 (4.0 to 8.0) for 3-vessel disease. Consequently, the NNT to prevent 1 ASCVD event in 6 years by treating LDL-C to targets varied greatly from 233 (ESC) and 110 (ACC/AHA) for patients with no CAD to 8-9 for patients with 3-vessel disease (both ACC/AHA and ESC). The estimated percentage of ASCVD events that could be prevented by achieving guideline targets was 30% to 36% for patients with obstructive disease. However, <20% of patients achieved targets. CONCLUSIONS: An individualized approach based on CAD severity can identify symptomatic patients that are likely to derive most and least benefit from treating LDL-C to ACC/AHA and ESC treatment targets.