Publications by authors named "Frederik Dalgaard"

34 Publications

Electrical cardioversion of atrial fibrillation and the risk of brady-arrhythmic events.

Am Heart J 2021 Oct 16;244:42-49. Epub 2021 Oct 16.

Department of Cardiology, Herlev-Gentofte University Hospital, University of Copenhagen, Hellerup, Denmark.

Background: Electrical cardioversion (ECV) is a common procedure for terminating atrial fibrillation (AF). ECV is associated with brady-arrhythmic events, however, the age-specific risks of clinically significant brady-arrhythmic events are unknown.

Methods: Using Danish nationwide registers, we identified patients with AF at their first non-emergent ECV between 2005 and 2018 and estimated their 30-day risk of brady-arrhythmic events. Moreover, factors associated with increased risks of brady-arrhythmias were identified. Absolute risks were estimated using logistic regression models fitted with natural splines as well as standardization (G-formula).

Results: We identified 20,725 eligible patients with a median age of 66 years (IQR 60-72) and most males (73%). The 30-day risks of brady-arrhythmic events after ECV were highly dependent on age with estimated risks ranging from 0.5% (95% CI 0.2-1.7) and 1.2% (95% CI 0.99-1.5) to 2.7% (95% CI 2.1-3.3) and 5.1% (95% CI 2.6-9.7) in patients aged 40, 65, 80, and 90 years, respectively. Factors associated with brady-arrhythmias were generally related to cardiovascular disease (eg, ischemic heart disease, heart failure, valvular AF) or a history of syncope. We found no indications that pre-treatment with anti-arrhythmic drugs conferred increased risks of brady-arrhythmic events (standardized absolute risk difference -0.25% [95% CI -0.67 to 0.17]).

Conclusions: ECV conferred clinically relevant 30-day risks of brady-arrhythmic events, especially in older patients. Anti-arrhythmic drug treatment was not found to increase the risk of brady-arrhythmias. Given the widespread use of ECV, these data should provide insights regarding the potential risks of brady-arrhythmic events.
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http://dx.doi.org/10.1016/j.ahj.2021.10.182DOI Listing
October 2021

Association between vitamin K intake and mortality in the Danish Diet, Cancer, and Health cohort.

Eur J Epidemiol 2021 Oct 30;36(10):1005-1014. Epub 2021 Sep 30.

Institute for Nutrition Research, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.

Reported associations between vitamin K and both all-cause and cause-specific mortality are conflicting. The 56,048 participants from the Danish Diet, Cancer, and Health prospective cohort study, with a median [IQR] age of 56 [52-60] years at entry and of whom 47.6% male, were followed for 23 years, with 14,083 reported deaths. Of these, 5015 deaths were CVD-related, and 6342 deaths were cancer-related. Intake of vitamin K (phylloquinone) was estimated from a food-frequency questionnaire (FFQ), and its relationship with mortality outcomes was investigated using Cox proportional hazards models. A moderate to high (87-192 µg/d) intake of vitamin K was associated with a lower risk of all-cause [HR (95%CI) for quintile 5 vs quintile 1: 0.76 (0.72, 0.79)], cardiovascular disease (CVD)-related [quintile 5 vs quintile 1: 0.72 (0.66, 0.79)], and cancer-related mortality [quintile 5 vs quintile 1: 0.80 (0.75, 0.86)], after adjusting for demographic and lifestyle confounders. The association between vitamin K intake and cardiovascular disease-related mortality was present in all subpopulations (categorised according to sex, smoking status, diabetes status, and hypertension status), while the association with cancer-related mortality was only present in current/former smokers (p for interaction = 0.002). These findings suggest that promoting adequate intakes of foods rich in vitamin K may help to reduce all-cause, CVD-related, and cancer-related mortality at the population level.
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http://dx.doi.org/10.1007/s10654-021-00806-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542554PMC
October 2021

Vitamin K Intake and Atherosclerotic Cardiovascular Disease in the Danish Diet Cancer and Health Study.

J Am Heart Assoc 2021 08 7;10(16):e020551. Epub 2021 Aug 7.

Institute for Nutrition Research School of Medical and Health Sciences Edith Cowan University Perth Australia.

Background Dietary vitamin K (K and K) may reduce atherosclerotic cardiovascular disease (ASCVD) risk via several mechanisms. However, studies linking vitamin K intake with incident ASCVD are limited. We aimed to determine the relationship between dietary vitamin K intake and ASCVD hospitalizations. Methods and Results In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study, with no prior ASCVD, completed a food-frequency questionnaire at baseline and were followed up for hospital admissions of ASCVD; ischemic heart disease, ischemic stroke, or peripheral artery disease. Intakes of vitamin K and vitamin K were estimated from the food-frequency questionnaire, and their relationship with ASCVD hospitalizations was determined using Cox proportional hazards models. Among 53 372 Danish citizens with a median (interquartile range) age of 56 (52-60) years, 8726 individuals were hospitalized for any ASCVD during 21 (17-22) years of follow-up. Compared with participants with the lowest vitamin K intakes, participants with the highest intakes had a 21% lower risk of an ASCVD-related hospitalization (hazard ratio, 0.79; 95% CI: 0.74-0.84), after multivariable adjustments for relevant demographic covariates. Likewise for vitamin K, the risk of an ASCVD-related hospitalization for participants with the highest intakes was 14% lower than participants with the lowest vitamin K intake (hazard ratio, 0.86; 95% CI, 0.81-0.91). Conclusions Risk of ASCVD was inversely associated with diets high in vitamin K or K. The similar inverse associations with both vitamin K and K, despite very different dietary sources, highlight the potential importance of vitamin K for ASCVD prevention.
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http://dx.doi.org/10.1161/JAHA.120.020551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475061PMC
August 2021

Higher Habitual Flavonoid Intakes Are Associated with a Lower Incidence of Diabetes.

J Nutr 2021 Nov;151(11):3533-3542

Institute for Nutrition Research, School of Medical and Health Sciences, Edith Cowan University, Perth, Australia.

Background: Higher flavonoid intakes are hypothesized to confer protection against type 2 diabetes mellitus.

Objectives: We aimed to 1) investigate associations between flavonoid intakes and diabetes, 2) examine the mediating impact of body fat, and 3) identify subpopulations that may receive the greatest benefit from higher flavonoid intakes in participants of the Danish Diet, Cancer, and Health Study followed up for 23 y.

Methods: Cross-sectional associations between baseline flavonoid intake, estimated using FFQs and the Phenol Explorer database, and body fat, estimated by bioelectrical impedance, were assessed using multivariable-adjusted linear regression models. Nonlinear associations between flavonoid intake and incident diabetes were examined using restricted cubic splines with multivariable-adjusted Cox proportional hazards models.

Results: Among 54,787 participants (median age: 56 y; IQR: 52-60 y; 47.3% men), 6700 individuals were diagnosed with diabetes. Participants in the highest total flavonoid intake quintile (median, 1202 mg/d) had a 1.52 kg lower body fat (95% CI: -1.74, -1.30 kg) and a 19% lower risk of diabetes (HR: 0.81; 95% CI: 0.75, 0.87) after multivariable adjustments and compared with participants in the lowest intake quintile (median: 174 mg/d). Body fat mediated 57% (95% CI: 42, 83%) of the association between flavonoid intake and incident diabetes. Of the flavonoid subclasses, moderate to high intakes of flavonols, flavanol monomers, flavanol oligo + polymers, and anthocyanins were significantly associated with a lower risk of diabetes. Although associations were not modified by sex, smoking status, BMI, or physical activity (Pinteraction > 0.05 for all), findings on an absolute scale suggest that those at a higher risk (those with obesity) may benefit the most from a higher flavonoid intake.

Conclusions: The findings reported in this study suggest that a diet abundant in flavonoid-rich foods may help ameliorate diabetes risk, in part through a reduction in body fat.
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http://dx.doi.org/10.1093/jn/nxab269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8562076PMC
November 2021

Flavonoid intake and incident dementia in the Danish Diet, Cancer, and Health cohort.

Alzheimers Dement (N Y) 2021 13;7(1):e12175. Epub 2021 May 13.

School of Medical and Health Sciences Edith Cowan University Perth Australia.

Introduction: Prospective studies investigating flavonoid intake and dementia risk are scarce. The aims of this study were to examine associations between flavonoid intake and the risk of incident dementia and to investigate whether this association differs in the presence of lifestyle risk factors for dementia.

Methods: We examined associations in 55,985 participants of the Danish Diet, Cancer, and Health Study followed for 23 years. The Phenol-Explorer database was used to estimate flavonoid intakes. Information on incident dementia and dementia subtypes was obtained using Danish patient and prescription registries. Hazard ratios (HRs) were calculated using restricted cubic splines in multivariable-adjusted Cox proportional hazards models.

Results: For incident dementia, moderate compared to low intakes of flavonols (HR: 0.90 [0.82, 0.99]), flavanol oligo+polymers (HR: 0.87 [0.79, 0.96]), anthocyanins (HR: 0.84 [0.76, 0.93]), flavanones (HR: 0.89 [0.80, 0.99]), and flavones (HR: 0.85 [0.77, 0.95]) were associated with a lower risk. For vascular dementia, moderate intakes of flavonols (HR: 0.69 [0.53, 0.89]) and flavanol oligo + polymers (HR: 0.65 [0.51, 0.83]) were associated with lower risk. Flavonoid intakes were not significantly associated with Alzheimer's disease or unspecified dementia. The inverse association between total flavonoid intake and incident dementia was stronger in "ever" smokers than in "never" smokers and in those without hypercholesterolemia versus those with hypercholesteremia. Furthermore, the inverse association of vascular dementia with a moderate total flavonoid intake was stronger in "ever" smokers and those who were "normal" to "overweight" versus "never" smokers or those who were "obese," respectively.

Conclusion: A moderate intake of flavonoid-rich foods may help to reduce dementia risk.
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http://dx.doi.org/10.1002/trc2.12175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118115PMC
May 2021

Habitual flavonoid intake and ischemic stroke incidence in the Danish Diet, Cancer, and Health Cohort.

Am J Clin Nutr 2021 07;114(1):348-357

School of Biomedical Sciences, University of Western Australia, Royal Perth Hospital, Perth, Australia.

Background: Flavonoid-rich foods have antiinflammatory, antiatherogenic, and antithrombotic properties that may contribute to a lower risk of ischemic stroke.

Objectives: We aimed to investigate the relationship between habitual flavonoid consumption and incidence of ischemic stroke in participants from the Danish Diet, Cancer and Health Study.

Design: In this prospective cohort study, 55,169 Danish residents without a prior ischemic stroke [median (IQR) age at enrolment of 56 y (52-60)], were followed for 21 y (20-22). We used Phenol-Explorer to estimate flavonoid intake from food frequency questionnaires obtained at study entry. Incident cases of ischemic stroke were identified from Danish nationwide registries and restricted cubic splines in Cox proportional hazards models were used to investigate relationships with flavonoid intake.

Results: During follow-up, 4237 individuals experienced an ischemic stroke. Compared with participants in Q1 and after multivariable adjustment for demographics and lifestyle factors, those in Q5-for intake of total flavonoids, flavonols, and flavanol oligo + polymers-had a 12% [HR (95% CI): 0.88 (0.81, 0.96)], 10% [0.90 (0.82, 0.98)], and 18% [0.82 (0.75, 0.89)] lower risk of ischemic stroke incidence, respectively. Multivariable (demographic and lifestyle) adjusted associations for anthocyanins and flavones with risk of ischemic stroke were not linear, with moderate but not higher intakes associated with lower risk [anthocyanins Q3 vs. Q1 HR (95% CI): 0.85 (0.79, 0.93); flavones: 0.90 (0.84, 0.97)]. Following additional adjustment for dietary confounders, similar point estimates were observed; however, significance was only retained for anthocyanins and flavanol oligo + polymers [anthocyanins Q3 vs. Q1 HR (95% CI): 0.86 (0.79, 0.94); flavanol oligo + polymers Q5 vs. Q1 0.86 (0.78, 0.94)].

Conclusions: These findings suggest that moderate habitual consumption of healthy flavonoid-rich foods is associated with a lower risk of ischemic stroke and further investigation is therefore warranted.
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http://dx.doi.org/10.1093/ajcn/nqab138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246625PMC
July 2021

GARFIELD-AF risk score for mortality, stroke and bleeding within 2 years in patients with atrial fibrillation.

Eur Heart J Qual Care Clin Outcomes 2021 Apr 21. Epub 2021 Apr 21.

Thrombosis Research Institute (TRI), London, UK.

Aims: To determine whether the GARFIELD-AF integrated risk tool predicts mortality, non-haemorrhagic stroke/systemic embolism (SE), and major bleeding for up to two years after new onset AF and to assess how this risk tool performs compared with CHA2DS2-VASc and HAS-BLED.

Methods And Results: Potential predictors of events included demographic and clinical characteristics, choice of treatment, and lifestyle factors. A Cox proportional hazards model was identified for each outcome by least absolute shrinkage and selection operator (LASSO) methods. Indices were evaluated in comparison with CHA2DS2-VASc and HAS-BLED risk predictors. Models were validated internally and externally in ORBIT-AF and Danish nationwide registries. Among the 52,080 patients enrolled in GARFIELD-AF, 52,032 had follow-up data. The GARFIELD-AF risk tool outperformed CHA2DS2-VASc for all-cause mortality in all cohorts. The GARFIELD-AF risk score was superior to CHA2DS2-VASc for non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in internal validation and in Danish AF cohort. In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the GARFIELD-AF risk score offered strong discriminatory value for all the endpoints when compared to CHA2DS2-VASc and HAS-BLED. The GARFIELD-AF tool also included the effect of OAC therapy, thus allowing clinicians to compare the expected outcome of different anticoagulant treatment decisions (i.e., No OAC, NOACs or VKAs).

Conclusions: The GARFIELD-AF risk tool outperformed CHA2DS2-VASc at predicting death and non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in overall as well as in very low to low risk group patients with AF.
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http://dx.doi.org/10.1093/ehjqcco/qcab028DOI Listing
April 2021

Vegetable nitrate intake, blood pressure and incident cardiovascular disease: Danish Diet, Cancer, and Health Study.

Eur J Epidemiol 2021 Aug 21;36(8):813-825. Epub 2021 Apr 21.

Institute for Nutrition Research, School of Medical and Health Sciences, Edith Cowan University, Level 3, Royal Perth Hospital Research Foundation, Rear 50 Murray St, Perth, WA, 6000, Australia.

Whether the vascular effects of inorganic nitrate, observed in clinical trials, translate to a reduction in cardiovascular disease (CVD) with habitual dietary nitrate intake in prospective studies warrants investigation. We aimed to determine if vegetable nitrate, the major dietary nitrate source, is associated with lower blood pressure (BP) and lower risk of incident CVD. Among 53,150 participants of the Danish Diet, Cancer, and Health Study, without CVD at baseline, vegetable nitrate intake was assessed using a comprehensive vegetable nitrate database. Hazard ratios (HRs) were calculated using restricted cubic splines based on multivariable-adjusted Cox proportional hazards models. During 23 years of follow-up, 14,088 cases of incident CVD were recorded. Participants in the highest vegetable nitrate intake quintile (median, 141 mg/day) had 2.58 mmHg lower baseline systolic BP (95%CI - 3.12, - 2.05) and 1.38 mmHg lower diastolic BP (95%CI - 1.66, - 1.10), compared with participants in the lowest quintile. Vegetable nitrate intake was inversely associated with CVD plateauing at moderate intakes (~ 60 mg/day); this appeared to be mediated by systolic BP (21.9%). Compared to participants in the lowest intake quintile (median, 23 mg/day), a moderate vegetable nitrate intake (median, 59 mg/day) was associated with 15% lower risk of CVD [HR (95% CI) 0.85 (0.82, 0.89)]. Moderate vegetable nitrate intake was associated with 12%, 15%, 17% and 26% lower risk of ischemic heart disease, heart failure, ischemic stroke and peripheral artery disease hospitalizations respectively. Consumption of at least ~ 60 mg/day of vegetable nitrate (~ 1 cup of green leafy vegetables) may mitigate risk of CVD.
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http://dx.doi.org/10.1007/s10654-021-00747-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416839PMC
August 2021

Right ventricular lead location and outcomes among patients with cardiac resynchronization therapy: A meta-analysis.

Prog Cardiovasc Dis 2021 May-Jun;66:53-60. Epub 2021 Apr 20.

Division of Cardiology, Duke University Medical Center, Durham, NC 27710, United States of America; Duke Clinical Research Institute, Durham, NC 27710, United States of America.

Background: Cardiac resynchronization therapy (CRT) has been demonstrated to improve heart failure (HF) symptoms, reverse LV remodeling, and reduce mortality and HF hospitalization (HFH) in patients with a reduced left ventricular (LV) ejection fraction (LVEF). Prior studies examining outcomes based on right ventricular (RV) lead position among CRT patients have provided mixed results. We performed a systematic review and meta-analysis of randomized controlled trials and prospective observational studies comparing RV apical (RVA) and non-apical (RVNA) lead position in CRT.

Methods: Our meta-analysis was constructed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses. We searched EMBASE and MEDLINE. Eligible studies reported on at least one of the following outcomes of interest: all-cause mortality, the composite endpoint of death and first HFH hospitalization, change in LVEF, New York Heart Association (NYHA) class improvement, and change in LV end systolic volume (LVESV). We performed meta-analysis summaries using a DerSimonian-Laird random-effects model and conservatively used the Knapp-Hartung approach to adjust the standard errors of the estimated model coefficients.

Results: We included nine studies representing a total of 1832 patients. Of those, 1318 (72%) patients had RVA lead placement and 514 (28%) had RVNA lead placement. The mean age of patients was 65.5 ± 4.4 years, and they were predominantly men (69%-97%). There was no statistically significant difference in all-cause mortality by RVA vs. RVNA (OR = 0.77, 95% CI 0.32-1.89; I = 16.7%, p = 0.31), or in the combined endpoint of all-cause mortality and first HFH (OR 0.88, 95% CI 0.62-1.25; I = 0%, p = 0.84). Also, there was no difference between RVA and RVNA for NYHA class improvement (OR = 1.03, 95% CI 0.9-1.17; I = 0%, p = 0.99), change in LVEF (mean difference (MD) = 1.33, 95% CI -1.45 to 4.10; I = 47%; p = 0.093), and change in LVESV (MD = -1.11, 95% CI -3.34 to 1.12; I = 0%; p = 0.92).

Conclusion: This meta-analysis shows that in CRT pacing, RV lead position does not appear to be associated with clinical outcomes or LV reverse remodeling. Further studies should focus on the relationship of RV lead vis-à-vis LV lead location, and its clinical importance.
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http://dx.doi.org/10.1016/j.pcad.2021.04.002DOI Listing
August 2021

Management of Atrial Fibrillation in Older Patients by Morbidity Burden: Insights From Get With The Guidelines-Atrial Fibrillation.

J Am Heart Assoc 2020 12 26;9(23):e017024. Epub 2020 Nov 26.

Duke Clinical Research Institute Duke University Durham NC.

Background Knowledge is scarce regarding how multimorbidity is associated with therapeutic decisions regarding oral anticoagulants (OACs) in patients with atrial fibrillation. Methods and Results We conducted a cross-sectional study of hospitalized patients with atrial fibrillation using the Get With The Guidelines-Atrial Fibrillation registry from 2013 to 2019. We identified patients ≥65 years and eligible for OAC therapy. Using 16 available comorbidity categories, patients were stratified by morbidity burden. A multivariable logistic regression model was used to determine the odds of receiving OAC prescription at discharge by morbidity burden. We included 34 174 patients with a median (interquartile range) age of 76 (71-83) years, 56.6% women, and 41.9% were not anticoagulated at admission. Of these patients, 38.6% had 0 to 2 comorbidities, 50.7% had 3 to 5 comorbidities, and 10.7% had ≥6 comorbidities. The overall discharge OAC prescription was high (85.6%). The prevalence of patients with multimorbidity increased from 59.7% in 2014 to 64.3% in 2019 ( trend=0.002). Using 0 to 2 comorbidities as the reference, the adjusted odds ratio (95% CI) of OAC prescription were 0.93 (0.82, 1.05) for patients with 3 to 5 comorbidities and 0.72 (0.60, 0.86) for patients with ≥6 comorbidities. In those with ≥6 comorbidities, the most common reason for nonprescription of OACs were frequent falls/frailty (31.0%). Conclusions In a contemporary quality-of-care database of hospitalized patients with atrial fibrillation eligible for OAC therapy, multimorbidity was common. A higher morbidity burden was associated with a lower odds of OAC prescription. This highlights the need for interventions to improve adherence to guideline-recommended anticoagulation in multimorbid patients with atrial fibrillation.
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http://dx.doi.org/10.1161/JAHA.120.017024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763767PMC
December 2020

Higher habitual flavonoid intakes are associated with a lower risk of peripheral artery disease hospitalizations.

Am J Clin Nutr 2020 Nov 24. Epub 2020 Nov 24.

Department of Cardiology, Herlev & Gentofte University Hospital, Copenhagen, Denmark.

Background: The role of nutrition in the primary prevention of peripheral artery disease (PAD), the third leading cause of atherosclerotic cardiovascular disease, is undetermined. Flavonoids may attenuate atherosclerosis and therefore persons who consume flavonoid-rich foods may have a lower risk of developing PAD.

Objectives: We aimed to examine the association between flavonoid intake and PAD hospitalizations and investigate if the association differs according to established risk factors for PAD.

Methods: Baseline data from 55,647 participants of the Danish Diet, Cancer, and Health Study without PAD, recruited from 1993 to 1997, were cross-linked with Danish nationwide registries. Flavonoid intake was calculated from FFQs using the Phenol-Explorer database. Associations were examined using multivariable-adjusted restricted cubic splines based on Cox proportional hazards models.

Results: After a median [IQR] follow-up time of 21 [20-22] y, 2131 participants had been hospitalized for any PAD. The association between total flavonoid intake and total PAD hospitalizations was nonlinear, reaching a plateau at ∼750-1000 mg/d. Compared with the median flavonoid intake in quintile 1 (174 mg/d), an intake of 1000 mg/d was associated with a 32% lower risk of any PAD hospitalization (HR: 0.68; 95% CI: 0.60, 0.77), a 26% lower risk of atherosclerosis (HR: 0.74; 95% CI: 0.62, 0.88), a 28% lower risk of an aneurysm (HR: 0.72; 95% CI: 0.59, 0.88), and a 47% lower risk of a hospitalization for other peripheral vascular disease (HR: 0.53; 95% CI: 0.42, 0.67). A higher total flavonoid intake was also significantly associated with a lower incidence of revascularization or endovascular surgery and lower extremity amputation. The association between total flavonoid intake and PAD hospitalizations differed according to baseline smoking status, alcohol intake, BMI, and diabetes status.

Conclusions: Ensuring the adequate consumption of flavonoid-rich foods, particularly in subpopulations prone to the development of atherosclerosis, may be a key strategy to lower the risk of PAD.
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http://dx.doi.org/10.1093/ajcn/nqaa300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779235PMC
November 2020

Premature permanent discontinuation of apixaban or warfarin in patients with atrial fibrillation.

Heart 2021 May 16;107(9):713-720. Epub 2020 Sep 16.

Duke Clinical Research Institute, Durham, North Carolina, USA

Aims: The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial randomised patients with atrial fibrillation at risk of stroke to apixaban or warfarin. We sought to describe patients from ARISTOTLE who prematurely permanently discontinued study drug.

Methods/results: We performed a posthoc analysis of patients from ARISTOTLE who prematurely permanently discontinued study drug during the study or follow-up period. Discontinuation rates and reasons for discontinuation were described. Death, thromboembolism (stroke, transient ischaemic attack, systemic embolism), myocardial infarction and major bleeding rates were stratified by ≤30 days or >30 days after discontinuation. A total of 4063/18 140 (22.4%) patients discontinued study drug at a median of 7.3 (2.2, 15.2) months after randomisation. Patients with discontinuation were more likely to be female and had a higher prevalence of cardiovascular disease, diabetes, renal impairment and anaemia. Premature permanent discontinuation was more common in those randomised to warfarin than apixaban (23.4% vs 21.4%; p=0.002). The most common reasons for discontinuation were patient request (46.1%) and adverse event (34.9%), with no significant difference between treatment groups. The cumulative incidence of clinical events ≤30 days after premature permanent discontinuation for all-cause death, thromboembolism, myocardial infarction, and major bleeding was 5.8%, 2.6%, 0.9%, and 3.0%, respectively. No significant difference was seen between treatment groups with respect to clinical outcomes after discontinuation.

Conclusion: Premature permanent discontinuation of study drug in ARISTOTLE was common, less frequent in patients receiving apixaban than warfarin and was followed by high 30-day rates of death, thromboembolism and major bleeding. Initiatives are needed to reduce discontinuation of oral anticoagulation.
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http://dx.doi.org/10.1136/heartjnl-2020-317229DOI Listing
May 2021

Treatment of Older Patients with Atrial Fibrillation by Morbidity Burden.

Eur Heart J Qual Care Clin Outcomes 2020 Aug 28. Epub 2020 Aug 28.

Department of Cardiology, Herlev-Gentofte University Hospital, University of Copenhagen, Hellerup, Denmark.

Aims: Older patients with atrial fibrillation (AF) are at risk of adverse outcomes, which is accentuated by comorbidities. We sought to examine the association between morbidity burden and the treatment of older AF patients.

Methods And Results: Using Danish nationwide registers we included patients ≥ 70 years of age between 2010 and 2017 at their first hospitalization due to AF. Using multiple logistic regression models we examined the association between morbidity burden and the odds of receiving oral anticoagulants (OACs), anti-arrhythmic drugs (AAD), and rhythm control procedures (direct current cardioversions and catheter ablations).A total of 48,995 patients were included with a majority of women (54%), with a median age of 80 years (interquartile range [IQR] 75-85), and a median morbidity burden of 2 comorbidities (IQR 1-3). Increasing morbidity burden was associated with decreasing odds of OAC treatment with patients having > 5 comorbidities having the lowest odds (Odds Ratio [OR] 0.38, 95% Confidence Interval [CI] 0.35-0.42) compared to patients with low morbidity burden (0-1 comorbidities). Having > 5 comorbidities was associated with increased odds of AAD treatment (OR 1.90, 95% CI 1.64-2.21) and decreased odds of AF procedures (OR 0.39, 95% CI 0.31-0.48), compared to patients with a low morbidity burden (0-1 comorbidities). Examining morbidity burden continuously revealed similar results.

Conclusions: In older AF patients, multimorbidity was associated with lower odds of receiving OACs and rhythm control procedures but increased odds of AADs. This presents a clinical conundrum as multimorbid patients potentially benefit the most from treatment with OACs.
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http://dx.doi.org/10.1093/ehjqcco/qcaa070DOI Listing
August 2020

An overview and update on the epidemiology of flavonoid intake and cardiovascular disease risk.

Food Funct 2020 Aug;11(8):6777-6806

School of Biomedical Sciences, University of Western Australia, Royal Perth Hospital Research Foundation, Perth, Australia. and School of Medical and Health Sciences, Edith Cowan University, Perth, Australia and Institute for Global Food Security, Queen's University, Belfast, Northern Ireland.

There is an accumulating body of literature reporting on dietary flavonoid intake and the risk of cardiovascular disease (CVD) in prospective cohort studies. This makes apparent the need for an overview and update on the current state of the science. To date, at least 27 prospective cohorts (in 44 publications) have evaluated the association between estimated habitual flavonoid intake and CVD risk. At this time, the totality of evidence suggests long-term consumption of flavonoid-rich foods may be associated with a lower risk of fatal and non-fatal ischemic heart disease (IHD), cerebrovascular disease, and total CVD; disease outcomes which are principally, though not exclusively, composed of cases of atherosclerotic CVD (ASCVD). To date, few studies have investigated outcome specific ASCVD, such as peripheral artery disease (PAD) or ischemic stroke. Of the flavonoid subclasses investigated, evidence more often implicates diets rich in anthocyanins, flavan-3-ols, and flavonols in lowering the risk of CVD. Although inferences are restricted by confounding and other inherent limitations of observational studies, causality appears possible based on biological plausibility, temporality, and the relative consistency of the reported associations. However, whether the associations observed represent a benefit of the isolated bioactives per se, or are a signal of the bioactives acting in concert with the co-occurring nutrient matrix within flavonoid-bearing foods, are issues of consideration. Thus, the simple interpretation, and the one most relevant for dietary advice, is that consumption of flavonoid-rich foods or diets higher in flavonoids, appear nutritionally beneficial in the prevention of CVD.
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http://dx.doi.org/10.1039/d0fo01118eDOI Listing
August 2020

Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI.

J Am Coll Cardiol 2020 07;76(2):162-171

Duke Clinical Research Institute, Durham, North Carolina; Division of Cardiology, Duke University School of Medicine, Durham, North Carolina. Electronic address:

Background: The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.

Objectives: The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.

Methods: In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.

Results: Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).

Conclusions: Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.
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http://dx.doi.org/10.1016/j.jacc.2020.05.031DOI Listing
July 2020

Flavonoid intake and its association with atrial fibrillation.

Clin Nutr 2020 12 23;39(12):3821-3828. Epub 2020 Apr 23.

Department of Cardiology, Herlev & Gentofte University Hospital, Copenhagen, Denmark.

Background & Aims: Primary prevention of atrial fibrillation (AF) through behavioural and dietary modification is a critically important and unmet need. Flavonoids are bioactive dietary compounds with promising cardiovascular health benefits. Our aim was to investigate the association between flavonoid intake and clinically apparent AF.

Methods: Baseline data from 55 613 participants of the Danish Diet, Cancer and Health Study, without AF, recruited between 1993 and 1997, were cross-linked with Danish nationwide registries. Total flavonoid and flavonoid subclass intakes were calculated from validated food frequency questionnaires using the Phenol-Explorer database. Associations between flavonoid intake and incident AF (first-time hospitalization or outpatient visit) were examined using restricted cubic splines based on Cox proportional hazards models.

Results: During a median [IQR] follow-up of 21 [18-22] years, 7291 participants were diagnosed with AF. Total flavonoid intake was not statistically significantly associated with risk of incident AF in the whole cohort. However, compared to the lowest quintile, a total flavonoid intake of 1000 mg/day was associated with a lower risk of AF in smokers [0.86 (0.77, 0.96)] but not in non-smokers [0.96 (0.88, 1.06)], and a lower risk of AF in high alcohol consumers [>20 g/d: 0.84 (0.75, 0.95)] but not in low-to-moderate alcohol consumers [<20 g/d: 0.97 (0.89, 1.07)].

Conclusion: Intake of flavonoids was not significantly associated with a lower risk of incident AF. However, higher intakes of flavonoids may be beneficial for those at a higher risk of developing AF.
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http://dx.doi.org/10.1016/j.clnu.2020.04.025DOI Listing
December 2020

Haematuria and urinary tract cancers in patients with atrial fibrillation treated with oral anticoagulants.

Eur Heart J Cardiovasc Pharmacother 2021 Sep;7(5):373-379

Department of Cardiology, Herlev-Gentofte University Hospital, University of Copenhagen, Kildegårdsvej 28, 2900 Hellerup, Denmark.

Aims: Patients with atrial fibrillation (AF) treated with oral anticoagulants (OACs) have an increased risk of bleeding including haematuria. In the general population, gross haematuria is associated with urinary tract cancer. Consequently, we aimed to investigate the potential association between gross haematuria and urinary tract cancer in anticoagulated patients with AF.

Methods And Results : Using Danish nationwide registers, we included Danish AF patients treated with OACs between 2001 and 2015. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risk of urinary tract cancer in patients with and without gross haematuria. We included 125 063 AF patients with a median age of 74 years (interquartile range 65-80) and a majority of males (57%). The absolute risk of gross haematuria 12 months after treatment initiation increased with age ranging from 0.37% [95% confidence interval (CI) 0.31-0.42] to 0.85% (95% CI 0.75-0.96) in the youngest and oldest age groups of ≤70 and >80 years of age, respectively. The 1-year risk of urinary tract cancer after haematuria ranged from 4.2% (95% CI 2.6-6.6) to 6.5% (95% CI 4.6-9.0) for patients in age group >80 and 71-80 years, respectively. Gross haematuria conferred large risk ratios of urinary tract cancer when comparing patients with and without haematuria across all age groups.

Conclusion : Gross haematuria was associated with clinically relevant risks of urinary tract cancer in anticoagulated patients with AF. These findings underline the importance of meticulously examining anticoagulated patients with haematuria.
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http://dx.doi.org/10.1093/ehjcvp/pvaa045DOI Listing
September 2021

Risk factors and a 3-month risk score for predicting pacemaker implantation in patients with atrial fibrillations.

Open Heart 2020 24;7(1):e001125. Epub 2020 Mar 24.

Cardiology, Gentofte Hospital, Hellerup, Denmark.

Objectives: To identify risk factors and to develop a predictive risk score for pacemaker implantation in patients with atrial fibrillation (AF).

Methods: Using Danish nationwide registries, patients with newly diagnosed AF from 2000 to 2014 were identified. Cox proportional-hazards regression computed HRs for risk factors of pacemaker implantation. A logistic regression was used to fit a prediction model for 3-month risk of pacemaker implantation and derived a risk score using 80% of the data and its predictive accuracy estimated using the remaining 20%.

Results: Among 155 934 AF patients included, the median age (IQR) was 75 (65-83) and 51.3% were men. During a median follow-up time of 3.4 (1.2-5.0) years, 8348 (5.4%) patients received a pacemaker implantation. Risk factors of pacemaker implantation were (in order of highest risk first) age above 60 years, congenital heart disease, heart failure at age under 60 years, prior syncope, valvular AF, hypertension, ischaemic heart disease, male sex and diabetes mellitus. The derived risk score assigns points ranging from 1 to 14 to each of these risk factors. The 3-month risk of pacemaker implantation increased from 0.4% (95% CI: 0.2 to 0.8) at 1 point to 2.6% (95% CI: 1.9 to 3.6) at 18 points. Area under the receiver operator characteristics curve was 62.9 (95% CI: 60.3 to 65.5).

Conclusion: We highlighted risk factors of pacemaker implantation in newly diagnosed AF patients and created a risk score. The clinical utility of the risk score needs further investigation.
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http://dx.doi.org/10.1136/openhrt-2019-001125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103856PMC
June 2020

Risk of major cardiovascular and neurologic events with obstructive sleep apnea among patients with atrial fibrillation.

Am Heart J 2020 05 7;223:65-71. Epub 2020 Jan 7.

Duke Clinical Research Institute, Duke University, Durham, NC. Electronic address:

Background: Obstructive sleep apnea (OSA) is a known risk factor for atrial fibrillation (AF). However, it remains unclear whether OSA is independently associated with worse cardiovascular and neurological outcomes in patients with AF.

Methods: We used the ORBIT-AF I and ORBIT-AF II to conduct a retrospective cohort study of 22,760 patients with AF with and without OSA. Adjusted multivariable Cox proportional hazards models was used to determine whether OSA was associated with increased risk for major adverse cardiac and neurologic events (MACNEs) (cardiovascular death, myocardial infarction, stroke/transient ischemic attack/non-central nervous system embolism (stroke/SE), and new-onset heart failure], combined and individually.

Results: A total of 4,045 (17.8%) patients had OSA at baseline. Median follow-up time was 1.5 (interquartile range: 1-2.2) years, and 1,895 patients experienced a MACNE. OSA patients were younger (median [interquartile range] 68 [61-75] years vs 74 [66-81] years), were more likely male (70.7% vs 55.3%), and had increased body mass index (median 34.6 kg/m [29.8-40.2] vs 28.7 kg/m [25.2-33.0]). Those with OSA had a higher prevalence of concomitant comorbidities such as diabetes, chronic obstructive pulmonary disease, and heart failure. OSA patients had higher use of antithrombotic therapy. After adjustment, the presence of OSA was significantly associated with MACNE (hazard ratio: 1.16 [95% CI: 1.03-1.31], P = .011). OSA was also an independent risk factor for stroke/SE beyond the CHADS-VASc risk factors (HR: 1.38 [95% CI 1.12-1.70], P = .003) but not cardiovascular death, myocardial infarction, new-onset heart failure, or major bleeding.

Conclusions: Among patients with AF, OSA is an independent risk factor for MACNE and, more specifically, stroke/SE.
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http://dx.doi.org/10.1016/j.ahj.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214210PMC
May 2020

Future research prioritization in cardiac resynchronization therapy.

Am Heart J 2020 05 21;223:48-58. Epub 2020 Feb 21.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; Department of Medicine, Duke University School of Medicine, Durham, NC; Duke-Margolis Center for Health Policy, Duke University, Durham, NC; Evidence Synthesis Group, Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC; Department of Population Health Sciences, Duke University School of Medicine, Durham, NC. Electronic address:

Background: Although cardiac resynchronization therapy (CRT) is effective for some patients with heart failure and a reduced left ventricular ejection fraction (HFrEF), evidence gaps remain for key clinical and policy areas. The objective of the study was to review the data on the effects of CRT for patients with HFrEF receiving pharmacological therapy alone or pharmacological therapy and an implantable cardioverter-defibrillator (ICD) and then, informed by a diverse group of stakeholders, to identify evidence gaps, prioritize them, and develop a research plan.

Methods: Relevant studies were identified using PubMed and EMBASE and ongoing trials using clinicaltrials.gov. Forced-ranking prioritization method was applied by stakeholders to reach a consensus on the most important questions. Twenty-six stakeholders contributed to the expanded list of evidence gaps, including key investigators from existing randomized controlled trials and others representing different perspectives, including patients, the public, device manufacturers, and policymakers.

Results: Of the 18 top-tier evidence gaps, 8 were related to specific populations or subgroups of interest. Seven were related to the comparative effectiveness and safety of CRT interventions or comparators, and 3 were related to the association of CRT treatment with specific outcomes. The association of comorbidities with CRT effectiveness ranked highest, followed by questions about the effectiveness of CRT among patients with atrial fibrillation and the relationship between gender, QRS morphology and duration, and outcomes for patients either with CRT plus ICD or with ICD.

Conclusions: Evidence gaps presented in this article highlight numerous, important clinical and policy questions for which there is inconclusive evidence on the role of CRT and provide a framework for future collaborative research.
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http://dx.doi.org/10.1016/j.ahj.2020.02.011DOI Listing
May 2020

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

Eur Heart J 2020 Feb 7. Epub 2020 Feb 7.

Department of Cardiology, Herlev and Gentofte University Hospital, University of Copenhagen, Gentofte Hospitalsvej 1, 2900, Hellerup, Denmark.

Aims: Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer.

Methods And Results: A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively.

Conclusion: In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.
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http://dx.doi.org/10.1093/eurheartj/ehz964DOI Listing
February 2020

Amiodarone treatment in atrial fibrillation and the risk of incident cancers: A nationwide observational study.

Heart Rhythm 2020 04 29;17(4):560-566. Epub 2019 Nov 29.

Department of Cardiology, Herlev-Gentofte University Hospital, University of Copenhagen, Hellerup, Denmark.

Background: In observational studies, case reports, and animal studies, amiodarone has been associated with incident cancer.

Objective: The purpose of this study was to examine whether a dose-response relationship between amiodarone use and the risk of cancer could be ascertained in a large nationwide study cohort.

Methods: Using nationwide registers, we included all Danish patients with atrial fibrillation (AF) treated with amiodarone from 1996 to 2014. Exposure was defined both by categories and as a continuous variable of the cumulative defined daily doses (cDDDs) of amiodarone. The associations between amiodarone cDDD and incident cancer, as well as organ-specific types of cancer (skin, liver, lung), were estimated using multivariable Cox regression models and reported as hazard ratios (HR) with 95% confidence intervals (CI) and using cubic restricted spline plots.

Results: We included 18,503 patients with a median follow-up time of 8.1 years (interquartile range [IQR] 4.3-12.4). Median age was 70 years (IQR 63-77). A total of 2974 individuals developed cancer during follow-up. We found no association between increasing amiodarone exposure (cDDD 181-400 and cDDD >400) and the hazard of incident cancer (HR 0.95; 95% CI 0.87-1.04; and HR 1.01; 95% CI 0.92-1.10) with reference to patients with cDDD <181. Similar results were found when investigating specific cancer types (skin, liver, and lung) as well as cDDD as a continuous variable.

Conclusion: In a large nationwide cohort of AF patients treated with amiodarone, we found no evidence of a dose-response relationship between cumulative dose of amiodarone and incident cancer risk.
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http://dx.doi.org/10.1016/j.hrthm.2019.11.025DOI Listing
April 2020

Associations between habitual flavonoid intake and hospital admissions for atherosclerotic cardiovascular disease: a prospective cohort study.

Lancet Planet Health 2019 11;3(11):e450-e459

School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia; School of Biomedical Sciences, University of Western Australia, Royal Perth Hospital, Perth, WA, Australia.

Background: Flavonoids, compounds found in plant-based foods and beverages, might ameliorate vascular damage and atherosclerosis. Therefore, our aim was to assess the association between flavonoid intake and hospital admissions due to atherosclerotic cardiovascular disease.

Methods: In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study were cross-linked with Danish nationwide registries. Eligible participants were aged 50-65 years, had no previous history of atherosclerotic cardiovascular disease, and had completed a food-frequency questionnaire at baseline. We examined associations between flavonoid intake (calculated from food-frequency questionnaires with use of the Phenol-Explorer database) and hospital admissions for atherosclerotic cardiovascular disease, ischaemic heart disease, ischaemic stroke, or peripheral arterial disease. We obtained hazard ratios (HRs) using restricted cubic splines based on Cox proportional hazards models.

Findings: Of the participants recruited to the Danish Diet, Cancer, and Health study between 1993 and 1997, our study population was comprised of 53 552 participants, with a median follow-up of 21 years (IQR 15-22). During follow-up, 8773 participants were admitted to hospital for atherosclerotic cardiovascular disease. We observed non-linear associations between flavonoid intake and hospital admissions, plateauing at total flavonoid intakes of approximately 1000 mg per day. Compared with an intake of 175 mg per day, an intake of 1000 mg per day was associated with a 14% lower risk of atherosclerotic cardiovascular disease (HR 0·86, 95% CI 0·81-0·91). For disease subtypes, we observed a 9% lower risk of ischaemic heart disease (0·91, 0·85-0·98), a non-significant 9% lower risk of ischaemic stroke (0·91, 0·82-1·01), and a 32% lower risk of peripheral artery disease (0·68, 0·60-0·78). The overall associations were stronger in smokers than in non-smokers, as well as stronger in consumers of high (>20 g per day) quantities of alcohol than in those consuming low-to-moderate (≤20 g per day) quantities.

Interpretation: Our results suggest that ensuring an adequate consumption of flavonoid-rich foods, particularly in subpopulations at risk of atherosclerosis such as smokers and consumers of high quantities of alcohol might mitigate some of the risk of atherosclerotic cardiovascular disease. More studies are needed to support and validate these data.

Funding: Danish Cancer Society.
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http://dx.doi.org/10.1016/S2542-5196(19)30212-8DOI Listing
November 2019

Sudden cardiac death in patients with myocarditis: Evaluation, risk stratification, and management.

Am Heart J 2020 02 15;220:29-40. Epub 2019 Aug 15.

Duke Clinical Research Institute, Durham, NC, USA; Division of Cardiology, Duke University Medical Center, Durham, NC, USA. Electronic address:

Myocarditis is a major cause of sudden cardiac death (SCD) and dilated cardiomyopathy (DCM) in young adults. Cardiac magnetic resonance is the established tool for the diagnosis of myocarditis, and late gadolinium enhancement detected on cardiac magnetic resonance imaging is the strongest independent predictor of SCD, all-cause mortality, and cardiac mortality. Several other factors have been associated with SCD or cardiac transplantation including New York Heart Association functional class III/IV, reduced left ventricular ejection fraction <35%, and right ventricular ejection fraction ≤45%. A fragmented QRS and a prolonged QTc interval on an electrocardiogram are predictors of VAs. The postulated mechanism of VA in acute myocarditis is ion channel dysfunction and inflammation that alter intracellular signaling, producing interstitial edema and fibrosis and thereby causing conduction abnormalities. VAs in chronic myocarditis are generally due to scar-mediated reentry. Treatment of myocarditis is tailored toward supportive care and symptomatic relief. The subset of patients who develop DCM should be treated with heart failure medications according to professional guideline recommendations. Indications for an implantable cardioverter-defibrillator are similar to those for nonischemic cardiomyopathy; however, an implantable cardioverter-defibrillator should be held in the acute phase of myocarditis to allow left ventricular ejection fraction recovery, and a wearable cardioverter-defibrillator may be beneficial for some patients. Antiarrhythmic medications are reserved for patients with symptomatic nonsustained or sustained VAs. Radiofrequency ablation appears to be an effective treatment option for VAs; however, more data on its safety and effectiveness are needed. This review addresses risk factors of SCD and VAs in patients with myocarditis with special emphasis on treatment and prevention of these outcomes.
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http://dx.doi.org/10.1016/j.ahj.2019.08.007DOI Listing
February 2020

Patients With Atrial Fibrillation Taking Nonsteroidal Anti-Inflammatory Drugs and Oral Anticoagulants in the ARISTOTLE Trial.

Circulation 2020 01 21;141(1):10-20. Epub 2019 Nov 21.

Duke Clinical Research Institute, Duke University, Durham, NC (F.D., H.M., D.M.W., R.D.L., J.H.A., J.B.W., C.B.G., S.M.A-K.).

Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) with oral anticoagulants has been associated with an increased risk of bleeding. We investigated the risk of bleeding and major cardiovascular outcomes in patients with atrial fibrillation taking NSAIDs and apixaban or warfarin.

Methods: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; n=18 201) compared apixaban with warfarin in patients with atrial fibrillation at an increased risk of stroke. Patients in ARISTOTLE without severe renal (creatine clearance ≤30 mL/min) or liver disease were included in this analysis (n=17 423). NSAID use at baseline, NSAID use during the trial (incident NSAID use), and never users were described. The primary outcome was major bleeding. Secondary outcomes included clinically relevant nonmajor bleeding, gastrointestinal bleeding, heart failure hospitalization, stroke or systemic embolism, and all-cause mortality. NSAID use during the trial, and the interaction between randomized treatment, was analyzed using time-dependent Cox proportional hazards models.

Results: Those with baseline NSAID use (n=832 [4.8%]), incident NSAID use (n=2185 [13.2%]), and never users were similar in median age (age [25th, 75th]; 70 [64, 77] versus 70 [63, 75] versus 70 [62, 76]). Those with NSAID use at baseline and incident NSAID use were more likely to have a history of bleeding than never users (24.5% versus 21.0% versus 15.6%, respectively). During a median follow-up (25th, 75th) of 1.8 (1.4, 2.3) years and when excluding those taking NSAID at baseline, we found that incident NSAID use was associated with an increased risk of major bleeding (hazard ratio [HR], 1.61 [95% CI, 1.11-2.33]) and clinically relevant nonmajor bleeding (HR, 1.70 [95% CI, 1.16-2.48]), but not gastrointestinal bleeding. No significant interaction was observed between NSAID use and randomized treatment for any outcome.

Conclusions: A substantial number of patients in the ARISTOTLE trial took NSAIDs. Incident NSAID use was associated with major and clinically relevant nonmajor bleeding, but not with gastrointestinal bleeding. The safety and efficacy of apixaban versus warfarin appeared not significantly to be altered by NSAID use. This study warrants more investigation of the effect of NSAIDs on the outcomes of patients treated with apixaban.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00412984.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041296DOI Listing
January 2020

GARFIELD-AF model for prediction of stroke and major bleeding in atrial fibrillation: a Danish nationwide validation study.

BMJ Open 2019 11 11;9(11):e033283. Epub 2019 Nov 11.

Department of General Practice, Amsterdam UMC, Amsterdam Public Health and Amsterdam Cardiovascular Sciences Research Institutes, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Objectives: To externally validate the accuracy of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) model against existing risk scores for stroke and major bleeding risk in patients with non-valvular AF in a population-based cohort.

Design: Retrospective cohort study.

Setting: Danish nationwide registries.

Participants: 90 693 patients with newly diagnosed non-valvular AF were included between 2010 and 2016, with follow-up censored at 1 year.

Primary And Secondary Outcome Measures: External validation was performed using discrimination and calibration plots. C-statistics were compared with CHADSVASc score for ischaemic stroke/systemic embolism (SE) and HAS-BLED score for major bleeding/haemorrhagic stroke outcomes.

Results: Of the 90 693 included, 51 180 patients received oral anticoagulants (OAC). Overall median age (Q1, Q3) were 75 (66-83) years and 48 486 (53.5%) were male. At 1-year follow-up, a total of 2094 (2.3%) strokes/SE, 2642 (2.9%) major bleedings and 10 915 (12.0%) deaths occurred. The GARFIELD-AF model was well calibrated with the predicted risk for stroke/SE and major bleeding. The discriminatory value of GARFIELD-AF risk model was superior to CHADSVASc for predicting stroke in the overall cohort (C-index: 0.71, 95% CI: 0.70 to 0.72 vs C-index: 0.67, 95% CI: 0.66 to 0.68, p<0.001) as well as in low-risk patients (C-index: 0.64, 95% CI: 0.59 to 0.69 vs C-index: 0.57, 95% CI: 0.53 to 0.61, p=0.007). The GARFIELD-AF model was comparable to HAS-BLED in predicting the risk of major bleeding in patients on OAC therapy (C-index: 0.64, 95% CI: 0.63 to 0.66 vs C-index: 0.64, 95% CI: 0.63 to 0.65, p=0.60).

Conclusion: In a nationwide Danish cohort with non-valvular AF, the GARFIELD-AF model adequately predicted the risk of ischaemic stroke/SE and major bleeding. Our external validation confirms that the GARFIELD-AF model was superior to CHADSVASc in predicting stroke/SE and comparable with HAS-BLED for predicting major bleeding.
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http://dx.doi.org/10.1136/bmjopen-2019-033283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858250PMC
November 2019

Atrial Fibrillation and Percutaneous Coronary Intervention.

Circ Cardiovasc Interv 2019 08 16;12(8):e008269. Epub 2019 Aug 16.

Division of Cardiology and Duke Clinical Research Institute, Duke University, Durham, NC (F.D., W.S.J., J.P.P.).

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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.008269DOI Listing
August 2019

Flavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort.

Nat Commun 2019 08 13;10(1):3651. Epub 2019 Aug 13.

School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia.

Flavonoids, plant-derived polyphenolic compounds, have been linked with health benefits. However, evidence from observational studies is incomplete; studies on cancer mortality are scarce and moderating effects of lifestyle risk factors for early mortality are unknown. In this prospective cohort study including 56,048 participants of the Danish Diet, Cancer, and Health cohort crosslinked with Danish nationwide registries and followed for 23 years, there are 14,083 deaths. A moderate habitual intake of flavonoids is inversely associated with all-cause, cardiovascular- and cancer-related mortality. This strong association plateaus at intakes of approximately 500 mg/day. Furthermore, the inverse associations between total flavonoid intake and mortality outcomes are stronger and more linear in smokers than in non-smokers, as well as in heavy (>20 g/d) vs. low-moderate (<20 g/d) alcohol consumers. These findings highlight the potential to reduce mortality through recommendations to increase intakes of flavonoid-rich foods, particularly in smokers and high alcohol consumers.
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http://dx.doi.org/10.1038/s41467-019-11622-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692395PMC
August 2019

Rate or Rhythm Control in Older Atrial Fibrillation Patients: Risk of Fall-Related Injuries and Syncope.

J Am Geriatr Soc 2019 10 24;67(10):2023-2030. Epub 2019 Jul 24.

Department of Cardiology, Herlev and Gentofte Hospital, Hellerup, Denmark.

Objectives: Management of atrial fibrillation (AF) with rate and/or rhythm control could lead to fall-related injuries and syncope, especially in the older AF population. We aimed to determine the association of rate and/or rhythm control with fall-related injuries and syncope in a real-world older AF cohort.

Design: A retrospective cohort study.

Setting: Danish nationwide administrative registries from 2000 to 2015.

Participants: A total of 100 935 patients with AF aged 65 years or older claiming prescription of rate-lowering drugs (RLDs) and/or anti-arrhythmic drugs (AADs) were included. We compared the use of rate-lowering monotherapy with rate-lowering dual therapy, AAD monotherapy, and AAD combined with rate-lowering therapy.

Measurements: Outcomes were fall-related injuries and syncope as a composite end point (primary) or separate end point (secondary).

Results: In this population, the median age was 78 years (interquartile range [IQR] = 72-84 y), and 53 481 (53.0%) were women. During a median follow-up of 2.1 years (IQR = 1.0-5.1), 17 132 (17.0%) experienced a fall-related injury, 5745 (5.7%) had a syncope, and 21 093 (20.9%) experienced either. Compared with rate-lowering monotherapy, AADs were associated with a higher risk of fall-related injuries and syncope. The incidence rate ratio (IRR) for the composite end point was 1.29 (95% confidence interval [CI]: 1.17-1.43) for AAD monotherapy and 1.46 [95% CI = 1.34-1.58] for AAD combined with rate-lowering therapy. When stratifying by individual drugs, amiodarone significantly increased the risk of fall-related injuries and syncope (IRR = 1.40 [1.26-1.55]). Compared with more than 180 days of rate-lowering monotherapy, a higher risk of all outcomes was seen in the first 90 days of any treatment; however, the greatest risk was in the first 14 days for those treated with AADs.

Conclusion: In AF patients aged 65 years and older, AAD use was associated with a higher risk of fall-related injuries and syncope, and the risk was highest within the first 14 days for those treated with AADs. Only amiodarone use was associated with a higher risk. J Am Geriatr Soc 67:2023-2030, 2019.
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http://dx.doi.org/10.1111/jgs.16062DOI Listing
October 2019
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