Lifetime risk of comorbidity in patients with simple congenital heart disease: a Danish nationwide study.

AIMS: In a continuously ageing population of patients with congenital heart disease (CHD), understanding the long-term risk of morbidity is crucial. The aim of this study was to compare the lifetime risks of developing comorbidities in patients with simple CHD and matched controls. METHODS AND RESULTS: Using the Danish nationwide registers spanning from 1977 to 2018, simple CHD cases were defined as isolated atrial septal defect (ASD), ventricular septal defect (VSD), pulmonary stenosis, or patent ductus arteriosus in patients surviving until at least 5 years of age. There were 10 controls identified per case. Reported were absolute lifetime risks and lifetime risk differences (between patients with simple CHD and controls) of incident comorbidities stratified by groups and specific cardiovascular comorbidities. Of the included 17 157 individuals with simple CHD, the largest subgroups were ASD (37.7%) and VSD (33.9%), and 52% were females. The median follow-up time for patients with CHD was 21.2 years (interquartile range: 9.4-39.0) and for controls, 19.8 years (9.0-37.0). The lifetime risks for the investigated comorbidities were higher and appeared overall at younger ages for simple CHD compared with controls, except for neoplasms and chronic kidney disease. The lifetime risk difference among the comorbidity groups was highest for neurological disease (male: 15.2%, female: 11.3%), pulmonary disease (male: 9.1%, female: 11.7%), and among the specific comorbidities for stroke (male: 18.9%, female: 11.4%). The overall risk of stroke in patients with simple CHD was mainly driven by ASD (male: 28.9%, female: 17.5%), while the risks of myocardial infarction and heart failure were driven by VSD. The associated lifetime risks of stroke, myocardial infarction, and heart failure in both sexes were smaller in invasively treated patients compared with untreated patients with simple CHD. CONCLUSION: Patients with simple CHD had increased lifetime risks of all comorbidities compared with matched controls, except for neoplasms and chronic kidney disease. These findings highlight the need for increased attention towards early management of comorbidity risk factors.

Familial Clustering of Aortic Size, Aneurysms, and Dissections in the Community.

BACKGROUND: Ruptured aortic aneurysm and aortic dissections are potentially preventable disorders associated with high mortality. Screening of individuals at risk may translate into elective surgical interventions and lowered mortality. It is uncertain if the risk of aortic dilation of varying degrees aggregates within families. METHODS: We investigated the risk of having thoracic and abdominal aortic sizes in the highest quartile (measured by computed tomography scans and indexed for body size) if at least 1 parent did so in the Framingham Heart Study cohorts, and estimated the incidence rates and hazard ratios of developing aortic aneurysm or dissection among first-degree relatives of those with aortic aneurysm or dissection, in comparison with age- and sex-matched controls (1:10 for aortic aneurysm and 1:100 for aortic dissection) using the Danish nationwide administrative registries. RESULTS: In the Framingham Heart Study, offspring (n=235) whose parent(s) had a sex- and age-standardized aortic size in the upper quartile had a multivariable-adjusted ≈3-fold increased odds ratio of belonging to the upper quartile themselves. In Denmark, a total of 68 939 individuals (mean age, 42 years) had a first-degree relative with aortic aneurysm and 7209 persons (mean age, 39 years) had a first-degree relative with aortic dissection. During an average follow-up of 7 years, first-degree relatives of patients with aortic aneurysm and dissection had a hazard ratio of 6.70 (95% CI, 5.96-7.52) for developing aortic aneurysm and a hazard ratio of 9.24 (95% CI, 5.53-15.44) for dissection in comparison with matched controls. These estimates remained unchanged on adjusting for several comorbidities, including prevalent hypertension, bicuspid aortic valve, and the Marfan syndrome. For both aortic aneurysm and dissections, the absolute event rates approached 1 per 1000 person-years for first-degree relatives versus 11 to 13 (aortic aneurysm) and 2 to 3 (aortic dissections) per 100 000 person-years among controls. CONCLUSIONS: Increased aortic size, a precursor of aortic aneurysm and a risk factor for dissection, clusters in families. The incidence rates of aortic aneurysm and dissections approach the incidence rates of other common cardiovascular conditions in first-degree relatives, supporting the use of systematic screening for these conditions.

Infective endocarditis and risk of death after cardiac implantable electronic device implantation: a nationwide cohort study.

AIMS: To determine the incidence, risk factors, and mortality of infective endocarditis (IE) following implantation of a first-time, permanent, cardiac implantable electronic device (CIED). METHODS AND RESULTS: From Danish nationwide administrative registers (beginning in 1996), we identified all de-novo permanent pacemakers (PMs) and implantable cardioverter defibrillators (ICDs) together with the occurrence of post-implantation IE-events in the period from 2000-2012. Included were 43 048 first-time PM/ICD recipients. Total follow-up time was 168 343 person-years (PYs). The incidence rate (per 1000 PYs) of IE in PM was 2.1 (95% confidence interval [CI]: 1.7-2.6) for single chamber devices and 6.2 (95% CI: 4.5-8.7) for cardiac resynchronization therapy (CRT); similarly, the rate of IE in ICD was 3.7 (95% CI: 2.9-4.7) in single chamber devices and 6.3 (95% CI: 4.4-9.0) in CRT. In multivariable analysis, increased PM complexity served as independent risk factor for IE {dual chamber PM [hazard ratio (HR) 1.39; 95% CI: 1.07-1.80] and CRT [HR: 1.84; 95% CI: 1.20-2.84]}. During follow-up, generator replacement (HR: 2.79; 95% CI: 1.87-4.17) and lead revision (HR: 4.33; 95% CI: 3.25-5.78) in PMs were associated with increased risk. Corresponding estimates in ICDs were 2.49 (95% CI: 1.28-4.86) and 6.58 (95% CI: 4.49-9.63). Risk of death after IE was significantly increased in PM and ICD with HRs of 1.56 (95% CI: 1.33-1.82) and 2.63 (95% CI: 2.00-3.48), respectively. CONCLUSION: The risk of IE increased with increasing PM complexity. Other important risk factors were subsequent generator replacement and lead revision. IE was associated with an increased risk of mortality in the area of CIED.

Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: a nationwide cohort study.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are assumed to increase bleeding risk, but their actual relation to serious bleeding in patients with atrial fibrillation (AF) who are receiving antithrombotic medication is unknown. OBJECTIVE: To investigate the risk for serious bleeding and thromboembolism associated with ongoing NSAID and antithrombotic therapy. DESIGN: Observational cohort study. SETTING: Nationwide registries. PATIENTS: Danish patients with AF hospitalized between 1997 and 2011. MEASUREMENTS: Absolute risk for serious bleeding and thromboembolism with ongoing NSAID and antithrombotic therapy, assessed by using Cox models. RESULTS: Of 150 900 patients with AF (median age, 75 years [interquartile range, 65 to 83 years]; 47% female), 53 732 (35.6%) were prescribed an NSAID during a median follow-up of 6.2 years (interquartile range, 2.1 to 14.0 years). There were 17 187 (11.4%) and 19 561 (13.0%) occurrences of serious bleeding and thromboembolism, respectively. At 3 months, the absolute risk for serious bleeding within 14 days of NSAID exposure was 3.5 events per 1000 patients compared with 1.5 events per 1000 patients without NSAID exposure. The risk difference was 1.9 events per 1000 patients. In patients selected for oral anticoagulant therapy, the absolute risk difference was 2.5 events per 1000 patients. Use of NSAIDs was associated with increased absolute risks for serious bleeding and thromboembolism across all antithrombotic regimens and NSAID types. An NSAID dosage above the recommended minimum was associated with a substantially increased hazard ratio for bleeding. LIMITATION: Observational design and unmeasured confounders. CONCLUSION: Use of NSAIDs was associated with an independent risk for serious bleeding and thromboembolism in patients with AF. Short-term NSAID exposure was associated with increased bleeding risk. Physicians should exercise caution with NSAIDs in patients with AF. PRIMARY FUNDING SOURCE: None.

Increased short-term risk of thrombo-embolism or death after interruption of warfarin treatment in patients with atrial fibrillation.

AIMS: It is presently unknown whether patients with atrial fibrillation (AF) are at increased risk of thrombo-embolic adverse events after interruption of warfarin treatment. The purpose of this study was to assess the risk and timing of thrombo-embolism after warfarin treatment interruption. METHODS AND RESULTS: A retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with AF in the period 1997-2008. Incidence rate ratios (IRRs) of thrombo-embolic events and all-cause mortality were calculated using the Poisson regression analyses. In total, 48 989 AF patients receiving warfarin treatment were included. Of these, 35 396 patients had at least one episode of warfarin treatment interruption. In all, 8255 deaths or thrombo-embolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0-90, 91-180, 181-270, and 271-360 days after treatment interruption, respectively. Correspondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient-years. In a multivariable analysis, the first 90-day interval of treatment interruption was associated with a markedly higher risk of death or thrombo-embolism (IRR 2.5; 95% confidence interval 2.3-2.8) vs. the interval of 271-360 days. CONCLUSION: In patients with AF, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thrombo-embolic events within the first 90 days of treatment interruption.

Endothelial function is unaffected by changing between carvedilol and metoprolol in patients with heart failure--a randomized study.

BACKGROUND: Carvedilol has been shown to be superior to metoprolol tartrate to improve clinical outcomes in patients with heart failure (HF), yet the mechanisms responsible for these differences remain unclear. We examined if there were differences in endothelial function, insulin stimulated endothelial function, 24 hour ambulatory blood pressure and heart rate during treatment with carvedilol, metoprolol tartrate and metoprolol succinate in patients with HF. METHODS: Twenty-seven patients with mild HF, all initially treated with carvedilol, were randomized to a two-month treatment with carvedilol, metoprolol tartrate or metoprolol succinate. Venous occlusion plethysmography, 24-hour blood pressure and heart rate measurements were done before and after a two-month treatment period. RESULTS: Endothelium-dependent vasodilatation was not affected by changing from carvedilol to either metoprolol tartrate or metoprolol succinate. The relative forearm blood flow at the highest dose of serotonin was 2.42 ± 0.33 in the carvedilol group at baseline and 2.14 ± 0.24 after two months continuation of carvedilol (P = 0.34); 2.57 ± 0.33 before metoprolol tartrate treatment and 2.42 ± 0.55 after treatment (p = 0.74) and in the metoprolol succinate group 1.82 ± 0.29 and 2.10 ± 0.37 before and after treatment, respectively (p = 0.27). Diurnal blood pressures as well as heart rate were also unchanged by changing from carvedilol to metoprolol tartrate or metoprolol succinate. CONCLUSION: Endothelial function remained unchanged when switching the beta blocker treatment from carvedilol to either metoprolol tartrate or metoprolol succinate in this study, where blood pressure and heart rate also remained unchanged in patients with mild HF. TRIAL REGISTRATION: Current Controlled Trials NCT00497003.

Time Trends in Simple Congenital Heart Disease Over 39 Years: A Danish Nationwide Study.

Background We describe calendar time trends of patients with simple congenital heart disease. Methods and Results Using the nationwide Danish registries, we identified individuals diagnosed with isolated ventricular septal defect, atrial septal defect, patent ductus arteriosus, or pulmonary stenosis during 1977 to 2015, who were alive at 5 years of age. We reported incidence per 1 000 000 person-years with 95% CIs, 1-year invasive cardiac procedure probability and age at time of diagnosis stratified by diagnosis age (children ≤18 years, adults >18 years), and 1-year all-cause mortality stratified by diagnosis age groups (5-30, 30-60, 60+ years). We identified 15 900 individuals with simple congenital heart disease (ventricular septal defect, 35.2%; atrial septal defect, 35.0%; patent ductus arteriosus, 25.2%; pulmonary stenosis, 4.6%), of which 75.7% were children. From 1977 to 1986 and 2007 to 2015, the incidence rates increased for atrial septal defect in adults (8.8 [95% CI, 7.1-10.5] to 31.8 [95% CI, 29.2-34.5]) and in children (26.6 [95% CI, 20.9-32.3] to 150.8 [95% CI, 126.5-175.0]). An increase was only observed in children for ventricular septal defect (72.1 [95% CI, 60.3-83.9] to 115.4 [95% CI, 109.1-121.6]), patent ductus arteriosus (49.2 [95% CI, 39.8-58.5] to 102.2 [95% CI, 86.7-117.6]) and pulmonary stenosis (5.7 [95% CI, 3.0-8.3] to 21.5 [95% CI, 17.2-25.7]) while the incidence rates remained unchanged for adults. From 1977-1986 to 2007-2015, 1-year mortality decreased for all age groups (>60 years, 30.1%-9.6%; 30-60 years, 9.5%-1.0%; 5-30 years, 1.9%-0.0%), and 1-year procedure probability decreased for children (13.8%-6.6%) but increased for adults (13.3%-29.6%) were observed. Conclusions Increasing incidence and treatment and decreasing mortality among individuals with simple congenital heart disease point toward an aging and growing population. Broader screening methods for asymptomatic congenital heart disease are needed to initiate timely treatment and follow-up.

Metoprolol compared to carvedilol deteriorates insulin-stimulated endothelial function in patients with type 2 diabetes - a randomized study.

AIM: Studies of beta blockade in patients with type 2 diabetes have shown inferiority of metoprolol treatment compared to carvedilol on indices of insulin resistance. The aim of this study was to examine the effect of metoprolol versus carvedilol on endothelial function and insulin-stimulated endothelial function in patients with type 2 diabetes. METHOD: 24 patients with type 2 diabetes were randomized to receive either 200 mg metoprolol succinate or 50 mg carvedilol daily. Endothelium-dependent vasodilation was assessed by using venous occlusion plethysmography with increasing doses of intra-arterial infusions of the agonist serotonin. Insulin-stimulated endothelial function was assessed after co-infusion of insulin for sixty minutes. Vaso-reactivity studies were done before and after the two-month treatment period. RESULTS: Insulin-stimulated endothelial function was deteriorated after treatment with metoprolol, the percentage change in forearm blood-flow was 60.19% +/- 17.89 (at the highest serotonin dosages) before treatment and -33.80% +/- 23.38 after treatment (p = 0.007). Treatment with carvedilol did not change insulin-stimulated endothelial function. Endothelium-dependent vasodilation without insulin was not changed in either of the two treatment groups. CONCLUSION: This study shows that vascular insulin sensitivity was preserved during treatment with carvedilol while blunted during treatment with metoprolol in patients with type 2 diabetes. TRIAL REGISTRATION: Current Controlled Trials NCT00497003.

Clarithromycin use and risk of death in patients with ischemic heart disease.

OBJECTIVES: To examine whether treatment with clarithromycin was associated with an increased risk of death in patients with preexisting ischemic heart disease (IHD). METHODS: Employing nationwide registers, all patients with IHD events from 1997 to 2007 who subsequently claimed prescriptions for dual antibiotic treatment for eradication treatment were identified. The primary endpoint was all-cause mortality. RESULTS: The study included 214,330 individuals with IHD; 5,265 (2.5 %) of these claimed prescriptions for dual antibiotics. Compared with IHD patients not undergoing eradication therapy, no increase in the risk of all-cause mortality was demonstrated (HR 1.02; 95% CI 0.84-1.23, p = 0.87) after 5 years. CONCLUSIONS: The use of clarithromycin in the setting of eradication treatment for Helicobacter pylori in patients with IHD was not associated with an increased risk of death.

Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist.

BACKGROUND: The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. METHODS: First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion. RESULTS: Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours. CONCLUSIONS: Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.

Jeopardized Myocardium and Survival in Patients Presenting to the Catheterization Laboratory With ST-Elevation Myocardial Infarction and Shock.

OBJECTIVE: We aimed to relate the amount of jeopardized myocardium to mortality in shocked patients presenting to the catheterization laboratory with ST-elevation myocardial infarction (STEMI) and cardiogenic shock. BACKGROUND: In contrast with historical data and previous professional guidance, contemporary randomized data suggest that multi-vessel revascularization in such patients does not improve survival; mechanistic insight is incomplete. METHODS: Clinical databases identified cases of STEMI and shock triaged for primary percutaneous coronary intervention (PPCI) in Eastern Denmark from June 2011 to December 2014 (n = 128). British Cardiovascular Intervention Society (BCIS)-1 jeopardy scores were calculated from angiography. The study endpoint was 30-day mortality. RESULTS: Median lactate values were 6.0 [2.9-10.7] mmol/L. 30-day mortality was 53.9%. 68% of patients had multi-vessel coronary disease. Median pre-PCI BCIS-1 myocardial jeopardy scores were 8 [6-10]. After multiple logistic regression increasing age (p = 0.008; odds ratio [OR] 1.06), lactate values (p = 0.017; OR 1.02), mechanical ventilation (p = 0.011; OR 1.25) and a systolic blood pressure ≤ 90 mmHg at end-case (p = 0.005; OR 1.26) were predictive of 30-day mortality. Post-PPCI culprit vessel TIMI 3 flow was associated with reduced mortality (p < 0.001; OR 0.66). There was no association between pre-PCI jeopardy scores and the primary endpoint. CONCLUSIONS: In patients with STEMI and shock, myocardial jeopardy scores do not relate to patient outcomes. Jeopardy scores may be applied to existing datasets in order to understand why multi-vessel revascularization does not lead to the anticipated clinical benefits in cardiogenic shock.

Prognostic importance of a restrictive transmitral filling pattern in patients with symptomatic congestive heart failure and atrial fibrillation.

BACKGROUND: Restrictive diastolic filling pattern is associated with increased mortality in patients with myocardial infarction and heart failure. Most studies have excluded patients with atrial fibrillation. The aim of the present study was to assess the prognostic value of a restrictive filling pattern in patients with atrial fibrillation. METHODS: Doppler echocardiography including pulsed wave Doppler assessment of transmitral flow was performed in 880 patients with a clinical diagnosis of heart failure on hospital admission. Filling was considered restrictive when the mitral deceleration time

Comparison of the novel vasodilator uridine triphosphate and adenosine for the measurement of fractional flow reserve.

AIM: Examination of the fractional flow reserve (FFR) responses of intravenous (IV) adenosine with increasing doses of intracoronary (IC) adenosine versus IC uridine triphosphate (UTP) in patients with coronary artery disease. METHODS AND RESULTS: We measured FFR in 25 patients during continuous IV and IC infusion (using a microcatheter in the coronary ostium). Standard IV adenosine infusion (140 µg/kg/min) was compared to 8 equimolar incremental doses of IC UTP and IC adenosine (20, 40, 60, 80, 160, 240, 320 and 640 µg/min) in a randomized order. Across all doses, ΔFFR[IC UTP - IC adenosine] was -0.038 ± 0.008, P<.001. At the highest dose of IC UTP, FFR was significantly lower (FFR[IC UTP] = 0.62 ± 0.04) than during IV adenosine (FFR[IV adenosine] = 0.72 ± 0.05; P=.02) and IC adenosine (FFR[IC adenosine] = 0.68 ± 0.05; P=.03). Furthermore, UTP had significantly fewer side effects compared to IV (P<.001) and IC adenosine (P<.05). CONCLUSION: IC UTP lowered FFR significantly more than both IV and IC adenosine and with fewer side effects, and could be a more precise alternative to adenosine.

Hormone replacement therapy and risk of new-onset atrial fibrillation after myocardial infarction--a nationwide cohort study.

OBJECTIVES: Our aim was to assess the association between use of hormone replacement therapy (HRT) and risk of new-onset atrial fibrillation (AF) after myocardial infarction. DESIGN, SETTING AND PARTICIPANTS: We used Danish nationwide registers of hospitalizations and prescriptions to identify all women admitted with myocardial infarction in the period 1997 to 2009 and with no known diagnosis of AF. Their use of overall HRT and HRT categories was assessed. Multivariable Cox proportional hazards analysis was used to calculate the risk of new-onset AF first year after discharge, comparing use of HRT to no use. MAIN OUTCOME MEASURES: New-onset atrial fibrillation. RESULTS: In the period 1997 to 2009, 32 925 women were discharged alive after MI. In the first year after MI, new-onset AF was diagnosed in 1381 women (4.2%). Unadjusted incidence rates of AF decreased with use of HRT (incidence rate 37.4 for use of overall HRT and 53.7 for no use). Overall HRT was associated with a decreased risk of AF (HR 0.82, 95% confidence interval [CI] 0.68-1.00). The lowest risk of AF was found in women ≥80 years old for use of overall HRT and vaginal estrogen (HR 0.63, CI 0.42-0.94, and HR 0.58, CI 0.34-0.99, respectively). Decreased risk of AF with use of overall HRT and HRT categories was also found in other age groups. CONCLUSIONS: Use of HRT is associated with a decreased risk of new-onset AF in women with myocardial infarction first year after discharge. The underlying mechanisms remain to be determined. Unmeasured confounding might be one of them.

The effect of chronic heart failure and type 2 diabetes on insulin-stimulated endothelial function is similar and additive.

AIM: Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes. METHODS: Twenty-three patients with systolic heart failure and no history of diabetes, seven patients with both systolic heart failure and type 2 diabetes, 19 patients with type 2 diabetes, and ten healthy controls were included in the study. Endothelial function was studied by venous occlusion plethysmography. Insulin-stimulated endothelial function was assessed after intra-arterial infusion of insulin followed by co-infusion with serotonin in three different dosages. Forearm glucose uptake was measured during the insulin infusion. RESULTS: Patients with systolic heart failure had impaired insulin-stimulated endothelial function. The percentage increase in blood flow during co-infusion with insulin and serotonin dose response study was 24.74% ± 6.16%, 23.50% ± 8.32%, and 22.29% ± 10.77% at the three doses respectively, compared to the healthy control group 45.96% ± 11.56%, 67.40% ± 18.11% and 84.57% ± 25.73% (P = 0.01). Insulin-stimulated endothelial function was similar in heart failure patients and patients with type 2 diabetes, while it was further deteriorated in patients suffering from both heart failure and diabetes with a percentage increase in blood flow of 19.15% ± 7.81%, -2.35% ± 11.76%, and 5.82% ± 17.70% at the three doses of serotonin, respectively. Forearm glucose uptake was impaired in patients with heart failure compared to healthy controls (P = 0.03) and tended to be further impaired by co-existence of diabetes (P = 0.08). CONCLUSION: Systolic heart failure and type 2 diabetes result in similar vascular insulin resistance and reduced muscular insulin-stimulated glucose uptake. The effects of systolic heart failure and type 2 diabetes appear to be additive.

Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a 'real world' nationwide cohort study.

It was the aim of this study to determine the efficacy and safety of vitamin K antagonists (VKAs) and acetylsalicylic acid (ASA) in patients with non-valvular atrial fibrillation (AF), with separate analyses according to predicted thromboembolic and bleeding risk. By individual level-linkage of nationwide registries, we identified all patients discharged with non-valvular AF in Denmark (n=132,372). For every patient, the risk of stroke and bleeding was calculated by CHADS2, CHA2DS2-VASc, and HAS-BLED. During follow-up, treatment with VKA and ASA was determined time-dependently. VKA consistently lowered the risk of thromboembolism compared to ASA and no treatment; the combination of VKA+ASA did not yield any additional benefit. In patients at high thromboembolic risk, hazard ratios (95% confidence interval) for thromboembolism were: 1.81 (1.73-1.90), 1.14 (1.06-1.23), and 1.86 (1.78-1.95) for ASA, VKA+ASA, and no treatment, respectively, compared to VKA. The risk of bleeding was increased with VKA, ASA, and VKA+ASA compared to no treatment, the hazard ratios were: 1.0 (VKA; reference), 0.93 (ASA; 0.89-0.97), 1.64 (VKA+ASA; 1.55-1.74), and 0.84 (no treatment; 0.81-0.88), respectively. There was a neutral or positive net clinical benefit (ischaemic stroke vs. intracranial haemorrhage) with VKA alone in patients with a CHADS2 score of ≥ 0, and CHA2DS2-VASc score of ≥ 1. This large cohort study confirms the efficacy of VKA and no effect of ASA treatment on the risk of stroke/thromboembolism. Also, the risk of bleeding was increased with both VKA and ASA treatment, but the net clinical benefit was clearly positive, in favour of VKA in patients with increased risk of stroke/thromboembolism.

National Background is Associated with Disparities in Initiation and Persistence to Statin Treatment in Subjects with Diabetes in Denmark.

BACKGROUND: To investigate the effects of statin use over the last 10 years among diabetic patients who initiated glucose-lowering medications (GLMs) in Denmark. METHODS: we identified all Danish citizens 30 years and older who claimed their first GLM between 1997 and 2006, with follow-up until 2007. Use of medications, national background, income, and hospitalizations were obtained by cross-linkage of national registries in Denmark. We analyzed factors related to initiation and interruption of statin treatment. The analyses included country of birth, citizenship and, as proxy for ethnic origin, we constructed variables based on both the subjects and on their parent's country of birth. Countries were grouped as Denmark, Western countries, Eastern countries, and Africa. RESULTS: the cohort included 143,625 subjects. Compared with persons of Danish origin, the initiation of a statin medication during follow-up was significantly lower among patients of non-Danish origin: Odds ratio for subjects of Eastern origin 0.61 [CI 0.49-0.76] and 0.37 for subjects of African origin, [CI 0.24-0.59], both p < 0.001. The risk of interrupting statin treatment once it had been initiated was also higher in these groups (hazard ratio 2.03, [CI 1.91-2.17] for Eastern subjects and 1.94, [CI 1.63-2.32] for African subjects, both p < 0.0001). Combination of ethnic parameters to refine identification of the cohort led to the same conclusions as the analysis based only on country of birth or citizenship respectively. CONCLUSION: diabetes patients of African and Eastern origin in Denmark have less chance of being treated with a statin than those of western and Danish origin despite similar access to the Danish health care system.

Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease.

AIMS: The prognostic importance of atrial fibrillation (AF) in heart failure (HF) populations is controversial and may depend on patient selection. In the present study, we investigated the prognostic impact of AF in a large population with HF of various aetiologies. METHODS AND RESULTS: We included 2881 patients admitted to hospital with symptoms of worsening HF over a 4-year period (2001-2004), all patients were participants in the Echocardiography and Heart Outcome Study (ECHOS). Patients were followed for up to 7 years for all-cause mortality stratified according to heart rhythm (sinus rhythm, paroxysmal, or chronic AF) and according to the presence of ischaemic heart disease (IHD). During follow-up, 1934 patients (67%) died. In HF patients with a history of IHD, chronic AF was associated with an increased risk of death [hazard ratio (HR) 1.44; 95% confidence interval (CI): 1.18-1.77; P < 0.001). In contrast, in patients without IHD, chronic AF was not associated with an increased mortality risk (HR 0.88; 95% CI: 0.71-1.09; P = 0.25). There was significant interaction between the aetiology of HF and the prognostic importance of chronic AF (P(interaction) = 0.003). CONCLUSION: In patients with HF, AF is associated with an increased risk of death only in patients with underlying IHD.

Heart failure severity, as determined by loop diuretic dosages, predicts the risk of developing diabetes after myocardial infarction: a nationwide cohort study.

AIMS: Heart failure (HF) is associated with increased insulin resistance, but the consequences of HF for development of diabetes are not well studied. The aim of the present study was to investigate the relationship between HF severity and risk of developing diabetes in a nationwide cohort of patients with myocardial infarction (MI). METHODS AND RESULTS: Patients discharged from first-time MI during 1997-2006 and not previously treated with glucose-lowering medications (GLM) or loop diuretics were identified from Danish nationwide registers. Heart failure severity was determined by loop diuretic dosage after discharge. Patients were followed until first claimed prescription of GLM, death, or until the end of 2006. The cohort comprised 50 874 patients. A total of 3006 (6%) had mild (loop-diuretic dosage≤40 mg/day), 5383 (11%) moderate (>40-120 mg/day), and 1127 (2%) severe (>120 mg/day) HF. During follow-up, 2531 (5%) patients developed diabetes. Increasing HF severity was associated with increased risk of diabetes, but the use of renin-angiotensin system inhibitors (RASi) attenuated the risk (P-value for interaction between the HF group and RASi<0.05). Compared with no HF, the adjusted hazard ratios (95% confidence interval) for the development of diabetes were 1.34 (1.11-1.63), 1.63 (1.40-1.90), and 1.68 (1.25-2.25) for mild, moderate, and severe HF with RASi treatment; and 1.45 (1.13-1.88), 1.90 (1.56-2.33), and 3.02 (2.01-4.54) for mild, moderate, and severe HF without RASi treatment. CONCLUSION: Heart failure predicts the development of diabetes in a severity-dependent manner among patients with MI. Focus on increased predisposition to diabetes is warranted and needs further investigations.

Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) often require anticoagulation and platelet inhibition, but data are limited on the bleeding risk of combination therapy. METHODS: We performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF between January 1, 1997, and December 31, 2006, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding. RESULTS: A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89-4.76) for warfarin-aspirin-clopidogrel. CONCLUSIONS: In patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk than did warfarin monotherapy.