Blood-brain barrier permeable ß-blockers linked to lower risk of Alzheimer's disease in hypertension.

Alzheimer's disease is a neurodegenerative disorder in which the pathological accumulation of amyloid-ß and tau begins years before symptom onset. Emerging evidence suggests that ß-blockers (ß-adrenergic antagonists) increase brain clearance of these metabolites by enhancing CSF flow. Our objective was to determine whether ß-blocker treatments that easily cross the blood-brain barrier reduce the risk of Alzheimer's disease compared to less permeable ß-blockers. Data from the Danish national registers were used to identify a retrospective cohort of individuals with hypertension, and those treated with ß-blockers were included in the analysis. People with indications for ß-blocker use other than hypertension (e.g. heart failure) were only retained in a sensitivity analysis. ß-blockers were divided into three permeability groups: low, moderate and high. We used multivariable cause-specific Cox regression to model the effect of ß-blocker blood-brain barrier permeability on time to dementia outcomes, adjusting for baseline comorbidities, demographics and socioeconomic variables. Death was modelled as a competing risk. The 10-year standardized absolute risk was estimated as the averaged person-specific risks per treatment. In a cohort of 69 081 (median age = 64.4 years, 64.8% female) people treated with ß-blockers for hypertension, highly blood-brain barrier-permeable ß-blockers were associated with reduced risk of Alzheimer's disease versus low permeability ß-blockers (-0.45%, P < 0.036). This effect was specific to Alzheimer's diagnoses and did not extend to dementia in general. Propensity score analysis matching high and low blood-brain barrier-permeable patients also detected a decreased Alzheimer's risk (-0.92%, P < 0.001) in the high permeability group compared to the low, as did a 1-year landmark analysis (-0.57%, P < 0.029) in which events within the first year of follow-up were ignored as likely unrelated to treatment. Our results suggest that amongst people taking ß-blockers for hypertension, treatment with highly blood-brain barrier permeable ß-blockers reduces the risk of Alzheimer's disease compared to low permeability drugs. Our findings support the hypothesis that highly permeable ß-blockers protect against Alzheimer's disease by promoting waste brain metabolite clearance.

Serial troponin-T and long-term outcomes in suspected acute coronary syndrome.

BACKGROUND: Long-term prognostic implications of serial high-sensitivity troponin concentrations in subjects with suspected acute coronary syndrome are unknown. METHODS AND RESULTS: Individuals with a first diagnosis of myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019 who underwent two high-sensitivity troponin-T (hsTnT) measurements 1-7 h apart were identified through Danish national registries. Absolute and relative risks for death at days 0-30 and 31-365, stratified for whether subjects had normal or elevated hsTnT concentrations, and whether these concentrations changed by <20%, > 20 to 50%, or >50% in either direction from first to second measurement, were calculated through multivariable logistic regression with average treatment effect modeling. Of the 28 902 individuals included, 2.8% had died at 30 days, whereas 4.9% of those who had survived the first 30 days died between days 31-365. The standardized risk of death was highest among subjects with two elevated hsTnT concentrations (0-30 days: 4.3%, 31-365 days: 7.2%). In this group, mortality was significantly higher in those with a > 20 to 50% or >50% rise from first to second measurement, though only at 30 days. The risk of death was very low in subjects with two normal hsTnT concentrations (0-30 days: 0.1%, 31-365 days: 0.9%) and did not depend on relative or absolute changes between measurements. CONCLUSIONS: Individuals with suspected acute coronary syndrome and two consecutively elevated hsTnT concentrations consistently had the highest risk of death. Mortality was very low in subjects with two normal hsTnT concentrations, irrespective of changes between measurements.

Men who live alone have worse anticoagulation control: A Danish registry study.

Men living alone may have particular difficulty in managing chronic medical conditions. Anticoagulation control, a sensitive indicator of self-management, was significantly worse among men living alone.

Secondary stroke prophylaxis in atrial fibrillation patients with chronic kidney disease: a nationwide cohort study.

AIMS: Oral anticoagulation (OAC) therapy as secondary stroke prophylaxis in atrial fibrillation (AF) patients with chronic kidney disease (CKD) remains unexplored and poses a clinical treatment dilemma. We assessed the long-term risk of thromboembolic events according to post-stroke OAC therapy in AF patients with CKD after their first ischaemic stroke. METHODS AND RESULTS: We identified Danish AF patients with CKD who presented with first-time ischaemic stroke from 2005 to 2014. Chronic kidney disease was defined as a diagnosis code for CKD before baseline, defined as 100 days after stroke discharge. Post-stroke antithrombotic therapy (OAC therapy and antiplatelet therapy) was identified from prescription claims from discharge to baseline. Cumulative incidences and adjusted hazard ratios (HRs) of thromboembolic events according to post-stroke OAC therapy were examined. Of 1252 AF patients with CKD presenting with ischaemic stroke, 631 (50.4%) patients were on OAC therapy and 621 (49.6%) were on antiplatelet therapy alone at baseline [median age 76 (interquartile range, IQR 71-83) and 80 (IQR 72-86), respectively]. The median follow-up period was 1.9 years (IQR 0.8-3.6). Cumulative incidence rates of thromboembolic events and bleeding showed no significant difference between those on OAC therapy and antiplatelet therapy. The results from the multivariable analysis revealed similar results: thromboembolic risk was not modified by OAC treatment [adjusted HR 0.89, 95% confidence interval (CI) 0.73-1.09] nor was the risk of bleeding (adjusted HR 0.88, 95% CI 0.67-1.17). CONCLUSION: Oral anticoagulation in patients with CKD and prior stroke was not associated with a reduced risk of recurrent thromboembolic events compared with antiplatelet therapy.

Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study.

AIMS: To investigate the risk of stroke/thromboembolism (TE) and major bleeding associated with anaemia among patients with atrial fibrillation (AF). Also, to assess the effects of oral anticoagulation (OAC) and time in therapeutic range (TTR) with vitamin K antagonists according to level of haemoglobin (Hb). METHODS AND RESULTS: Through administrative registry databases, we identified all Danish patients diagnosed with AF from 1997 to 2012. We included 18 734 AF patients with recent available data on Hb. Multiple Cox regression analyses were used to estimate hazard ratios and to compute standardized absolute 1-year risks of stroke/TE and major bleeding. Among included patients, 3796 (20%) had mild anaemia (Hb 6.83-7.45 mmol/L for women and Hb 6.83-8.03 mmol/L for men) and 2562 (14%) had moderate/severe anaemia (Hb <6.83 mmol/L). Moderate/severe anaemia was associated with increased risk of major bleeding and 9.1% lower median TTR compared with no anaemia. Use of OAC was associated with reduced risk of stroke/TE among patients without anaemia [standardized absolute 1-year difference -2.5%, 95% confidence interval (CI) -3.8 to -1.7%] or with mild anaemia (-2.3%, 95% CI -2.8 to -1.8%), but not with moderate/severe anaemia, (0.03%, -1.8 to +2.8%, interaction P = 0.01). Oral anticoagulation was associated with a 5.3% (95% CI 2.1-8.7%) increased standardized absolute risk of major bleeding among AF patients with moderate/severe anaemia. CONCLUSION: Anaemia was common in patients with AF and associated with major bleeding and lower TTR. Oral anticoagulation was associated with more major bleeding, but no reduction in risk of stroke/TE among AF patients with moderate/severe anaemia.

The importance of time in therapeutic range in switching from vitamin K antagonist to non-vitamin K antagonist oral anticoagulants in atrial fibrillation.

AIMS: Patients with non-valvular atrial fibrillation (NVAF) receiving vitamin K antagonists (VKAs) with time in therapeutic international normalized ratio (INR) range (TTR) <70%, despite good adherence, are by guidelines recommended to switch to non-VKA oral anticoagulants (NOACs). The aim was to assess if patients are switched from VKA to NOAC when TTR is <70% in a real-world setting. METHODS AND RESULTS: Non-valvular atrial fibrillation patients receiving VKA (1 January 2010 to 31 December 2012) were identified in nationwide registries. Time in therapeutic range was calculated by the Rosendaal method by a minimum of three INR values. Time in therapeutic range of patients continuing VKA (non-switchers) were compared with patients switched from VKA to dabigatran or rivaroxaban (switchers), the only NOACs available at that time. Factors associated with switching were analysed in a multivariable logistic regression model. 7276 patients with NVAF receiving VKA were included; of these, 6437 (88.5%) patients continued VKA [57.9% male, median age 76.7 years (Q1-Q3 68.9-83.5)] and 839 (11.5%) switched to NOAC [54.0% male, median age 76.5 years (Q1-Q3 68.4-83.6)]. No significant differences in CHA2DS2-VASc and HAS-BLED scores were seen between the groups. The mean TTR for non-switchers was 64.0 [standard deviation (SD) 27.8] and 52.9 (SD 28.1) for switchers. Among non-switchers, 51% had a TTR <70% vs. 69% among switchers. 85% of patients with TTR <70%, were not switched contrary to recommendations. Time in therapeutic range <70% was associated with the switch [odds ratio 2.28, 95% confidence interval (1.92-2.72)]. CONCLUSION: A TTR below 70% was associated with switching from VKA to NOAC, yet by guidelines, most patients were still not switched.

Non-vitamin K antagonist oral anticoagulants vs. vitamin-K antagonists in patients with atrial fibrillation and chronic kidney disease: a nationwide cohort study.

BACKGROUND: We aimed to compare effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin-K antagonists (VKA) in atrial fibrillation (AF) patients with chronic kidney disease (CKD) not receiving dialysis. METHODS: By using personal identification numbers, we cross-linked individual-level data from Danish administrative registries. We identified every citizen with a prior diagnosis of AF and CKD who initiated NOAC or VKA (2011-2017). An external analysis of 727 AF patients with CKD (no dialysis) was performed to demonstrate level of kidney function in a comparable population. Study outcomes included incidents of stroke/thromboembolisms (TEs), major bleedings, myocardial infarctions (MIs), and all-cause mortality. We used Cox proportional hazards models to determine associations between oral anticoagulant treatment and outcomes. RESULTS: Of 1560 patients included, 1008 (64.6%) initiated VKA and 552 (35.4%) initiated NOAC. In a comparable population we found that 95.3% of the patients had an estimated glomerular filtration rate (eGFR) < 59 mL/min. Patients treated with NOAC had a significantly decreased risk of major bleeding (hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.26-0.84) compared to VKA. There was not found a significant association between type of anticoagulant and risk of stroke/TE (HR: 0.83, 95% CI: 0.39-1.78), MI (HR: 0.45, 95% CI: 0.18-1.11), or all-cause mortality (HR: 0.99, 95% CI: 0.77-1.26). CONCLUSION: NOAC was associated with a lower risk of major bleeding in patients with AF and CKD compared to VKA. No difference was found in risk of stroke/TE, MI, and all-cause mortality.

Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study.

Aims: We examined the risks of all-cause mortality, stroke, major bleeding, and recurrent traumatic injury associated with resumption of vitamin K antagonists (VKAs) and non-VKAs oral anticoagulants (NOACs) following traumatic injury in atrial fibrillation (AF) patients. Methods and results: This was a Danish nationwide registry-based study (2005-16), including 4541 oral anticoagulant (OAC)-treated AF patients experiencing traumatic injury (defined as traumatic brain injury, hip fracture, or traumatic torso or abdominal injury). Within 90 days following discharge from traumatic injury, 60.6% resumed VKA (median age = 80, CHA2DS2-VASc = 4, HAS-BLED = 2), 16.7% resumed NOAC (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 2), and 22.7% did not resume OAC treatment (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 3). Switch from VKA to NOAC occurred among 9.5%. Since 2009, the trend in OAC resumption increased (P-value <0.0001), in particular with NOACs (P-value <0.0001). Follow-up started 90 days after discharge, and time-varying multiple Cox regression analyses were used for comparisons. Compared with non-resumption, VKA and NOAC resumption were associated with lower hazard [95% confidence interval (CI)] of all-cause mortality [hazard ratio (HR) 0.48 (0.42-0.53) and HR 0.55 (0.47-0.66), respectively] and ischaemic stroke [HR 0.56 (0.43-0.72) and HR 0.54 (0.35-0.82), respectively], increased major bleeding hazard [HR 1.30 (1.03-1.64) and HR 1.15 (0.81-1.63), respectively], and similar hazard of recurrent traumatic injury [HR 0.93 (0.73-1.18) and HR 0.87 (0.60-1.27), respectively]. Conclusion: AF patients resuming VKA and NOAC treatment following traumatic injury have lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleeding but without additional hazards of recurrent traumatic injury. Withholding OAC following a traumatic injury in AF patients may not be warranted.

Comparative thromboembolic risk in atrial fibrillation patients with and without a concurrent infection.

BACKGROUND: The aim of this study was to compare long-term thromboembolic risk in infection-related and non-infection-related atrial fibrillation (AF). METHODS: Using Danish nationwide registries, we identified patients with first-time AF from 1996-2015 and performed a retrospective cohort study. We did a 1:1 match (upon sex, age, calendar year, and oral anticoagulation (OAC) status at the beginning of follow-up) of patients with infection-related (concurrent discharge diagnosis code for infection) and non-infection-related AF. Long-term outcomes were examined using multivariable Cox regression analyses. RESULTS: Our study population comprised 48,644 patients equally distributed on infection-related and non-infection-related AF. In both groups, those initiated on OAC therapy were younger than those not initiated on OAC therapy (median age 77 years, interquartile range 69-83 versus median age 79 years, interquartile range 71-86). During the 1st year of follow up, infection-related AF was associated with an increased risk of thromboembolic events compared with non-infection-related AF: adjusted hazard ratio (HR) 1.44 (95% confidence interval (CI) 1.16-1.78) for those initiated on OAC therapy and HR 1.17 (95% CI 1.06-1.28) for those not initiated on OAC therapy. In both groups, OAC therapy was associated with better outcomes than no OAC therapy (HR of thromboembolic events 0.75 (95% CI 0.68-0.83) and HR 0.70 (95% CI 0.63-0.78) for patients with infection-related and non-infection-related AF, respectively). CONCLUSION: Infection was associated with an increased thromboembolic risk in patients with first-time AF. OAC therapy was associated with a similar risk-reduction in AF patients with and without a concurrent infection.

Ischaemic and haemorrhagic stroke associated with non-vitamin K antagonist oral anticoagulants and warfarin use in patients with atrial fibrillation: a nationwide cohort study.

BACKGROUND: Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are widely used as stroke prophylaxis in non-valvular atrial fibrillation (AF), but comparative data are sparse. PURPOSE: To compare dabigatran, rivaroxaban, and apixaban vs. VKA and the risk of stroke/thromboembolism (TE) and intracranial bleeding in AF. METHODS: Using Danish nationwide registries (2011-15), anticoagulant-naïve AF patients were identified when initiating VKA or an NOAC. Outcomes were stroke/TE and intracranial bleeding. Multiple outcome-specific Cox regression was performed to calculate average treatment effects as standardized differences in 1-year absolute risks. RESULTS: Overall, 43 299 AF patients initiated VKA (42%), dabigatran (29%), rivaroxaban (13%), and apixaban (16%). Mean CHA2DS2-VASc (SD) score was: VKA 2.9 (1.6), dabigatran 2.7 (1.6), rivaroxaban 3.0 (1.6), and apixaban 3.1 (1.6). Within patient-specific follow-up limited to the first 2 years, 1054 stroke/TE occurred and 261 intracranial bleedings. Standardized absolute risk (95% CI) of stroke/TE at 1 year after initiation of VKA was 2.01% (1.80% to 2.21%). In relation to VKA, the absolute risk differences were for dabigatran 0.11% (-0.16% to 0.42%), rivaroxaban 0.05% (-0.33% to 0.48%), and apixaban 0.45% (-0.001% to 0.93%). For the intracranial bleeding outcome, the standardized absolute risk at 1 year was for VKA 0.60% (0.49% to 0.72%); the corresponding absolute risk differences were for dabigatran -0.34% (-0.47% to - 0.21%), rivaroxaban -0.13% (-0.33% to 0.08%), and apixaban -0.20% (-0.38% to - 0.01%). CONCLUSIONS: Among anticoagulant-naïve AF patients, treatment with NOACs was not associated with significantly lower risk of stroke/TE compared with VKA, but intracranial bleeding risk was significantly lower with dabigatran and apixaban.

Renal Function and the Risk of Stroke and Bleeding in Patients With Atrial Fibrillation: An Observational Cohort Study.

BACKGROUND AND PURPOSE: We sought to determine the risk of stroke/thromboembolism and bleeding associated with reduced renal function in patients with atrial fibrillation and the risk of stroke and bleeding associated with warfarin treatment in specific estimated glomerular filtration rate (eGFR) groups. METHODS: We conducted a register-based cohort study and included patients discharged with nonvalvular atrial fibrillation from 1997 to 2011 with available eGFR. RESULTS: A total of 17 349 patients were identified with eGFR available at baseline. All levels of lower eGFR were associated with higher risk of stroke/thromboembolism and bleeding. Use of warfarin was associated with higher bleeding risk in all eGFR groups; hazard ratios 1.23 (95% confidence interval [CI], 0.97-1.56), 1.26 (95% CI, 1.14-1.40), 1.18 (95% CI, 1.07-1.31), 1.11 (95% CI, 0.87-1.42), 2.01 (95% CI, 1.14-3.54) in patients with eGFR ≥90, 60 to 89, 30 to 59, 15 to 29, and <15 mL/min per 1.73 m2, respectively. Use of warfarin was associated with lower risk of stroke/thromboembolism in patients with eGFR ≥15 mL/min per 1.73 m2; hazard ratios 0.57 (95% CI, 0.43-0.76), 0.57 (95% CI, 0.51-0.64), 0.48 (95% CI, 0.44-0.54), 0.60 (95% CI, 0.45-0.80) in patients with eGFR ≥90, 60 to 89, 30 to 59, and 15 to 29 mL/min per 1.73 m2, respectively. Use of warfarin was not associated with lower risk of stroke/thromboembolism in patients with eGFR<15 mL/min per 1.73 m2; hazard ratio 1.18 (95% CI, 0.58-2.40). CONCLUSIONS: In patients with atrial fibrillation, the risk of stroke and bleeding was associated with levels of renal function. Warfarin treatment was associated with higher risk of bleeding in all eGFR groups and lower risk of stroke in patients with eGFR≥15 mL/min per 1.73 m2.

Risk of gastrointestinal adverse effects of dabigatran compared with warfarin among patients with atrial fibrillation: a nationwide cohort study.

AIMS: To examine the risk of gastrointestinal adverse effects associated with dabigatran use compared with warfarin among patients with atrial fibrillation (AF). METHODS AND RESULTS: Patients with AF and no history of gastrointestinal diseases initiating dabigatran or warfarin were identified from Danish nationwide registries from 22 August 2011 until 31 December 2012. Patients were classified as naive or experienced users, according to prior use of oral anticoagulant (OAC) therapy. The risk of subsequent proton pump inhibitor (PPI) use, upper dyspepsia-like diagnoses (gastroesophageal reflux, gastritis, gastric, and duodenal ulcer) and gastrointestinal bleeding requiring hospitalization, gastroscopy, and discontinuation of dabigatran and warfarin was examined by cumulative incidence rates and multivariable adjusted Cox regression models. We identified five groups: OAC-naive warfarin (n = 4534); OAC-naive dabigatran 110 mg b.i.d. (dabigatran 110) (n = 1168); OAC-naive dabigatran 150 mg b.i.d. (dabigatran 150) (n = 1844); OAC-experienced dabigatran 110 (n = 1143); and OAC-experienced dabigatran 150 (n = 1748). Compared with OAC-naive warfarin, the rate of initiating PPIs was significantly increased for OAC-naive dabigatran 110 [hazard ratio (HR), 1.24; 95% confidence interval (CI), 1.02-1.50]. Other dabigatran regimes were not associated with a higher risk of initiating PPIs, upper dyspepsia-like diagnoses, gastrointestinal bleeding, or gastroscopy. The risk of discontinuation was increased for OAC-experienced dabigatran 150 (HR, 1.13; 95% CI, 1.02-1.25), but not for the other dabigatran-treated groups, relative to OAC-naive warfarin. CONCLUSION: Dabigatran was not associated with upper dyspepsia-like diagnoses or gastrointestinal bleeding requiring hospitalization, and gastroscopy. The risk of subsequent PPI use was increased for OAC-naive dabigatran 110 mg users, and the risk of discontinuation was increased for OAC-experienced dabigatran 150 mg users.

Efficacy and safety of oral anticoagulants according to kidney function among patients with atrial fibrillation.

BACKGROUND AND AIMS: Patients with severely reduced kidney function have been excluded from randomized controlled trials and data on the safety and efficacy of direct oral anticoagulants (DOACs) according to kidney function remain sparse. The aim was to evaluate the safety and efficacy of the DOACs across subgroups of kidney function. METHODS: Using multiple Danish nationwide registers and laboratory databases, we included patients initiated on oral anticoagulants (OACs) with atrial fibrillation and available creatinine level and followed patients for 2 years to evaluate occurrence of stroke/thromboembolism (TE) and major bleeding. RESULTS: Among 26 686 included patients, 3667 (13.7%) had an estimated glomerular filtration rate (eGFR) of 30-49 mL/min/1.73 m2 and 596 (2.2%) had an eGFR below 30 mL/min/1.73 m2. We found no evidence of differences regarding the risk of stroke/TE between the OACs (P-value interaction >0.05 for all). Apixaban was associated with a lower 2-year risk of major bleeding compared to vitamin K antagonists (VKA) [hazard ratio 0.79, 95% confidence interval (CI) 0.67-0.93], and the risk difference was significantly larger among patients with reduced kidney function (P-value interaction 0.018). Rivaroxaban was associated with a higher risk of bleeding compared to apixaban (hazard ratio 1.78, 95%CI 1.32-2.39) among patients with eGFR 30-49 mL/min/1.73 m2. CONCLUSIONS: Overall, we found no differences regarding the risk of stroke/TE, but apixaban was associated with a 21% lower relative risk of major bleeding compared to VKA. This risk reduction was even greater when comparing apixaban to VKA among patients with eGFR 15-30 mL/min/1.73 m2, and when comparing apixaban to dabigatran and rivaroxaban among patients with eGFR 30-49 mL/min/1.73 m2.

Serial troponin-I and long-term outcomes in subjects with suspected acute coronary syndrome.

AIMS: It is unclear how serial high-sensitivity troponin-I (hsTnI) concentrations affect long-term prognosis in individuals with suspected acute coronary syndrome (ACS). METHODS AND RESULTS: Subjects who underwent two hsTnI measurements (Siemens TnI Flex® Reagent) separated by 1-7 h, during a first-time hospitalization for myocardial infarction, unstable angina, observation for suspected myocardial infarction, or chest pain from 2012 through 2019, were identified through Danish national registries. Individuals were stratified per their hsTnI concentration pattern (normal, rising, persistently elevated, or falling) and the magnitude of hsTnI concentration change (<20%, >20-50%, or >50% in either direction). We calculated absolute and relative mortality risks standardized to the distributions of risk factors for the entire study population. A total of 20 609 individuals were included of whom 2.3% had died at 30 days, and an additional 4.7% had died at 365 days. The standardized risk of death was highest among persons with a persistently elevated hsTnI concentration (0-30 days: 8.0%, 31-365 days: 11.1%) and lowest among those with two normal hsTnI concentrations (0-30 days: 0.5%, 31-365 days: 2.6%). In neither case did relative hsTnI concentration changes between measurements clearly affect mortality risk. Among persons with a rising hsTnI concentration pattern, 30-day mortality was higher in subjects with a >50% rise compared with those with a less pronounced rise (2.2% vs. <0.1%). CONCLUSION: Among individuals with suspected ACS, those with a persistently elevated hsTnI concentration consistently had the highest risk of death. In subjects with two normal hsTnI concentrations, mortality was very low and not affected by the magnitude of change between measurements.

In this Danish study of >20 000 individuals with suspected heart attack, we confirmed the clinical importance of drawing two consecutive blood samples for measurement of high-sensitivity troponin-I concentrations (a marker of damage to the heart): The risk of death was highest in persons with two elevated high-sensitivity troponin-I concentrations and lowest in those with two normal concentrations.Among persons who had a first normal and a subsequently elevated high-sensitivity troponin-I concentration, a >50% relative rise was associated with significantly higher risk of death at 30 days.

Discontinuation of direct oral anticoagulants among patients with atrial fibrillation according to gender and cohabitation status: a nationwide cohort study.

AIMS: The aim of this study was to evaluate the risk of discontinuing treatment with direct oral anticoagulants (DOACs) among patients with atrial fibrillation (AF) according to cohabitation status and gender. METHODS AND RESULTS: Using the Danish national registers, we identified 32 364 patients with AF aged 40-90 years undergoing treatment with DOACs. The study period was from 2013 to 2017, and patients were followed for 2 years, or until death, outcome, or emigration. The main outcome was discontinuation of DOAC treatment for at least 30 days. The absolute 2-year risk of DOAC discontinuation was highest among men living alone [35.7%, 95% confidence interval (CI): 37.3-34.1%]. Men living alone had a 4.6% (95% CI: 6.4-2.8%) higher absolute risk of discontinuation and a 12% [hazard ratio (HR): 1.12, 95% CI: 1.04-1.20] higher relative risk of discontinuation compared with men living with a partner. Female patients living alone likewise had a higher absolute risk of DOAC discontinuation (2.6%, 95% CI: 4.4-0.09%) compared with female patients living with a partner, yet no statistically significant difference in relative risk. In an analysis evaluating gender, we found male gender to be associated with a significantly higher relative risk of DOAC discontinuation (HR: 1.33, 95% CI: 1.26-1.40) compared with female gender (P-value for interaction with cohabitant status = 0.5996). CONCLUSION: In this nationwide population study, male gender and living alone were associated with a higher risk of DOAC discontinuation among patients with AF.

Association Between Inappropriately Dosed Anticoagulation Therapy With Stroke Severity and Outcomes in Patients With Atrial Fibrillation.

Background Oral anticoagulation (OAC) is effective for stroke prevention in patients with atrial fibrillation. However, some patients experience stroke despite OAC therapy, and knowledge about the impact of prior treatment quality is lacking. Methods and Results Patients with atrial fibrillation on OAC therapy who had a first-time ischemic stroke were identified in the Danish Stroke Registry (2005-2018). Patients treated with vitamin K antagonist (VKA) therapy were compared according to the international normalized ratio just before stroke (international normalized ratio <2 [subtherapeutic], international normalized ratio 2-3 [therapeutic], international normalized ratio >3 [supratherapeutic]), and patients on underdosed, appropriately dosed, and overdosed direct OAC (DOAC) therapy were compared. Stroke severity was determined using the Scandinavia Stroke Scale (0-58 points), and the risk of very severe stroke (0-14 points) was analyzed by multivariable logistic regression. One-year mortality was determined using multivariable Cox regression. A total of 2319 patients with atrial fibrillation and stroke were included; 1196 were taking a VKA (subtherapeutic [46%], therapeutic [43%], supratherapeutic [11%]), and 1123 were taking DOAC (underdosed [23%], appropriately dosed [60%], and overdosed [17%]). Subtherapeutic and supratherapeutic VKA therapy (compared with therapeutic) and underdosed DOAC therapy (compared with appropriate and underdosed DOAC) patients were older, more often women, and more comorbid. Subtherapeutic VKA therapy was associated with very severe stroke (odds ratio [OR], 2.06 [95% CI, 1.28-3.31]), whereas supratherapeutic VKA therapy was not (OR, 1.24 [95% CI, 0.60-2.57]) compared with therapeutic VKA therapy. Patients on subtherapeutic and supratherapeutic VKA therapy had a higher 1-year mortality (hazard ratio [HR], 1.66 [95% CI, 1.29-2.13]); HR, 1.55 [95% CI, 1.08-2.22], respectively) than those on therapeutic VKA therapy. Treatment with underdosed or overdosed DOAC therapy was not associated with very severe stroke (OR, 1.27 [95% CI, 0.76-2.15]; OR, 0.73 [95% CI, 0.37-1.43], respectively) and was not associated with 1-year mortality (HR, 1.09 [95% CI, 0.83-1.44]; HR, 0.82 [95% CI, 0.57-1.18], respectively) than appropriate DOAC. Conclusions Half of the patients with atrial fibrillation with stroke were on inappropriate OAC therapy. Subtherapeutic VKA was associated with worse stroke severity and higher mortality rate than therapeutic VKA therapy. Neither underdosed nor overdosed DOAC was associated with worse outcomes in adjusted models compared with appropriately dosed DOAC. This study supports DOAC as a first-line therapy over VKA.

Switching from vitamin K antagonist to dabigatran in atrial fibrillation: differences according to dose.

AIMS: In atrial fibrillation (AF) patients 150 mg b.i.d. dabigatran is the standard dose, yet guidelines recommend 110 mg b.i.d. when bleeding risk is high. It is unknown to which extend these recommendations are followed in patients switching from vitamin K antagonist (VKA) to dabigatran. The aim of this study was to investigate if AF patients are switched from VKA to the appropriate dose of dabigatran. METHODS AND RESULTS: Using nationwide registries (22 August 2011 to 31 December 2012), we identified VKA-experienced AF patients with available creatinine values who switched to dabigatran. European guidelines criteria 2012 on dabigatran dosing were examined: age ≥80 years, HAS-BLED ≥3, estimated glomerular filtration rate (eGFR)<50 mL/min/1.73 m2, or use of interacting drugs. We identified 1626 VKA-experienced AF patients who switched to dabigatran 110 mg (820 patients) or 150 mg (806 patients). Patients who switched to 110 mg compared with 150 mg were older [median age 82 years (Q1-Q3: 77-86) vs. 68 years (Q1-Q3: 64-74)], more often females (54% vs. 35%), had a higher comorbidity burden, higher proportion with CHA2DS2-VASc score ≥2 (98% vs. 80%), and more with a HAS-BLED score ≥3 (46% vs. 28%). Patients switched to 110 mg had a higher absolute risk of mortality compared with patients switched to 150 mg. Overall, 26% were inappropriately dosed and 14% were switched to 110 mg although the higher dose was indicated. Furthermore, 39% of patients switched to 150 mg fulfilled one or more criteria for 110 mg, this mostly driven by high HAS-BLED scores (28.2% of patients on 150 mg). Female sex, age ≥80 years, eGFR < 50 mL/min/1.73 m2, drugs interacting with dabigatran, and prior bleeding were associated with switch to 110 mg. Patients inappropriately dosed had similar risk of mortality as patients appropriately dosed. CONCLUSION: Among VKA-experienced AF patients one in four were switched to a dabigatran dose contrary to guideline recommendations.

Symptomatic Venous Thromboembolism After Achilles Tendon Rupture: A Nationwide Danish Cohort Study of 28,546 Patients With Achilles Tendon Rupture.

BACKGROUND: Venous thromboembolism (VTE) is a well-known complication of Achilles tendon rupture (ATR) and carries a high risk of morbidity and mortality. Although routine thromboprophylaxis for patients with ATR is not recommended, sparse knowledge is available regarding risk factors associated with VTE in patients with ATR. PURPOSE: To use Danish nationwide registers to identify incidence rates for symptomatic VTE and risk factors associated with increased risk of developing VTE in patients with ATR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: By crosslinking nationwide registers, we identified all patients with diagnosed ATR in Denmark from 1997 to 2015. We stratified patients into 4 groups by age and treatment modality (ie, operative vs nonoperative treatment). The main outcome was VTE within 180 days. We calculated crude incidence rates and considered age, sex, year, comorbidities, and medications as risk factors for VTE in Poisson regression models. RESULTS: We identified 28,546 patients with ATR, of whom 389 (1.36%) were hospitalized with VTE during the follow-up period: 278 due to deep vein thromboses and 138 due to pulmonary embolism. Incidence rates were highest during the first month and ranged from 4.6 to 14.6 events per 100 person-years. VTEs were most frequent among nonoperatively treated patients aged ≥50 years. In Poisson regression analyses, having had VTE beforehand was associated with an increased risk of VTE, as was male sex in the nonoperative treatment group aged ≥50 years; among women <50 years of age, hormonal contraceptives led to a 4- to 6-fold higher risk of VTE compared with patients in the same group without the equivalent risk factor. CONCLUSION: In this nationwide cohort of patients with ATR, 1.36% developed symptomatic VTE during follow-up. Hormonal contraception, previous VTE, older age group, and male sex increased the risk of VTE. Taken together, the results of the present study suggest that focus on risk stratification and initiatives to prevent VTE might be warranted. A randomized controlled trial could answer this question.

Dose reduction of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: A Danish nationwide cohort study.

INTRODUCTION: To investigate the patterns of dose reduction of non-vitamin K antagonist oral anticoagulants (NOAC) in patients with atrial fibrillation (AF). MATERIALS AND METHODS: Using Danish nationwide registries, we identified all non-valvular AF patients initiated on standard-dose NOAC during 2011-2017 who were followed until dose reduction. The absolute risk of dose reduction was presented as cumulative incidence both overall and according to baseline characteristics. Moreover, to assess baseline comorbidities related to dose reduction, adjusted Cox regression models were used. In subgroup analysis, we investigated dose reduction following acute myocardial infarction and/or percutaneous coronary intervention (MI/PCI), chronic kidney disease (CKD), turned 80 years, intracranial hemorrhage, peripheral bleeding, ischemic stroke, cancer, bone fracture, and antiplatelet treatment start. RESULTS: Of 24,489 patients included, 12.2% experienced dose reduction during the study period. Dabigatran treatment, higher age at inclusion, high CHA2DS2-VASc score, and high HAS-BLED score were related to higher risk of dose reduction. Baseline ischemic heart disease (IHD), heart failure, cancer, CKD, chronic obstructive pulmonale disease (COPD), and hypertension were independent predictors of dose reduction. In subgroup analysis with six-month follow-up, MI/PCI, CKD, intracranial hemorrhage, peripheral bleeding, and antiplatelet treatment therapy were strongly associated with dose reduction. CONCLUSIONS: Dose reduction of NOACs was observed in 12.2% of AF patients during 2011-2017 and was associated with dabigatran treatment, advanced age at baseline, high CHA2DS2-VASc score, and high HAS-BLED score. Among comorbidities, IHD, heart failure, cancer, CKD, COPD, and hypertension predicted dose reduction independently. During six-month follow-up, MI/PCI showed the strongest association with dose reduction.

Comparative thromboembolic risk in atrial fibrillation with and without a secondary precipitant-Danish nationwide cohort study.

OBJECTIVES: We compared long-term outcomes in patients with atrial fibrillation (AF) with and without a secondary precipitant. DESIGN AND SETTING: Retrospective cohort study based on Danish nationwide registries. PARTICIPANTS: Patients with AF with and without secondary precipitants (1996-2015) were matched 1:1 according to age, sex, calendar year, CHA2DS2-VASc score and oral anticoagulation therapy (OAC), resulting in a cohort of 39 723 patients with AF with a secondary precipitant and the same number of patients with AF without a secondary precipitant. Secondary precipitants included alcohol intoxication, thyrotoxicosis, myocardial infarction, surgery and infection in conjunction with AF. PRIMARY AND SECONDARY OUTCOMES: The primary outcome in this study was thromboembolic events. Secondary outcomes included AF rehospitalisation and death. Long-term risks of outcomes were examined by multivariable Cox regression analysis. RESULTS: The most common precipitants were infection (55.0%), surgery (13.2%) and myocardial infarction (12.0%). The 5-year absolute risk of thromboembolic events (taking death into account as a competing risk) in patients with AF grouped according to secondary precipitants were 8.3% (alcohol intoxication), 8.5% (thyrotoxicosis), 12.1% (myocardial infarction), 11.6% (surgery), 12.2% (infection), 10.1% (>1 precipitant) and 12.3% (no secondary precipitant). In the multivariable analyses, AF with a secondary precipitant was associated with the same or an even higher thromboembolic risk than AF without a secondary precipitant. One exception was patients with AF and thyrotoxicosis: those not initiated on OAC therapy carried a lower thromboembolic risk the first year of follow-up than matched patients with AF without a secondary precipitant and no OAC therapy. CONCLUSIONS: In general, AF with a secondary precipitant was associated with the same thromboembolic risk as AF without a secondary precipitant. Consequently, this study highlights the need for more research regarding the long-term management of patients with AF associated with a secondary precipitant.