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Background: Albuminuria level is associated with cardiovascular events and mortality in patients with diabetes. However, little is known about the association between albuminuria level in diabetes patients without overt cardiovascular disease. We aimed to examine the association between albuminuria level and the risk of ischemic stroke, myocardial infarction, and all-cause mortality in patients with type 2 diabetes without overt cardiovascular disease., Methods: We linked Danish nationwide registries to identify patients with type 2 diabetes without cardiovascular disease from May 2005 through June 2015. Patients were followed for the outcomes ischemic stroke, myocardial infarction, and all-cause mortality until December 31, 2015. Albuminuria level was based on 2 consecutive measurements of the urinary albumin excretion rate or albumin-to-creatinine ratio. Associations between albuminuria level and incidence of cardiovascular disease and mortality were evaluated with Cox proportional hazard regression., Results: The study population consisted of 69,532 patients with type 2 diabetes without cardiovascular disease. When comparing patients with microalbuminuria to patients with normoalbuminuria, in an analysis adjusted for cardiovascular risk factors, we found hazard ratios of 1.28 (95% confidence interval [CI], 1.07-1.52), 1.34 (95% CI, 1.10-1.62), and 1.48 (95% CI, 1.36-1.61) for ischemic stroke, myocardial infarction, and all-cause mortality, respectively. For macroalbuminuria, the hazard ratios were 1.81 (95% CI, 1.46-2.23), 1.99 (95% CI, 1.59-2.48), and 1.83 (95% CI, 1.64-2.04). Similar results were found after adjusting for concomitant medication., Conclusions: This study showed that albuminuria level is associated with higher risk of incident ischemic stroke, myocardial infarction, and all-cause mortality in Type 2 diabetes patients without overt cardiovascular disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Importance: The increase in the risk for bleeding associated with antithrombotic therapy causes a dilemma in patients with atrial fibrillation (AF) who sustain an intracranial hemorrhage (ICH). A thrombotic risk is present; however, a risk for serious harm associated with resumption of anticoagulation therapy also exists., Objective: To investigate the prognosis associated with resuming warfarin treatment stratified by the type of ICH (hemorrhagic stroke or traumatic ICH)., Design, Setting, and Participants: This nationwide observational cohort study included patients with AF who sustained an incident ICH event during warfarin treatment from January 1, 1998, through February 28, 2016. Follow-up was completed April 30, 2016. Resumption of warfarin treatment was evaluated after hospital discharge., Exposures: No oral anticoagulant treatment or resumption of warfarin treatment, included as a time-dependent exposure., Main Outcomes and Measures: One-year observed event rates per 100 person-years were calculated, and treatment strategies were compared using time-dependent Cox proportional hazards regression models with adjustment for age, sex, length of hospital stay, comorbidities, and concomitant medication use., Results: A total of 2415 patients with AF in this cohort (1481 men [61.3%] and 934 women [38.7%]; mean [SD] age, 77.1 years [9.1 years]) sustained an ICH event. Of these events, 1325 were attributable to hemorrhagic stroke and 1090 were secondary to trauma. During the first year, 305 patients with a hemorrhagic stroke (23.0%) died, whereas 210 in the traumatic ICH group (19.3%) died. Among patients with hemorrhagic stroke, resuming warfarin therapy was associated with a lower rate of ischemic stroke or systemic embolism (SE) (adjusted hazard ratio [AHR], 0.49; 95% CI, 0.24-1.02) and an increased rate of recurrent ICH (AHR, 1.31; 95% CI, 0.68-2.50) compared with not resuming warfarin therapy, but these differences did not reach statistical significance. For patients with traumatic ICH, resuming warfarin therapy also was associated with a lower rate of ischemic stroke or SE (AHR, 0.40; 95% CI, 0.15-1.11); however, in contrast to patients with hemorrhagic stroke, therapy resumption was associated with a significantly lower rate of recurrent ICH (AHR, 0.45; 95% CI, 0.26-0.76). A reduction in mortality was associated with resuming warfarin therapy among patients with hemorrhagic stroke (AHR, 0.51; 95% CI, 0.37-0.71) and those with traumatic ICH (AHR, 0.35; 95% CI, 0.23-0.52)., Conclusions and Relevance: Resumption of warfarin therapy after spontaneous hemorrhagic stroke in patients with AF was associated with a lower rate of ischemic events and a higher rate of recurrent ICH. Among patients with a traumatic ICH, a similar lower rate of ischemic events was found; however, a lower relative risk for recurrent ICH despite resuming warfarin treatment was also revealed.

Background: Recent data suggest that β-blockers are associated with prognostic advantages in heart failure (HF) patients without concomitant atrial fibrillation (AF), but not in HF patients with concomitant AF. We aimed to investigate associations between β-blocker treatment and cardiovascular outcome and mortality in AF patients with and without HF., Methods and Results: Three nationwide registries were used to identify patients with nonvalvular AF patients with or without concomitant HF. Patients were stratified into β-blocker users and β-blocker nonusers, and according to the presence of a HF diagnosis. We followed the patients ≤ 5 years after baseline. Six different cardiovascular outcomes were investigated, including all-cause mortality and fatal thromboembolic events. Crude event rates were ascertained and propensity-matched Cox regression was used to compare event rates according to β-blocker usage status. A total of 205,174 patients were included, where 39,741 patients had prevalent HF. In the latter subgroup of patients, the 1-year propensity-matched hazard ratio (HR) for all-cause mortality was 0.75 (95% confidence interval, 0.71-0.79; nontreated used as reference). For patients without concomitant HF, the propensity-matched HR for all-cause mortality was 0.78 (95% confidence interval, 0.71-0.76)., Conclusions: In this large nationwide cohort study, evidence of a lower mortality with β-blocker therapy in AF patients with concomitant HF was observed. In addition, this association was accompanied with indications that β-blocker treatment is also associated with a better prognosis in AF patients without concomitant HF., (© 2016 American Heart Association, Inc.)

Background: How the adoption of prediction models to decide which patient with atrial fibrillation (AF) to anticoagulate can affect prescription rates and outcomes is unclear., Methods: We retrospectively analyzed data from Danish registries on patients with a first-time recorded AF from 2005 to 2010. We simulated the adoption of a decisional model based on the individual absolute risk reduction of stroke and absolute risk increase of bleeding with warfarin, as expected from the patient CHA2DS2-VASc and HAS-BLED, adjusted for a 0.6 relative value for bleeding versus stroke. We studied 3 different model versions and calculated for each of them the net benefit associated with its adoption, measured as the value-adjusted reduction in stroke and bleeding events at 1 year, compared with i) the actual practice, or ii) recommending warfarin consistently with the European Society of Cardiology (ESC) guidelines, irrespective of HAS-BLED., Results: We included 41,455 patients; 31.9% actually received warfarin. The expected treatment rate with the model ranged from 21% to 87% according to the version used. The model version resulting into the highest treatment rate (i.e. treating any patient with CHA2DS2-VASc ≥ 1) was associated with the greatest net benefit (0.98; 95% credible interval 0.72-1.23), compared with the actual practice, with a 1/3 reduction in overall mortality, as with the adoption of ESC guidelines., Conclusions: Preliminarily to a randomized impact study, our analysis suggests that individualizing anticoagulation for AF using a decisional model might have a clinical advantage over actual practice, and no added advantage over following ESC guidelines., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Our objective was to test the hypothesis that elevated blood pressure (BP) is associated with increased risk of stroke, bleeding and death in patients with incident heart failure (HF)., Methods: We conducted a prospective cohort study among subjects who were participants in the Diet, Cancer and Health study, born in Denmark, aged 50-64 years at recruitment. We assessed stroke (ischemic stroke or systemic embolic events), major bleeding, death and the composite endpoint according to degree of BP control in patients with incident HF. BP was assessed prior to HF at cohort entry., Results: Of the whole cohort of 55,748 subjects, n = 2159 (35 % female) had incident HF, of which 12 % had treatment for hypertension. Median follow-up after incident HF was 3.5 years. High systolic (SBP), diastolic (DBP) and pulse (PP) pressures were associated with an increased risk of stroke, major bleeding and the composite endpoint. For death and stroke/death, the relation appeared U-shaped for SBP and DBP. When comparing the highest quartile group (Q4) to first quartile group (Q1), SBP (Q4: SBP >163 mmHg) was associated with significantly higher adjusted hazard rate ratio (HR) for stroke (HR 1.46, 95 % CI 1.00-2.14) and major bleeding (HR 1.68, 95 % CI 1.12-2.53). For DBP (Q4: DBP >94 mmHg), adjusted HR was significantly higher for major bleeding (HR 1.63, 95 % CI 1.13-2.38). The highest quartile of pulse pressure (Q4: PP >74 mmHg) was associated with non-significantly higher risk of stroke (HR 1.40, 95 % CI 0.94-2.06)., Conclusion: We have shown for the first time that amongst a population with incident HF, higher baseline systolic, diastolic and pulse pressure levels were associated with a higher rate of adverse events. Our data support the importance for optimised BP control, as part of the holistic management of HF patients.

Study Question: What are the risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding associated with restarting antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation?, Methods: This Danish cohort study (1996-2012) included all patients with atrial fibrillation discharged from hospital after gastrointestinal bleeding while receiving antithrombotic treatment. Restarted treatment regimens were single or combined antithrombotic drugs with oral anticoagulation and antiplatelets. Follow-up started 90 days after discharge to avoid confounding from use of previously prescribed drugs on discharge. Risks of all cause mortality, thromboembolism, major bleeding, and recurrent gastrointestinal bleeding were estimated with competing risks models and time dependent multiple Cox regression models., Study Answer and Limitations: 4602 patients (mean age 78 years) were included. Within two years, 39.9% (95% confidence interval 38.4% to 41.3%, n=1745) of the patients had died, 12.0% (11.0% to 13.0%, n=526) had experienced thromboembolism, 17.7% (16.5% to 18.8%, n=788) major bleeding, and 12.1% (11.1% to 13.1%, n=546) recurrent gastrointestinal bleeding. 27.1% (n=924) of patients did not resume antithrombotic treatment. Compared with non-resumption of treatment, a reduced risk of all cause mortality was found in association with restart of oral anticoagulation (hazard ratio 0.39, 95% confidence interval 0.34 to 0.46), an antiplatelet agent (0.76, 0.68 to 0.86), and oral anticoagulation plus an antiplatelet agent (0.41, 0.32 to 0.52), and a reduced risk of thromboembolism was found in association with restart of oral anticoagulation (0.41, 0.31 to 0.54), an antiplatelet agent (0.76, 0.61 to 0.95), and oral anticoagulation plus an antiplatelet agent (0.54, 0.36 to 0.82). Restarting oral anticoagulation alone was the only regimen with an increased risk of major bleeding (1.37, 1.06 to 1.77) compared with non-resumption of treatment; however, the difference in risk of recurrent gastrointestinal bleeding was not significant between patients who restarted an antithrombotic treatment regimen and those who did not resume treatment., What This Study Adds: Among patients with atrial fibrillation who experience gastrointestinal bleeding while receiving antithrombotic treatment; subsequent restart of oral anticoagulation alone was associated with better outcomes for all cause mortality and thromboembolism compared with patients who did not resume treatment. This was despite an increased longitudinal associated risk of bleeding., Funding, Competing Interests, Data Sharing: This study was supported by a grant from Boehringer-Ingelheim. Competing interests are available in the full paper on bmj.com. The authors have no additional data to share., (© Staerk et al 2015.)

Oral anticoagulation (OAC) to prevent stroke has to be balanced against the potential harm of serious bleeding, especially intracranial haemorrhage (ICH). We determined the net clinical benefit (NCB) balancing effectiveness and safety of no antithrombotic therapy, aspirin and warfarin in AF patients with none or one stroke risk factor. Using Danish registries, we determined NCB using various definitions intrinsic to our cohort (Danish weights at 1 and 5 year follow-up), with risk weights which were derived from the hazard ratio (HR) of death following an event, relative to HR of death after ischaemic stroke. When aspirin was compared to no treatment, NCB was neutral or negative for both risk strata. For warfarin vs no treatment, NCB using Danish weights was neutral where no risk factors were present and using five years follow-up. For one stroke risk factor, NCB was positive for warfarin vs no treatment, for one year and five year follow-up. For warfarin vs aspirin use in patients with no risk factors, NCB was positive with one year follow-up, but neutral with five year follow-up. With one risk factor, NCB was generally positive for warfarin vs aspirin. In conclusion, we show a positive overall advantage (i.e. positive NCB) of effective stroke prevention with OAC, compared to no therapy or aspirin with one additional stroke risk factor, using Danish weights. 'Low risk' AF patients with no additional stroke risk factors (i.e.CHA2DS2-VASc 0 in males, 1 in females) do not derive any advantage (neutral or negative NCB) with aspirin, nor with warfarin therapy in the long run.

Importance: The CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is used clinically for stroke risk stratification in atrial fibrillation (AF). Its usefulness in a population of patients with heart failure (HF) is unclear., Objective: To investigate whether CHA2DS2-VASc predicts ischemic stroke, thromboembolism, and death in a cohort of patients with HF with and without AF., Design, Setting, and Population: Nationwide prospective cohort study using Danish registries, including 42 987 patients (21.9% with concomitant AF) not receiving anticoagulation who were diagnosed as having incident HF during 2000-2012. End of follow-up was December 31, 2012., Exposures: Levels of the CHA2DS2-VASc score (based on 10 possible points, with higher scores indicating higher risk), stratified by concomitant AF at baseline. Analyses took into account the competing risk of death., Main Outcomes and Measures: Ischemic stroke, thromboembolism, and death within 1 year after HF diagnosis., Results: In patients without AF, the risks of ischemic stroke, thromboembolism, and death were 3.1% (n = 977), 9.9% (n = 3187), and 21.8% (n = 6956), respectively; risks were greater with increasing CHA2DS2-VASc scores as follows, for scores of 1 through 6, respectively: (1) ischemic stroke with concomitant AF: 4.5%, 3.7%, 3.2%, 4.3%, 5.6%, and 8.4%; without concomitant AF: 1.5%, 1.5%, 2.0%, 3.0%, 3.7%, and 7% and (2) all-cause death with concomitant AF: 19.8%, 19.5%, 26.1%, 35.1%, 37.7%, and 45.5%; without concomitant AF: 7.6%, 8.3%, 17.8%, 25.6%, 27.9%, and 35.0%. At high CHA2DS2-VASc scores (≥4), the absolute risk of thromboembolism was high regardless of presence of AF (for a score of 4, 9.7% vs 8.2% for patients without and with concomitant AF, respectively; overall P<.001 for interaction). C statistics and negative predictive values indicate that the CHA2DS2-VASc score performed modestly in this HF population with and without AF (for ischemic stroke, 1-year C statistics, 0.67 [95% CI, 0.65-0.68] and 0.64 [95% CI, 0.61-0.67], respectively; 1-year negative predictive values, 92% [95% CI, 91%-93%] and 91% [95% CI, 88%-95%], respectively)., Conclusions and Relevance: Among patients with incident HF with or without AF, the CHA2DS2-VASc score was associated with risk of ischemic stroke, thromboembolism, and death. The absolute risk of thromboembolic complications was higher among patients without AF compared with patients with concomitant AF at high CHA2DS2-VASc scores. However, predictive accuracy was modest, and the clinical utility of the CHA2DS2-VASc score in patients with HF remains to be determined.

Background and Purpose: The CHA2DS2VASc score and the Essen Stroke Risk Score are respectively used for risk stratification in patients with atrial fibrillation and in patients with cerebrovascular incidents. We aimed to test the ability of the 2 scores to predict stroke recurrence, death, and cardiovascular events (stroke, transient ischemic attack, myocardial infarction, or arterial thromboembolism) in a nationwide Danish cohort study, among patients with incident ischemic stroke and no atrial fibrillation., Methods: We conducted a registry-based study in patients with incident ischemic stroke and no atrial fibrillation. Patients were stratified according to the CHA2DS2VASc score and the Essen Stroke Risk Score and were followed up until stroke recurrence or death. We estimated stratified incidence rates and hazard ratios and calculated the cumulative risks., Results: 42 182 patients with incident ischemic stroke with median age 70.1 years were included. The overall 1-year incidence rates of recurrent stroke, death, and cardiovascular events were 3.6%, 10.5%, and 6.7%, respectively. The incidence rates, the hazard ratios, and the cumulative risk of all outcomes increased with increasing risk scores. C-statistics for both risk scores were around 0.55 for 1-year stroke recurrence and cardiovascular events and correspondingly for death around 0.67 for both scores., Conclusions: In this cohort of non-atrial fibrillation patients with incident ischemic stroke, increasing CHA2DS2VASc score and Essen Stroke Risk Score was associated with increasing risk of recurrent stroke, death, and cardiovascular events. Their discriminatory performance was modest and further refinements are required for clinical application., (© 2015 American Heart Association, Inc.)

Background: Intracranial hemorrhage is the most feared complication of oral anticoagulant treatment. The optimal treatment option for patients with atrial fibrillation who survive an intracranial hemorrhage remains unknown. We hypothesized that restarting oral anticoagulant treatment was associated with a lower risk of stroke and mortality in comparison with not restarting., Methods and Results: Linkage of 3 Danish nationwide registries in the period between 1997 and 2013 identified patients with atrial fibrillation on oral anticoagulant treatment with incident intracranial hemorrhage. Patients were stratified by treatment regimens (no treatment, oral anticoagulant treatment, or antiplatelet therapy) after the intracranial hemorrhage. Event rates were assessed 6 weeks after hospital discharge and compared with Cox proportional hazard models. In 1752 patients (1 year of follow-up), the rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for patients treated with oral anticoagulants was 13.6, in comparison with 27.3 for nontreated patients and 25.7 for patients receiving antiplatelet therapy. The rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for recurrent intracranial hemorrhage, the rate of ischemic stroke/systemic embolism, and all-cause mortality (per 100 person-years) patients treated with oral anticoagulants was 8.0, in comparison with 8.6 for nontreated patients and 5.3 for patients receiving antiplatelet therapy. The adjusted hazard ratio of ischemic stroke/systemic embolism and all-cause mortality was 0.55 (95% confidence interval, 0.39-0.78) in patients on oral anticoagulant treatment in comparison with no treatment. For ischemic stroke/systemic embolism and for all-cause mortality, hazard ratios were 0.59 (95% confidence interval, 0.33-1.03) and 0.55 (95% confidence interval, 0.37-0.82), respectively., Conclusions: Oral anticoagulant treatment was associated with a significant reduction in ischemic stroke/all-cause mortality rates, supporting oral anticoagulant treatment reintroduction after intracranial hemorrhage as feasible. Future trials are encouraged to guide clinical practice in these patients., (© 2015 American Heart Association, Inc.)

Background and Purpose: Guidelines advocate anticoagulant treatment to all patients with atrial fibrillation and concomitant diabetes mellitus. The potential refinement to thromboembolic risk stratification that may spring from subdividing diabetes mellitus is unexplored. The purpose was to investigate duration of diabetes mellitus as a predictor of thromboembolism and anticoagulant-related bleeding in patients with atrial fibrillation., Methods: Using nationwide Danish registries, we identified all patients discharged from hospital with an incident diagnosis of atrial fibrillation from 2000 to 2011. Hazard ratios with 95% confidence intervals for thromboembolism and bleeding according to years of diabetes mellitus duration in categories (0-4, 5-9, 10-14, and ≥15) and as a continuous variable using cubic splines were calculated by Cox regression., Results: The study population comprised 137 222 patients with atrial fibrillation, of which 12.4% had diabetes mellitus. Compared with patients without diabetes mellitus and after adjustment for anticoagulant treatment and CHA2DS2-VASc components (congestive heart failure, hypertension, age, previous stroke, vascular disease, and sex), the risk of thromboembolism was lowest in the 0 to 4 years duration category (hazard ratio, 1.11; 95% confidence interval, 1.03-1.20), and highest in the longest duration category of ≥15 years (hazard ratio, 1.48; 95% confidence interval, 1.29-1.70). When analyzed as a continuous variable, duration of diabetes mellitus was associated with risk of thromboembolism in a dose-response-dependent manner, but not with a higher risk of bleeding during anticoagulant treatment., Conclusions: In patients with atrial fibrillation, longer duration of diabetes mellitus was associated with a higher risk of thromboembolism, but not with a higher risk of anticoagulant-related bleeding. Considering the critical balance between preventing thromboembolism and avoiding bleeding, longer duration of diabetes mellitus may favor initiation of anticoagulant therapy., (© 2015 American Heart Association, Inc.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Even a single additional stroke risk factor in patients with atrial fibrillation may confer a risk of stroke. However, there is no consensus on how best to treat these patients., Objectives: Our objective was to investigate the risk of stroke and bleeding and the impact of antithrombotic therapy among low-risk patients, i.e., with 0 or 1 CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65 to 74 years, sex category) score risk factor., Methods: The nationwide cohort for this study was established by linking data from the Danish Civil Registration System, the Danish National Patient Register, and the Danish National Prescription Registry. We studied 39,400 patients discharged with incident nonvalvular atrial fibrillation with 0 or 1 CHA2DS2-VASc risk factor; 23,572 were not treated, 5,353 were initiated on aspirin, and 10,475 were initiated on warfarin., Results: Stroke event rates for untreated low-risk patients (CHA2DS2-VASc = 0 [male], 1 [female]) were 0.49 per 100 person-years at 1 year and 0.47 per 100 person-years at full follow-up (intention-to-treat). Bleeding event rates among untreated low-risk patients were 1.08 per 100 person-years at 1 year and 0.97 at full follow-up. The presence of 1 additional stroke risk factor (CHA2DS2-VASc = 1 [male], = 2 [female]) among untreated patients increased the stroke rate at 1 year to 1.55 per 100 person-years, representing a significant 3.01-fold increase. At the 1-year follow-up, bleeding increased 2.35-fold, and death increased 3.12-fold., Conclusions: Low-risk patients (CHA2DS2-VASc = 0 [male], 1 [female]) have a truly low risk for stroke and bleeding. With 1 additional stroke risk factor (CHA2DS2-VASc = 1 [male], = 2 [female]), there was a significant increase in event rates (particularly mortality) if nonanticoagulated., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There is a perception among physicians that lack of routine monitoring with non-vitamin K antagonist oral anticoagulants (NOACs) may lead to poor adherence to medication. We studied adherence during the first year of usage in a cohort of patients with newly diagnosed non-valvular atrial fibrillation (AF) started on the NOAC, dabigatran etexilate., Methods and Results: Nationwide Danish patient and prescription purchase registries were used to identify newly diagnosed AF patients taking dabigatran, comorbidities, and refill patterns under a twice-daily, one pill regimen. Adherence was characterized among remaining users (N = 2960) after 1 year using the proportion of days covered (PDC), gap rates and restart rates. The overall 1-year PDC was 83.9%, with 76.8% of patients having a 1-year PDC in excess of 80%. Patients with a CHA2 DS2 -VASc score ≥ 2 were more adherent to medication regimes than patients with a CHA2 DS2 -VASc score of 1 (PDC ratio, 1.12; 95% confidence interval [CI], 1.08-1.17) and generally patients with higher morbidity showed more adherence. Patients with prior bleeding were not less adherent to medication regimes than patients with no prior bleeding (PDC ratio, 1.02; 95% CI, 0.98-1.06). The overall gap rate was 1.4 gaps per year. There were no clear tendencies in gap rates among subgroups, although patients with higher morbidity tended to have slightly more, but shorter, gap periods., Conclusions: More than 75% of patients were showed > 80% adherence to medication regimes during the first year. Patients with higher morbidity, including patients with a higher risk of stroke or bleeding, exhibited better adherence. This improvement may be attributable to more regular contact with the healthcare system., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial., Objectives: This study assessed the risk associated with CKD in individual CHA₂DS₂-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort., Methods: By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death., Results: From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA₂DS₂-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA₂DS₂-VASc score = 0 to a 1.6-fold higher risk in patients with CHA₂DS₂-VASc score ≥2. In patients receiving RRT with CHA₂DS₂-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA₂DS₂-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69)., Conclusions: CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA₂DS₂-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: This register-based observational study compares dabigatran to warfarin for secondary stroke prevention in atrial fibrillation patients among both "new starters" on dabigatran and "switchers" to dabigatran from warfarin., Methods: We identified, in nationwide Danish registries, 2398 patients with atrial fibrillation and a history of stroke/transient ischemic attack, making a first-time purchase of dabigatran 110 mg twice a day (bid; D110) and 150 mg bid (D150). Patients were categorized as either vitamin K antagonist (VKA) naive or experienced. Warfarin controls were identified using a complete (for VKA-naive dabigatran patients) or matched sampling approach (for VKA-experienced dabigatran patients). Subjects were followed for an average of 12.6 months for stroke and transient ischemic attacks. Confounder-adjusted Cox regression models were used to compare event rates between treatments., Results: Among patients with a history of stroke/transient ischemic attack and prior VKA experience, switching to dabigatran was associated with an increased stroke/transient ischemic attack rate for both dabigatran doses compared with continuing on warfarin (D110 hazard ratio [HR] 1.99; 95% confidence interval [CI], 1.42-2.78; D150 HR 2.34; 95% CI, 1.60-3.41). Among prior stroke/transient ischemic attack patients who were new starters on dabigatran or warfarin, the rate of stroke/transient ischemic attack for both doses of dabigatran was similar to or lower than warfarin (D110 HR 0.64; 95% CI, 0.50-0.80; D150 HR 0.92l; 95% CI, 0.73-1.15)., Conclusions: In this register-based study, VKA-experienced patients with a history of stroke or transient ischemic attack who switched to dabigatran therapy had an increased rate of stroke compared with patients persisting with warfarin therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The prognostic significance of age and continuous positive airway pressure (CPAP) therapy on cardiovascular disease in patients with sleep apnoea has not been assessed previously., Methods: Using nationwide databases, the entire Danish population was followed from 2000 until 2011. First-time sleep apnoea diagnoses and use of CPAP therapy were determined. Incidence rate ratios (IRRs) of ischaemic stroke and myocardial infarction (MI) were analysed using Poisson regression models., Results: Amongst 4.5 million individuals included in the study, 33 274 developed sleep apnoea (mean age 53, 79% men) of whom 44% received persistent CPAP therapy. Median time to initiation of CPAP therapy was 88 days (interquartile range 34-346). Patients with sleep apnoea had more comorbidities compared to the general population. Crude rates of MI and ischaemic stroke were increased for sleep apnoea patients (5.4 and 3.6 events per 1000 person-years compared to 4.0 and 3.0 in the general population, respectively). Relative to the general population, risk of MI [IRR 1.71, 95% confidence interval (CI) 1.57-1.86] and ischaemic stroke (IRR 1.50, 95% CI 1.35-1.66) was significantly increased in patients with sleep apnoea, in particular in patients younger than 50 years (IRR 2.12, 95% CI 1.64-2.74 and IRR 2.34, 95% CI 1.77-3.10, respectively). Subsequent CPAP therapy was not associated with altered prognosis., Conclusions: Sleep apnoea is associated with increased risk of ischaemic stroke and MI, particularly in patients younger than 50 years of age. CPAP therapy was not associated with a reduced rate of stroke or MI., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

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.

Several studies have demonstrated sex differences in risk of thromboembolism and death among patients with atrial fibrillation, but it is unclear to what extent these associations relate to actual physiological differences. To date, no study has investigated sex differences with concomitant control for lifestyle related factors known to influence stroke risk. We used data from the Danish Diet, Cancer and Health study, including 57,053 participants (52% female) aged 50-64 years. The study population for this study included the 2,895 patients (36% female) with incident atrial fibrillation after inclusion. Data were linked to outcomes identified using nationwide registries. Risk of thromboembolism and death according to female sex were analysed using Cox proportional hazards models. After a median follow-up of 5.0 years, 137 men and 62 women suffered a thromboembolic event, and 349 men and 151 women died. In a crude analysis, female sex was associated with a non-significant lower risk of thromboembolism (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.61-1.11). Adjustment for differences in antithrombotic therapy, relevant comorbidities and lifestyle did not change this association (HR 0.77, 95% CI 0.55-1.13). In the final model, female sex was associated with a lower risk of death (HR 0.65, 95% CI 0.51-0.84). The associations were similar in a sensitivity analysis of women not taking hormone replacement therapy, and the effect of hormone replacement therapy use within females was non-significant for both endpoints of thromboembolism and death. In conclusion, in a relatively young population of patients with atrial fibrillation, female sex was associated with a lower risk of thromboembolism and death.

Objectives: The aim of this study was to investigate the impact of atrial fibrillation (AF) and antithrombotic treatment on the prognosis in patients with heart failure (HF) as well as vascular disease., Background: HF, vascular disease, and AF are pathophysiologically related, and understanding antithrombotic treatment for these conditions is crucial., Methods: In hospitalized patients with HF and coexisting vascular disease (coronary artery disease or peripheral arterial disease) followed from 1997 to 2009, AF status was categorized as prevalent AF, incident AF, or no AF. Risk of thromboembolism (TE), myocardial infarction (MI), and serious bleeding was assessed by Cox regression models (hazard ratio [HR] with 95% confidence interval [CI]) with antithrombotic therapy and AF as time-dependent variables., Results: A total of 37,464 patients were included (age, 74.5 ± 10.7 years; 36.3% females) with a mean follow-up of 3 years during which 20.7% were categorized as prevalent AF and 17.2% as incident AF. Compared with vitamin K antagonist (VKA) in prevalent AF, VKA plus antiplatelet was not associated with a decreased risk of TE (HR: 0.91; 95% CI: 0.73 to 1.12) or MI (HR: 1.11; 95% CI: 0.96 to 1.28), whereas bleeding risk was significantly increased (HR: 1.31; 95% CI: 1.09 to 1.57). Corresponding estimates for incident AF were HRs of 0.77 (95% CI: 0.56 to 1.06), 1.07 (95% CI: 0.89 to 1.28), and 2.71 (95% CI: 1.33 to 2.21) for TE, MI, and bleeding, respectively. In no AF patients, no statistical differences were seen between antithrombotic therapies in TE or MI risk, whereas bleeding risk was significantly increased for VKA with and without single-antiplatelet therapy., Conclusions: In AF patients with coexisting HF and vascular disease, adding single-antiplatelet therapy to VKA therapy is not associated with additional benefit in thromboembolic or coronary risk, but notably increased bleeding risk., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: The risk of stroke and death in patients with atrial fibrillation is strongly associated with age and concomitant comorbidities. The aim of this study was to examine the age dependence of risk factors for stroke and mortality in young patients with atrial fibrillation., Methods: This study is a population-based cohort study of 30- to 65-year-old patients with atrial fibrillation and diagnosed during 2000 to 2011, identified by record linkage between nationwide Danish registries. Cox regression models were used to estimate the risk of stroke and mortality according to risk factors within age groups: 30 to 50, 50 to 65, and 65 to 75 years., Results: We identified 73,799 nonvalvular atrial fibrillation patients, of which 37,782 (51.2%) were <65 years old (mean age 62.8). A higher modified cardiac failure or dysfunction, hypertension, age 75 (doubled), diabetes, stroke (doubled), vascular disease, age 65-74 and sex category (female) score (CHA2DS2-VASc score) was associated with decreased survival probability in all age groups. The overall incidence of stroke per year for 1 year (5 years) follow-up was 1.2% (0.6%), 3.5% (1.6%), and 5.6% (2.8%), respectively, for the age groups of 30 to 50, 50 to 65, and 65 to 75. Overall, risk factors such as previous stroke, heart failure, vascular disease, diabetes mellitus, and hypertension remained independent predictors of stroke and death in patients<65 years old with nonvalvular atrial fibrillation., Conclusions: The CHA2DS2-VASc score is an applicable tool for all age groups and in nonvalvular atrial fibrillation patients<65 years old, the same risk factors apply.

Background: Smoking and atrial fibrillation (AF) are major health problems worldwide and are responsible for substantial health-care costs. Our aim was to investigate whether smoking impacts the risk of stroke and death in patients with AF. To test this hypothesis, we analyzed data from a large Danish cohort: the Diet, Cancer, and Health study., Methods: This was a cohort study of 57,053 people (27,178 men; 29,876 women) aged 50 to 64 years. The risk of thromboembolism (ischemic stroke/arterial thromboembolism) or death according to smoking habits among 3,161 patients with incident AF (mean age, 66.9 years; 2,032 men, 1,129 women) was assessed using Cox proportional hazard models after a median follow-up of 4.9 years., Results: Of those with AF, 34% were current smokers and 37% former smokers. After adjustment for vitamin K antagonist treatment, the hazard ratios (HRs) (95% CI) of thromboembolism or death were 3.13 (1.72-6.37) and 2.73 (2.02-3.70) among women and men who currently were heavy smokers (>25 g/d), respectively. The associations remained after adjustment for well-established risk factors with HRs of 3.64 (1.88-7.07) and 2.17 (1.59-2.95) among women and men, respectively. In a sensitivity analysis, smoking was still strongly associated with thromboembolism or death after censoring people with a cancer diagnosis during follow-up., Conclusions: Smoking is associated with a higher risk of thromboembolism or death in patients with AF even after adjusting for well-recognized risk factors used in stroke risk stratification schemes. The associations may be modified by sex, as the associations were strongest among women.

Objective: To assess alcohol intake as a risk factor for adverse events among patients with incident atrial fibrillation (AF)., Design: Prospective cohort study., Setting: Population based cohort study and nationwide Danish registries., Patients: The Danish Diet, Cancer and Health study included 57 053 participants (27 178 men and 29 875 women) aged between 50 and 64 years. The study population for this study included the 3107 participants (1999 men, 1108 women) who developed incident AF after inclusion., Main Outcome Measures: A composite of thromboembolism or death., Results: During a median follow-up of 4.9 years 608 deaths and 211 thromboembolic events occurred. Of those who developed AF, 690 (35%) men and 233 (21%) women had a high intake of alcohol (>20 drinks/week for men and >13 drinks/week for women). After adjustment for use of oral anticoagulation and components of the CHA2DS2-VASc score, men with an intake of >27 drinks/week had a higher risk for thromboembolism or death (hazard ratio (HR) 1.33, 95% CI 1.08 to 1.63) than men with an intake of <14 drinks/week. Women with an intake of >20 drinks/week also had a higher risk (HR 1.23, 95% CI 0.78 to 1.96) than women in the low intake category. The higher risk among men was primarily driven by mortality (HR 1.51, 95% CI 1.20 to 1.89), whereas the risk found among women was driven by thromboembolism (HR 1.71, 95% CI 0.81 to 3.60)., Conclusions: High alcohol intake predicts thromboembolism or death, even after adjustment for established clinical risk factors, and may help identify high risk AF patients who could be targeted for stroke and cardiovascular prevention strategies.

Background: Retinal vascular occlusions may constitute an independent risk factor for stroke in patients with atrial fibrillation., Methods: We performed a retrospective study on a nationwide cohort with atrial fibrillation from 1997 to 2008. The rate of stroke/systemic thromboembolism (TE)/transitory ischemic attack (TIA) was determined for atrial fibrillation patients with and without a history of retinal vascular occlusion. A Cox regression analysis, adjusted for risk factors and medications, was performed to determine the independent predictive value of retinal arterial or venous occlusion for the risk of ischemic stroke, TE or TIA in atrial fibrillation patients., Results: We included 87 202 patients with non-valvular atrial fibrillation. At baseline, a history of retinal arterial occlusion was diagnosed in 224 patients (0.26%) and a history of retinal venous occlusion in 361 (0.41%). Patients without retinal occlusion had a rate of stroke/TE/TIA of 4.52 (95% confidence interval [CI] 4.44-4.60). For patients with retinal arterial occlusion, the rate of stroke/TE/TIA was 8.16 (95% CI 6.35-10.49) per 100 person-years, and for patients with retinal venous occlusion it was 7.28 (95% CI 5.93-8.94) per 100 person-years. In multivariate analysis, both retinal arterial occlusions (hazard ratio [HR] 1.39, 95% CI 1.08-1.79) and retinal venous occlusions (HR 1.26, 95% CI 1.02-1.54) were associated with an increased risk of future stroke/TE/TIA., Conclusions: A history of retinal arterial or retinal venous occlusion is associated with an increased risk of stroke/TE/TIA in patients with atrial fibrillation. Thus, prior retinal vascular occlusion may be considered as a previous thromboembolic event when evaluating stroke risk in patients with atrial fibrillation., (© 2013 International Society on Thrombosis and Haemostasis.)

Background: Obesity is associated with the development of atrial fibrillation and may impact atrial fibrillation-related outcomes. To date, no anthropometric measure is included in any risk stratification scheme for stroke and death in atrial fibrillation patients., Methods: The prospective Danish Diet, Cancer and Health study is a cohort including 57,053 participants (27,178 men and 29,875 women) aged between 50 and 64 years. The study population for this study included the 3135 patients (2025 men and 1110 women) who developed incident atrial fibrillation during follow-up., Results: Of the subjects with atrial fibrillation, 1414 (45%) had a body mass index (BMI) in the overweight category (BMI 25 to <30 kg/m(2)) and 767 (24%) were categorized as obese (BMI ≥30 kg/m(2)). During a median follow-up of 4.9 years, 609 deaths and 216 thromboembolic events (98% ischemic strokes) occurred. Using normal-weight patients as reference, the risk of a composite end point of "ischemic stroke, thromboembolism, or death" was significantly higher in overweight (crude hazard ratio [HR] 1.31; 95% confidence interval [CI], 1.09-1.56) and obese patients (crude HR 1.55; 95% CI 1.27-1.90). After adjustment for CHADS2 and CHA2DS2-VASc scores, the HRs for the composite end point were 1.21 (95% CI 1.02-1.45) and 1.31 (95% CI 1.10-1.56), respectively, for overweight and 1.25 (95% CI 1.03-1.53) and 1.36 (95% CI 1.11-1.65), respectively, for obese. Continuous analyses of BMI stratified by sex identified obese men and normal-weight women as the sex-specific "high-risk" categories., Conclusion: Overweight and obesity are risk factors for "ischemic stroke, thromboembolism or death" in patients with atrial fibrillation, even after adjustment for CHADS2 and CHA2DS2-VASc scores. The association between BMI and outcomes among atrial fibrillation patients may be modified by sex., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the efficacy and safety in an "everyday clinical practice" population of anticoagulant-naïve patients with atrial fibrillation (AF) treated with dabigatran etexilate after its post-approval availability in Denmark, compared with warfarin., Background: Concerns have been raised about an excess of bleeding events or myocardial infarction (MI) among patients treated with the new oral direct thrombin inhibitor, dabigatran etexilate., Methods: From the Danish Registry of Medicinal Product Statistics, we identified a dabigatran-treated group and a 1:2 propensity-matched warfarin-treated group of 4,978 and 8,936, respectively. Comparisons on efficacy and safety outcomes were made on the basis of Cox-proportional hazards models stratified on propensity-matched groups., Results: Stroke and systemic embolism were not significantly different between warfarin- and dabigatran-treated patients. Adjusted mortality was significantly lower with both dabigatran doses (110 mg b.i.d., propensity-match group stratified hazard ratio [aHR]: 0.79, 95% confidence interval [CI]: 0.65 to 0.95; 150 mg b.i.d., aHR: 0.57, 95% CI: 0.40 to 0.80), when compared with warfarin. Pulmonary embolism was lower compared with warfarin for both doses of dabigatran. Less intracranial bleeding was seen with both dabigatran doses (110 mg b.i.d., aHR: 0.24, 95% CI: 0.08 to 0.56; 150 mg b.i.d., aHR: 0.08, 95% CI: 0.01 to 0.40). The incidence of MI was lower with both dabigatran doses (110 mg b.i.d., aHR: 0.30, 95% CI: 0.18 to 0.49; 150 mg b.i.d., aHR: 0.40, 95% CI: 0.21 to 0.70). Gastrointestinal bleeding was lower with dabigatran 110 mg b.i.d. (aHR: 0.60, 95% CI: 0.37 to 0.93) compared with warfarin but not dabigatran 150 mg b.i.d. The main findings were broadly consistent in a subgroup analysis of dabigatran users with ≥1-year follow-up (median follow-up 13.9 months [interquartile range: 12.6 to 15.3 months])., Conclusions: In this "everyday clinical practice" post-approval nationwide clinical cohort, there were similar stroke/systemic embolism and major bleeding rates with dabigatran (both doses) compared with warfarin. Mortality, intracranial bleeding, pulmonary embolism, and MI were lower with dabigatran, compared with warfarin. We found no evidence of an excess of bleeding events or MI among dabigatran-treated patients in this propensity-matched comparison against warfarin, even in the subgroup with ≥1-year follow-up., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Female sex has been suggested as a risk factor for stroke/thromboembolism in patients with non-valvular atrial fibrillation (AF) and has therefore been included within risk scores, e.g., the CHA2 DS2 -VASc score, and guidelines., Objectives: To investigate the risk of stroke/thromboembolism associated with female sex in non-valvular AF patients., Patients/methods: Using the national Danish registers, we identified non-anticoagulated patients discharged with non-valvular AF (1997-2008), and subdivided the population into three age intervals: < 65, 65-74 and ≥ 75 years. We calculated stroke rates according to sex, and assessed the stroke risk associated with female sex by using Cox regression analysis., Results: We included 87,202 AF patients, and 44,744 (51.3%) were female. The rate of stroke/thromboembolism for females aged < 65 and 65-74 years was not increased as compared with men, whereas the rate for females aged ≥ 75 years was increased. At both 1-year and 12-year follow-up, female sex did not increase the risk of stroke for patients aged < 75 years. At 1-year follow-up, the hazard ratios associated with female sex were 0.89 (95% confidence interval [CI] 0.70-1.13) and 0.91 (95 CI 0.79-1.05) for patients aged < 65 and 65-74 years, respectively, and being female and aged ≥ 75 years was associated with an increased risk of stroke of 1.20 (95 CI 1.12-1.28)., Conclusion: Female sex was only associated with an increased risk of stroke for AF patients aged ≥ 75 years. Our study suggests that female sex should not be automatically included as an independent stroke/thromboembolic risk factor in guidelines or in the CHA2 DS2 -VASc score, without careful prior consideration of the 'age < 65 and lone AF' criterion., (© 2012 International Society on Thrombosis and Haemostasis.)

Background: Vascular disease (including myocardial infarction and peripheral artery disease) has been proposed as a less well-validated risk factor for stroke in patients with atrial fibrillation. We investigated whether vascular disease is an independent risk factor of stroke/thromboembolism in atrial fibrillation and whether adding vascular disease improves Congestive heart failure, Hypertension, Age 75 years, Diabetes, previous Stroke (CHADS(2)) risk stratification., Methods: By using nationwide Danish registers, we identified all patients discharged with atrial fibrillation and not treated with vitamin K antagonist or heparin between 1997 and 2008. The rate of stroke/thromboembolism in patients with atrial fibrillation with and without vascular disease was determined, and the risk associated with vascular disease was estimated in Cox regression analyses. The value of adding vascular disease to the CHADS(2) score was evaluated by Net Reclassification Improvement and Integrated Discrimination Improvement., Results: We included 87,202 patients with non-valvular atrial fibrillation; of these, 15,212 (17.4%) had vascular disease, 11,750 (77.2%) had myocardial infarction, 2503 (16.5%) had peripheral artery disease, and 959 (6.3%) had both. In patients with a CHADS(2) score=0, the rate of stroke/thromboembolism at 1-year follow-up was 2.31 (1.63-3.26) and 1.52 (1.34-1.73) per 100 person-years in patients with and without vascular disease, respectively. Vascular disease increased the risk of stroke/thromboembolism in both univariate (hazard ratio [HR] 1.26; confidence interval [CI], 1.18-1.35) and multivariate (HR, 1.12; CI, 1.05-1.21) analyses. The risk of stroke/thromboembolism associated with peripheral artery disease alone (HR, 1.93; CI, 1.70-2.19) was greater than the risk with myocardial infarction alone (HR, 1.12; CI, 1.04-1.21), and vascular disease significantly improved the predictive ability of the CHADS(2) score (Net Reclassification Improvement 0.032, P<.001)., Conclusions: Vascular disease is an independent predictor of stroke/thromboembolism in atrial fibrillation and improves the predictive ability of the CHADS(2) score., (Copyright © 2012 Elsevier Inc. All rights reserved.)

North American and European guidelines on atrial fibrillation (AF) are conflicting regarding the classification of patients at low/intermediate risk of stroke. We aimed to investigate if the CHA2DS2-VASc score improved risk stratification of AF patients with a CHADS2 score of 0-1. Using individual-level-linkage of nationwide Danish registries 1997-2008, we identified patients discharged with AF having a CHADS2 score of 0-1 and not treated with vitamin K antagonist or heparin. In patients with a CHADS2 score of 0, 1, and 0-1, rates of stroke/ thromboembolism were determined according to CHA2DS2-VASc score, and the risk associated with increasing CHA2DS2-VASc score was estimated in Cox regression models adjusted for year of inclusion and antiplatelet therapy. The value of adding the extra CHA2DS2-VASc risk factors to the CHADS2 score was evaluated by c-statistics, Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI). We included 47,576 patients with a CHADS2 score of 0-1, from these 7,536 (15.8%) were CHA2DS2-VASc score=0, 10,062 (21.2%) were CHA2DS2-VASc score=1, 14,310 (30.1%) were CHA2DS2-VASc score=2, 14,188 (29.8%) were CHA2DS2-VASc score=3, and 1,480 (3.1%) were CHA2DS2-VASc score=4. Of the cohort with a CHADS2 score of 0-1, the stroke/thromboembolism rate per 100 person-years increased with increasing CHA2DS2-VASc score (95% confidence interval): 0.84 (0.65-1.08), 1.79 (1.53-2.09), 3.67 (3.34-4.03), 5.75 (5.33-6.21), and 8.18 (6.68-10.02) at one year follow-up with CHA2DS2-VASc scores of 0, 1, 2, 3, and 4, respectively. Patients with a CHADS2 score=0 were not all 'low risk', with one-year event rates ranging from 0.84 (CHA2DS2-VASc score=0) to 3.2 (CHA2DS2-VASc score=3). Results from Cox regression analyses, NRI, and IDI confirmed the improved predictive ability of the CHA2DS2-VASc score in the AF patients who have a CHADS2 score of 0-1. In conclusion, the CHA2DS2-VASc provides critical information on risk of stroke in AF patients with a CHADS2 score of 0-1 that can aid a decision of using anticoagulation. Even in patients categorised as 'low risk' using a CHADS2 score=0, the CHA2DS2-VASc score significantly improved the predictive value of the CHADS2 score alone and a CHA2DS2-VASc score=0 could clearly identify 'truly low risk' subjects. Use of the CHA2DS2-VASc score would significantly improve classification of AF patients at low and intermediate risk of stroke, compared to the commonly used CHADS2 score.

Background: The objective of this study was to evaluate the added predictive ability of the CHA(2)DS(2)VASc prediction rule for stroke and death in a nonanticoagulated population of patients with atrial fibrillation., Methods and Results: We included 1603 nonanticoagulated patients with incident atrial fibrillation from a Danish prospective cohort study of 57 053 middle-aged men and women. The Net Reclassification Improvement was calculated as a measure to estimate any overall improvement in reclassification with the CHA(2)DS(2)VASc sore as an alternative to the CHADS(2) score. After 1-year follow-up, crude incidence rates were 3.4 per 100 person-years for stroke and 13.6 for death. After a mean follow-up of 5.4 years (± 3.7 years), the crude incidence rates for stroke and death were 1.9 and 5.6, respectively. During the entire observation period, the c-statistics and negative predictive values were similar for both risk scores. The Net Reclassification Improvement analysis showed that 1 of 10 reclassified atrial fibrillation patients would have been upgraded correctly using the CHA(2)DS(2)VASc score., Conclusions: Both the CHADS(2) as well as the CHA(2)DS(2)VASc risk score can exclude a large proportion of patients from having high risk of stroke or death. However, using the CHA(2)DS(2)VASc risk score, fewer patients will fulfill the criterion for low risk (and are truly low risk for thromboembolism). For every 10 extra patients transferred to the treatment group at 5 years, using the CHA(2)DS(2)VASc risk score, 1 patient would have had a stroke that might have been avoided with effective treatment.

The concept of net clinical benefit has been used to quantify the balance between risk of ischaemic stroke (IS) and risk of intracranial haemorrhage (ICH) with the use oral anticoagulant therapy (OAC) in the setting of non-valvular atrial fibrillation (AF), and has shown that patients at highest risk of stroke and thromboembolism gain the greatest benefit from OAC with warfarin. There are no data for the new OACs, that is, dabigatran, rivaroxaban and apixaban, as yet. We calculated the net clinical benefit balancing IS against ICH using data from the Danish National Patient Registry on patients with non-valvular AF between 1997-2008, for dabigatran, rivaroxaban and apixaban on the basis of recent clinical trial outcome data for these new OACs. In patients with CHADS(2)=0 but at high bleeding risk, apixaban and dabigatran 110 mg bid had a positive net clinical benefit. At CHA(2)DS(2)-VASc=1, apixaban and both doses of dabigatran (110 mg and 150 mg bid) had a positive net clinical benefit. In patients with CHADS(2) score≥1 or CHA(2)DS(2)-VASc≥2, the three new OACs (dabigatran, rivaroxaban and apixaban) appear superior to warfarin for net clinical benefit, regardless of risk of bleeding. When risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit than warfarin. In the absence of head-to-head trials for these new OACs, our analysis may help inform decision making processes when all these new OACs become available to clinicians for stroke prevention in AF. Using 'real world' data, our modelling analysis has shown that when the risk of bleeding and stroke are both high, all three new drugs appear to have a greater net clinical benefit compared to warfarin.

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.

Background: The risk factors associated with, and the incidence of systemic embolism in patients with atrial fibrillation (AF) are poorly understood., Objectives: We studied the association between AF and upper limb thromboembolectomy involving brachial, ulnar or radial artery in a national cohort study that included all individuals aged 40-99 years with incident AF., Methods: Data were retrieved from the Danish National Vascular Registry, the National Registry of Patients, the Danish Civil Registration System and Statistics Denmark., Results: In total, 131,476 patients (68,042 men and 63,434 women) with AF without previous thromboembolectomy in the upper limb were registered. In the study cohort, 130 men underwent upper limb thromboembolectomy over 220,890 person-years of observation, whilst 275 women underwent thromboembolectomy over 197,777 patient-years. The incidence per 100,000 person-years was 58.9 (95% CI, 49.2-69.8) for men and 139.1 (95% CI, 123.1-156.5) for women. The relative risk of thromboembolectomy among patients with AF compared to the background population was 7.5 (95% CI, 6.3-8.9) for men, and 9.3 (95% CI, 8.3-10.5) for women. Women with AF had a relative thromboembolectomy risk of 1.8 (95% CI, 1.5-2.3) compared to men with AF. Among patients with AF, history of hypertension (HR 2.2-2.9), myocardial infarction (HR 2.9-3.9), heart failure (HR 1.6-1.9) and stroke (HR 2.2-3.8) were significantly associated with increased risk of thromboembolectomy in both men and women., Conclusions: AF substantially increases the risk of upper limb thromboembolectomy. This risk is higher with increasing age, female gender, and associated with hypertension, myocardial infarction, heart failure and stroke., (© 2011 International Society on Thrombosis and Haemostasis.)

Background: Oral anticoagulation (OAC) in patients with atrial fibrillation (AF) is a double-edged sword, because it decreases the risk of stroke at the cost of an increased risk of bleeding. We compared the performance of a new bleeding prediction scheme, HAS-BLED, with an older bleeding prediction scheme, HEMORR(2)HAGES, in a cohort of 'real-world' AF patients., Methods: By individual-level-linkage of nationwide registers, we identified all patients (n = 118,584) discharged with non-valvular AF in Denmark during the period 1997-2006, with and without OAC. Major bleeding rates during 1 year of follow-up were determined, and the predictive capabilities of the two schemes were compared by c-statistics. The risk of bleeding associated with individual risk factors composing HAS-BLED was estimated using Cox proportional-hazard analyses., Results: Of AF patients receiving OAC (n = 44,771), 34.8% and 47.3% were categorized as 'low bleeding risk' by HAS-BLED and HEMORR(2)HAGES, respectively, and the bleeding rates per 100 person-years were 2.66 (95% confidence interval [CI], 2.40-2.94) and 3.06 (2.83-3.32), respectively. C-statistics for the two schemes were 0.795 (0.759-0.829) and 0.771 (0.733-0.806), respectively. The risk factors composing HAS-BLED were associated with varying risks, with a history of bleeding (hazard ratio [HR] 2.98; 95% CI 2.68-3.31) and being elderly (HR 1.93; 95% CI 1.71-2.18) being associated with the highest risks. Comparable results were found in AF patients not receiving OAC (n = 77,813)., Conclusions: In an unselected nationwide cohort of hospitalized patients with atrial fibrillation, the HAS-BLED score performs similarly to HEMORR(2)HAGES in predicting bleeding risk but HAS-BLED is much simpler and easier to use in everyday clinical practise., (© 2011 International Society on Thrombosis and Haemostasis.)