Arterial Thromboembolism in Patients With Atrial Fibrillation and CHA2DS2-VASc Score 1: A Nationwide Study.

BACKGROUND: Oral anticoagulation is suggested in patients with atrial fibrillation and a CHA2DS2-VASc score ≥1 (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, and sex score). To assess granular differences within CHA2DS2-VASc 1, the incidence of arterial thromboembolism according to CHA2DS2-VASc 1 subgroups was examined. METHODS: The Danish National Patient Registry and the Danish Prescription Registry were linked on a nationwide level to identify patients with atrial fibrillation from 2000 to 2021 without oral anticoagulation and categorized according to CHA2DS2-VASc score: CHA2DS2-VASc 0 (male and female subjects); CHA2DS2-VASc 1 (hypertension, heart failure, diabetes, vascular disease, and age 65-74 years); or CHA2DS2-VASc 2 (age ≥75 years without other risk factors). Female sex was not considered a risk factor in any risk group. The outcome was arterial thromboembolism (ischemic stroke, embolism of extremity, or transient cerebral ischemia). Study groups were compared using Cox regression analysis. RESULTS: We included 26 701 patients with a CHA2DS2-VASc 0 score; 22 915 with CHA2DS2-VASc 1 (1483 patients with heart failure, 9066 with hypertension, 843 with diabetes, 770 with vascular disease, and 10 753 who were 65 to 74 years of age); and 14 525 patients with CHA2DS2-VASc 2 (≥75 years of age without other risk factors). With a median of 1 year of observation time, the cumulative incidence of arterial thromboembolism was 0.6% (n=154 [95% CI, 0.6%-0.8%]), 1.4% (n=16 [95% CI, 0.8%-2.2%]), 1.9% (n=141 [95% CI, 1.6%-2.2%]), 1.7% (n=12 [95% CI, 0.9%-2.9%]), 2.0% (n=13 [95% CI, 1.1%-3.4%]), 2.3% (n=187 [95% CI, 2.0%-2.7%]), and 4.4% (n=533 [95% CI, 4.1%-4.8%]) for CHA2DS2-VASc 0, heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years (CHA2DS2-VASc 1), and age ≥75 years (CHA2DS2-VASc 2), respectively. No statistically significant difference was identified among subgroups of CHA2DS2-VASc 1 (P=0.15 for difference). CONCLUSIONS: For patients with atrial fibrillation, all subgroups of CHA2DS2-VASc 1 were associated with lower incidence of arterial thromboembolism compared with age ≥75 years without other risk factors (ie, CHA2DS2-VASc 2) and a higher incidence compared with CHA2DS2-VASc 0. No statistically significant difference was identified between the subgroups of CHA2DS2-VASc 1. These findings support current recommendations that patients within this intermediate risk group could be identified with a similar risk of arterial thromboembolism.

High-risk admission prior to transcatheter aortic valve replacement and subsequent outcomes.

BACKGROUND: Severe, symptomatic aortic stenosis may cause heart failure, acute myocardial infarction, or syncope; limited data exist on the occurrence of such events before transcatheter aortic valve replacement (TAVR) and their impact on subsequent outcomes. Thus, we investigated the association between a preceding event and outcomes after TAVR. METHODS: From 2014 to 2021 all Danish patients who underwent TAVR were included. Preceding events up to 180 days before TAVR were identified. A preceding event was defined as a hospitalization for heart failure, acute myocardial infarction, or syncope. The 1-year risk of all-cause death, and cardiovascular or all-cause hospitalization was compared for patients with versus without a preceding event using Kaplan-Meier, Aalen-Johansen, and in Cox regression analyses adjusted for patient characteristics. RESULTS: Of 5,851 patients included, 759 (13.0%) had a preceding event. The median age was 81 years in both groups. Male sex and frailty were more prevalent in patients with a preceding event (males: 64.7% vs 55.2%, frailty: 49.6% vs 40.6%). The most common type of preceding event was a hospitalization for heart failure (n = 524). For patients with a preceding event, the 1-year risk of death was 11.7% (95% CI: 9.4%-14.1%) versus 8.0% (95% CI: 7.2%-8.7%) for patients without. The corresponding adjusted hazard ratio (aHR) was 1.29 (95%CI: 1.01-1.64). Mortality was highest for patients with a preceding event of a heart failure admission (1-year risk: 13.5% [95%CI: 10.5%-16.5%]). Comparing patients with a preceding event to those without, the 1-year risk for cardiovascular rehospitalization was 15.0% versus 8.2% (aHR 1.60 [95%CI: 1.29-1.99]) and 57.6% versus 50.6% for all-cause rehospitalization (aHR 1.08 [95%CI: 0.87-1.20]). CONCLUSIONS: A hospitalization for heart failure, myocardial infarction, or syncope prior to TAVR was associated with a poorer prognosis and could represent a group to focus resource management on. Interventions to prevent preceding events and improvements in pre- and post-TAVR optimization of these patients are warranted.

Patient Characteristics, Microbiology, and Mortality of Infective Endocarditis After Transcatheter Aortic Valve Implantation.

BACKGROUND: Infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) is associated with high mortality and surgery is rarely performed. Thus, to inform on preventive measures and treatment strategies, we investigated patient characteristics and microbiology of IE after TAVI. METHODS: Using Danish nationwide registries, we identified patients with IE after TAVI, IE after non-TAVI prosthetic valve (nTPV), and native valve IE. Patient characteristics; overall, early (≤12 m), and late IE (>12 m) microbiology; and unadjusted and adjusted mortality were compared. RESULTS: We identified 273, 1022, and 5376 cases of IE after TAVI, IE after nTPV, and native valve IE. Age and frailty were highest among TAVI IE (4.8%; median age: 82 y; 61.9% frail). Enterococcus spp. were common for IE after TAVI (27.1%) and IE after nTPV (21.2%) compared with native valve IE (11.4%). Blood culture-negative IE was rare in IE after TAVI (5.5%) compared with IE after nTPV (15.2%) and native valve IE (13.5%). The unadjusted 90-day mortality was comparable, but the 5-year mortality was highest for IE after TAVI (75.2% vs 57.2% vs 53.6%). In Cox models adjusted for patient characteristics and bacterial etiology for 1-90 days and 91-365 days, there was no significant difference in mortality rates. CONCLUSIONS: Patients with IE after TAVI are older and frailer, enterococci and streptococci are often the etiologic agents, and are rarely blood culture negative compared with other IE patients. Future studies regarding antibiotic prophylaxis strategies covering enterococci should be considered in this setting.

Outcomes of prolonged dual anti-platelet therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A nationwide registry-based study.

BACKGROUND: Randomized controlled trials have shown a reduced risk of ischemic events and an increased risk of bleeding in patients treated with prolonged dual anti-platelet therapy (DAPT) beyond 12 months following acute coronary syndrome (ACS). We aimed to investigate outcomes of prolonged DAPT vs aspirin monotherapy (ASA) in a real-world population. METHODS AND RESULTS: Using nationwide registries, we identified all patients with ACS who underwent percutaneous coronary intervention and received 12-month DAPT between January 2013 and October 2016. Patients still on DAPT were compared to patients on ASA at index date (15 months after ACS-date) and followed for up to 2 years. Cox regression models were employed to calculate standardized risks of all-cause mortality, major adverse cardiovascular event (MACE), and major bleeding. The study included 7,449 patients, 1,901 on DAPT (median age 66, 72.1% male) and 5,548 on ASA (median age 65, 75.1% male). Standardized absolute 2-year risk of all-cause mortality, MACE, and major bleeding was 2.7%, 3.7%, and 5.4% for DAPT vs 2.2%, 3.8%, and 1.3% for ASA. DAPT was not associated with a significant standardized 2-year risk difference (SRD) of all-cause mortality (SRD: 0.5%, 95% confidence interval [CI]: -0.9 to 1.7) or MACE (SRD: -0.1%, 95% CI -1.8 to 1.6), but a significantly higher risk of major bleeding (SRD: 4.1%, 95% CI 1.8-6.6). CONCLUSIONS: In a nationwide cohort of ACS patients undergoing percutaneous coronary intervention, prolonged DAPT was not significantly associated with a reduced risk of all-cause mortality or MACE, but an increased risk of major bleeding. Future randomized controlled trials should investigate the optimal anti-platelet regimen in this patient group.

Oral fluoroquinolones and risk of aortic or mitral regurgitation: a nationwide nested case-control study.

AIMS: Reports have suggested an increased risk of aortic and mitral regurgitation associated with oral fluoroquinolones (FQs) resulting in a safety warning published by the European Medicines Agency (EMA). However, these findings have not yet been replicated. METHODS AND RESULTS: Using Danish administrative registers, we conducted a nested case-control study in a nationwide cohort of individuals between 2005 and 2018. Cases were defined as the first occurrence of aortic or mitral regurgitation. Exposure of interest was the use of oral FQs. Hazard ratios (HRs) with 95% confidence intervals (95% CI) were obtained by fitting time-dependent Cox regression models, with penicillin V as comparator, to assess the association between FQ use and incident valvular regurgitation. We identified 38 370 cases of valvular regurgitation with 1 115 100 matched controls. FQ exposure was not significantly associated with increased rates of aortic or mitral regurgitation (HR 1.02, 95% CI 0.95-1.09) compared with penicillin V users. Investigating the cumulative defined daily doses (cDDD) of FQs yielded similar results with no significant association between increasing FQ use and valvular regurgitation (e.g. HR 1.08, 95% CI 0.95-1.23 for cDDD >10 compared with cDDD 1-5). These results were consistent across several analyses including a cohort of patients with hypertension and using a case definition based on valvular surgical interventions. CONCLUSIONS: In a nationwide nested case-control study, FQs were not significantly associated with increased rates of valvular regurgitation. Our findings do not support a possible causal connection between FQ exposure and incident valvular regurgitation.

One-year outcomes in atrial fibrillation presenting during infections: a nationwide registry-based study.

AIMS: Thromboprophylaxis guidelines for patients with concurrent atrial fibrillation (AF) during infections are unclear and not supported by data. We compared 1-year outcomes in patients with infection-related AF and infection without AF. METHODS AND RESULTS: By crosslinking Danish nationwide registry data, AF naïve patients admitted with infection (1996-2016) were identified. Those with AF during the infection (infection-related AF) were matched 1:3 according to age, sex, type of infection, and year with patients with infection without AF. Outcomes (AF, thromboembolic events) were assessed by multivariable Cox regression. The study population comprised 30 307 patients with infection-related AF and 90 912 patients with infection without AF [median age 79 years (interquartile range 71-86), 47.6% males in both groups]. The 1-year absolute risk of AF and thromboembolic events were 36.4% and 7.6%, respectively (infection-related AF) and 1.9% and 4.4%, respectively (infection without AF). In the multivariable analyses, infection-related AF was associated with an increased long-term risk of AF and thromboembolic events compared with infection without AF: hazard ratio (HR) 25.98, 95% confidence interval (CI) 24.64-27.39 for AF and HR 2.10, 95% CI 1.98-2.22 for thromboembolic events. Further, differences in risks existed across different subtypes of infections. CONCLUSION: During the first year after discharge, 36% of patients with infection-related AF had a new hospital contact with AF. Infection-related AF was associated with increased risk of thromboembolic events compared with infection without AF and our results suggest that AF related to infection may merit treatment and follow-up similar to that of AF not related to infection.

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.

Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation.

Aims: After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran, rivaroxaban, or apixaban) has not been quantified, and could help assess whether these drugs are used according to recommendations. Methods and results: Using Danish nationwide registries, we identified all VKA-experienced NVAF patients initiating a NOAC from 22 August 2011 to 31 December 2015 (shifters) and all VKA-experienced NVAF patients who were not switched to NOACs (non-shifters). Baseline characteristics and temporal utilization trends were examined. We included 62 065 patients with NVAF; of these, 19 386 (29.6%) shifted from a VKA to a NOAC (9973 (54.2%) shifted to dabigatran, 4775 (26.0%) to rivaroxaban, and 3638 (19.8%) to apixaban). Shifting was associated with lower age [odds ratio (OR) 0.95, 95% confidence interval (95% CI) 0.94-0.96 per 5 year increments], female gender (OR 1.33, 95% CI 1.28-1.38), and certain co-morbidities: more often stroke, bleeding, heart failure, and alcohol abuse, and less often hypertension, ischaemic heart disease, and diabetes. Shifting was common and initially dominated by shifting from VKA to dabigatran, but at the end of 2015, most shifters were shifted to rivaroxaban (45%) or apixaban (45%) whereas shifting to dabigatran decreased (to 10%). Conclusion: In a contemporary setting among VKA-experienced NVAF patients; VKA is still prevalent although about 30% by December 2015 had shifted to a NOAC.

Risk of incident atrial fibrillation in patients presenting with retinal artery or vein occlusion: a nationwide cohort study.

BACKGROUND: The inter-relationships of atrial fibrillation (AF) to retinal vascular occlusions (whether retinal artery occlusion (RAO) or retinal venous occlusion (RVO)) remain unclear. It is unknown if a presentation of retinal artery or venous occlusions may indicate a new onset cardiac arrhythmia. To shed light on this association, we investigated the risk of new onset AF in patients with known RAO and RVO. METHODS: Patients with retinal occlusions from 1997 to 2011 were identified through Danish nationwide registries and matched 1:5 according to sex and age. Cumulative incidence and unadjusted rates of AF according to retinal vascular occlusions (i.e. RAO or RVO) were determined. Hazard ratios (HR) of AF according to retinal vascular occlusion were adjusted for hypertension, diabetes, vascular disease and prior stroke/systemic thromboembolism/transient ischemic attack. RESULTS: One thousand three hundred sixty-eight cases with retinal vascular occlusions were identified (median age 71.4 (inter quartile range (IQR); 61.2-79.8), 47.3% male). RAO constituted 706 cases (51.6%) and RVO 529 (38.7%). The rate of incident AF amongst all cases with retinal vascular occlusion was 1.74 per 100 person-years (95% confidence interval (CI), 1.47-2.06) compared to 1.22 (95% CI, 1.12-1.33) in the matched control group. The rate of AF in RAO was 2.01 (95% CI, 1.6-2.52) and 1.52 (1.15-2.01) in RVO. HRs of incident AF adjusted for cardiovascular comorbidities were 1.26 (95% CI; 1.04-1.53, p = 0.019) for any retinal vascular occlusion, 1.45 (95% CI; 1.10-1.89, p = 0.015) for RAO, and 1.02 (95% CI; 0.74-1.39, p = 0.920) for RVO. CONCLUSIONS: A new diagnosis of retinal vascular occlusion in patients without prior AF was associated with increased risk of incident AF, particularly amongst patients with RAO. Awareness of AF in patients with retinal vascular occlusions is advised.

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.

Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark.

AIM: The aim of this study is to examine temporal trends in the use oral anticoagulants (OAC) as stroke prophylaxis in patients with atrial fibrillation (AF) and to examine factors associated with OAC initiation. METHODS AND RESULTS: From Danish nationwide registries, we identified patients diagnosed with AF at Danish hospitals and outpatient clinics between January 2005 and June 2015. OAC initiation was assessed from prescription fills ±180 days from date of AF diagnosis. We identified a total of 108 410 patients with newly diagnosed AF. Before 2010, 40-50% initiated OAC treatment. From 2010, OAC initiation rates increased (P < 0.0001 for trend) and by June 2015, 66.5% of the incident AF patients were initiated on OAC (74.5% increase since December 2009). Increased OAC prescription was especially seen among females and 'fragile' patients (age > 75 years and high risk of stroke). The increased OAC initiation was accompanied by introduction and increased uptake of the NOACs. By the end of the study, NOACs accounted for 72.5% of all OACs prescribed in newly diagnosed AF patients. OAC initiation was associated with male gender, age 65-74 years, few comorbidities and increased risk of stroke. CONCLUSION: Since 2010, more incident AF patients in Denmark were initiated on OAC therapy with predominant NOAC prescription. The increase was pronounced among females, among patients at high risk of stroke, and among older patients.

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.

Atrial fibrillation and risk of stroke: a nationwide cohort study.

AIM: Although the relation between stroke risk factors and stroke in patients with atrial fibrillation (AF) has been extensively examined, only few studies have explored the association of AF and the risk of ischaemic stroke/systemic thromboembolism/transient ischaemic attack (stroke/TE/TIA) in the presence of concomitant stroke risk factors. METHODS AND RESULTS: From nationwide registries, all persons who turned 50, 60, 70, or 80 from 1997 to 2011 were identified. Persons receiving warfarin were excluded. The absolute risk of stroke/TE/TIA was reported for a 5-year period, as was the absolute risk ratios for AF vs. no AF according to prior stroke and the number of additional risk factors. The study cohort comprised of 3 076 355 persons without AF and 48 189 with AF. For men aged 50 years, with no risk factors, the 5-year risk of stroke was 1.1% (95% confidence interval 1.1-1.1); with AF alone 2.5% (1.8-3.2); with one risk factor and no prior stroke or AF 2.5% (2.3-2.7); and with one factor, no prior stroke and AF 2.9% (1.4-4.3). In men aged 50 years with prior stroke as the only risk factor, 5-year risk was 10.2% (9.1-11.3). In men aged 70 years, the corresponding risks were 4.8% (4.7-4.9), 6.8% (5.7-7.9), 6.6% (6.3-6.8), 8.7 (7.4-9.9), and 19.1% (18.1-20.1), respectively. In women aged 50 years, the risk was of 0.7% (0.7-0.7), 2.1% (0.9-3.2), 1.6% (1.4-1.8), 4.1% (0.6-7.6), and 7.2% (6.3-8.2), respectively, and in women aged 70 years 3.4% (3.3-3.5), 8.2% (7.0-9.5), 4.6% (4.4-4.8), 9.1% (7.5-10.6), and 15.4% (14.5-16.4), respectively. CONCLUSIONS: Stroke/TE/TIA risk was particularly increased when prior stroke/TE/TIA was present. Atrial fibrillation is associated with an increase in risk of stroke/TE/TIA in the absence of other risk factors but only a moderate increase in risk when other risk factors are present.

Familial clustering and subsequent incidence of atrial fibrillation among first-degree relatives in Denmark.

AIMS: Atrial fibrillation (AF) is associated with increased morbidity and mortality. Determination and quantification of familial risk may help identify high-risk patients. METHODS AND RESULTS: Using Danish nationwide registry data (1978-2012), we identified all first-time AF patients (probands) in Denmark. Relatives to these probands were grouped according to proband-relation: offspring from either maternal or paternal proband, and siblings to proband. Age-specific incidence of AF for these three groups of relatives and for the general Danish population was estimated. Using the general population as reference, we calculated adjusted rate ratios (RRs) of AF in the three groups of relatives. We identified 67 310, 103 822, and 11 800 AF probands who were mothers (median age 74 years, IQR 66-81), fathers (70 years, IQR 62-78), and siblings (46 years, IQR 38-52), respectively. Among those, 133 516, 221 774, and 21 448 offspring from a maternal proband, offspring from a paternal proband, and siblings, respectively, were screened for incident AF. This was recorded in 2536 (1.9%), 2906 (1.3%), and 292 (1.4%) relatives, respectively. Compared with the general Danish population, the adjusted RRs for incident AF were 3.37 [95% confidence interval (CI) 3.21-3.53] for offspring from maternal probands, 2.81 (95% CI 2.69-2.93) for offspring from paternal probands, and 5.20 (95% CI 4.61-5.85) for siblings to sibling probands. Subgroup analyses showed increased RRs with younger aged probands. CONCLUSION: Familial AF was associated with an increased RR of AF in first-degree relatives compared with the general Danish population. This suggests that familial AF is a major risk factor for developing AF in relatives.

Substantial differences in initiation of oral anticoagulant therapy and clinical outcome among non-valvular atrial fibrillation patients treated in inpatient and outpatient settings.

AIMS: Patients with atrial fibrillation (AF) are encountered and treated in different healthcare settings, which may affect the quality of care. We investigated the use of oral anticoagulant (OAC) therapy and the risk of thrombo-embolism (TE) and bleeding, according to the healthcare setting. METHODS AND RESULTS: Using national Danish registers, we categorized non-valvular AF patients (2002-11) according to the setting of their first-time AF contact: hospitalization (inpatients), ambulatory (outpatients), or emergency department (ED). Event rates and hazard ratios (HRs), calculated using Cox regression analysis, were estimated for outcomes of TE and bleeding. We included 116 051 non-valvular AF patients [mean age 71.9 years (standard deviation 14.1), 51.3% males], of whom 55.2% were inpatients, 41.9% outpatients, and 2.9% ED patients. OAC therapy 180 days after AF diagnosis among patients with a CHADS2 ≥ 2 was 42.1, 63.0, and 32.4%, respectively. Initiation of OAC therapy was only modestly influenced by CHADS2 and HAS-BLED scores, regardless of the healthcare setting. The rate of TE was 4.30 [95% confidence interval (CI) 4.21-4.40] per 100 person-years for inpatients, 2.28 (95% CI 2.22-2.36) for outpatients, and 2.30 (95% CI 2.05-2.59) for ED patients. The adjusted HR of TE, with inpatients as reference, was 0.74 (95% CI 0.71-0.77) for outpatients and 0.89 (95% CI 0.79-1.01) for ED patients. CONCLUSION: In a nationwide cohort of non-valvular AF patients, outpatients were much more likely to receive OAC therapy and had a significantly lower risk of stroke/TE compared with inpatients and ED patients. However, across all settings investigated, OAC therapy was far from optimal.