The last three decades have been characterized by an exponential growth in knowledge and advances in the clinical treatment of atrial fibrillation (AF). It is now known that AF genesis requires a vulnerable atrial substrate and that the formation and composition of this substrate may vary depending on comorbid conditions, genetics, sex, and other factors. Population-based studies have identified numerous factors that modify the atrial substrate and increase AF susceptibility. To date, genetic studies have reported seventeen independent signals for AF at fourteen genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors, including sedentary lifestyle, smoking, obesity, diabetes mellitus, obstructive sleep apnea, and elevated blood pressure predispose to AF and each factor has been shown to induce structural and electrical remodeling of the atria. Both heart failure and myocardial infarction increase risk of AF and vice versa creating a feed forward loop that increases mortality. Other cardiovascular outcomes attributed to AF, including stroke and thromboembolism, are well established and epidemiology studies have championed therapeutics that mitigate these adverse outcomes. However, the role of anticoagulation for preventing dementia attributed to AF is less established. Our review is a comprehensive examination of the epidemiological data associating unmodifiable and modifiable risk factors for AF and of the pathophysiological evidence supporting the mechanistic link between each risk factor and AF genesis. Our review also critically examines the epidemiological data on clinical outcomes attributed to AF and summarizes current evidence linking each outcome with AF.

ObjectiveTo examine the association between risk factor burdens—categorized as optimal, borderline, or elevated—and the lifetime risk of atrial fibrillation.DesignCommunity based cohort study.SettingLongitudinal data from the Framingham Heart Study.ParticipantsIndividuals free of atrial fibrillation at index ages 55, 65, and 75 years were assessed. Smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction were assessed as being optimal (that is, all risk factors were optimal), borderline (presence of borderline risk factors and absence of any elevated risk factor), or elevated (presence of at least one elevated risk factor) at index age.Main outcome measureLifetime risk of atrial fibrillation at index age up to 95 years, accounting for the competing risk of death.ResultsAt index age 55 years, the study sample comprised 5338 participants (2531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1415 (26.5%) had a borderline risk profile, and 3676 (68.9%) an elevated risk profile. The prevalence of elevated risk factors increased gradually when the index ages rose. For index age of 55 years, the lifetime risk of atrial fibrillation was 37.0% (95% confidence interval 34.3% to 39.6%). The lifetime risk of atrial fibrillation was 23.4% (12.8% to 34.5%) with an optimal risk profile, 33.4% (27.9% to 38.9%) with a borderline risk profile, and 38.4% (35.5% to 41.4%) with an elevated risk profile. Overall, participants with at least one elevated risk factor were associated with at least 37.8% lifetime risk of atrial fibrillation. The gradient in lifetime risk across risk factor burden was similar at index ages 65 and 75 years.ConclusionsRegardless of index ages at 55, 65, or 75 years, an optimal risk factor profile was associated with a lifetime risk of atrial fibrillation of about one in five; this risk rose to more than one in three in individuals with at least one elevated risk factor.

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.

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BackgroundThe nonvitamin K antagonist oral anticoagulants have recently become available as an alternative to warfarin as stroke prophylaxis in atrial fibrillation, but data on real‐life patient experience, including bleeding risk, are lacking. Our objective was to compare major bleeding events and nonpersistence between the nonvitamin K antagonist oral anticoagulant apixaban and other nonvitamin K antagonist oral anticoagulants (dabigatran and rivaroxaban) and warfarin in a contemporary, nation‐wide cohort of patients with nonvalvular atrial fibrillation.Methods and ResultsOf 54 321 patients (median age, 73 years; 56% male; mean CHA 2 DS 2‐VASc score, 2.9), 7963, 6715, 15 413, and 24 230 patients initiated apixaban, rivaroxaban, dabigatran, and warfarin, respectively. Apixaban and rivaroxaban initiators were older, less often male, with higher HAS‐BLED and CHA 2 DS 2‐VASc scores compared with dabigatran and warfarin initiators. A total of 2418 patients (4.5%) experienced a major bleeding event over all available follow‐up. In this period, rivaroxaban (hazard ratio [HR] [95% CI], 1.49 [1.27–1.77]), dabigatran (HR, 1.17 [1.00–1.38]), and warfarin (HR, 1.23 [1.05–1.43]) users were significantly more likely to bleed than apixaban users. Findings were similar when restricted to the first 30 days after OAC initiation. Risk of nonpersistence was higher for dabigatran (HR, 1.45 [1.33–1.59]) and warfarin initiators (HR, 1.22 [1.12–1.33]), but not for rivaroxaban initiators (HR, 1.07 [0.96–1.20]) compared with apixaban initiators.ConclusionsIn a real‐world cohort of nonvalvular atrial fibrillation patients, apixaban had a lower adjusted major bleeding risk compared with rivaroxaban, dabigatran, and warfarin. Apixaban had a lower risk of nonpersistence compared with dabigatran and warfarin and similar risk compared with rivaroxaban.

Study queStionWhat 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? MethodSThis Danish cohort study (1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(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 nonresumption 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 addSAmong 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.

Background Comparative data of non‐vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). Objective We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. Methods Using Danish nationwide registries, we included all oral anticoagulant‐naïve AF patients who initiated NOAC treatment (2012–2016). Outcome‐specific and mortality‐specific multiple Cox regressions were combined to compute average treatment effects as 1‐year standardized differences in stroke and bleeding risks (g‐formula). Results Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran‐reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1‐year standardized absolute risks of stroke/thromboembolism were 1.73–1.98% and 2.51–2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1‐year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42–3.17%); corresponding absolute risk differences (95% CI) were for dabigatran −0.93% (−1.45% to −0.38%) and apixaban, −0.54% (−0.99% to −0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1‐year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22–0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06–0.41%) and apixaban, 0.18% (0.01–0.34%). Conclusions Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban.

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.