Laila Staerk

Stroke and recurrent haemorrhage associated with antithrombotic treatment after gastrointestinal bleeding in patients with atrial fibrillation: nationwide cohort study.

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.

Atrial Fibrillation: Epidemiology, Pathophysiology, and Clinical Outcomes

The past 3 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 17 independent signals for AF at 14 genomic regions. Studies have established that advanced age, male sex, and European ancestry are prominent AF risk factors. Other modifiable risk factors include 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 electric 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.

Non-Vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation: Temporal trends 2011–2015 in Denmark

Among atrial fibrillation (AF) patients, Danish nationwide registries (2011–2015) were used to examine temporal trends of initiation patterns of oral anticoagulation (OAC) treatment according to age. Overall, 43,299 AF patients initiating vitamin K antagonists (VKA) (42%), dabigatran (29%), rivaroxaban (13%), or apixaban (16%) were included with mean age (SD) 72.1 (11.3), 71.5 (11.0), 74.3 (11.1), and 75.3 (11.1) years, respectively. Patients aged ≥85 years comprised 15%. Trend tests showed increase in patients ≥85 years initiating OAC (p < 0.0001). VKA usage decreased from 92% to 24% (p < 0.0001). This decrease was independent of age. Dabigatran was the most common non-VKA OAC (NOAC) (40% users), but usage decreased from 2014 until study end (6%) (p < 0.0001). Apixaban was the most used OAC at study end (41%), in particular among those ≥85 years (44%). Compared with patients aged <65 years, the odds ratios associated with initiating VKA, dabigatran, rivaroxaban, or apixaban for patients aged ≥85 years were 0.81 (95% CI 0.75–0.86), 0.65 (95% CI 0.60–0.70), 1.52 (95% CI 1.38–1.67), and 2.09 (95% CI 1.89–2.30), respectively. In conclusion, substantial increase in NOAC usage has occurred. Increasing age was associated with upstart of rivaroxaban or apixaban with reference to age <65 within the specific agent.

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.

Major Bleeding Complications and Persistence With Oral Anticoagulation in Non‐Valvular Atrial Fibrillation: Contemporary Findings in Real‐Life Danish Patients

Background The 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 Results Of 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. Conclusions In 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.

Cardioversion and Risk of Adverse Events with Dabigatran versus Warfarin-A Nationwide Cohort Study.

Aim Cardioversion can rapidly and effectively restore sinus rhythm in patients with persistent atrial fibrillation. Since 2011 dabigatran has been available as an alternative to warfarin to prevent thromboembolic events in patients with non-valvular atrial fibrillation undergoing cardioversion. We studied time to cardioversion, risk of adverse events, and risk of readmission with atrial fibrillation after cardioversion according to anticoagulation therapy. Methods and Results Through the nationwide Danish registries we included 1,230 oral anticoagulation naïve patients with first time non-valvular atrial fibrillation and first time cardioversion from 2011 to 2012; 37% in the dabigatran group (n = 456), and 63% in the warfarin group (n = 774). Median time to cardioversion was 4.0 (interquartile range [IQR] 2.9 to 6.5) and 6.9 (IQR 3.9 to 12.1) weeks in the dabigatran and warfarin groups respectively, and the adjusted odds ratio of cardioversion within the first 4 weeks was 2.3 (95% confidence interval [CI] 1.7 to 3.1) in favor of dabigatran. The cumulative incidence of composite endpoint of stroke, bleeding or death were 2.0% and 1.0% at 30 weeks in the warfarin and dabigatran groups respectively, with an adjusted hazard ratio of 1.33 (95% CI 0.33 to 5.42). Cumulative incidence of readmission with atrial fibrillation after 30 weeks were 9% and 11% in the warfarin and dabigatran groups, respectively, and an adjusted hazard ratio of 0.66 (95% CI 0.41 to 1.08). Conclusion Anticoagulation treatment with dabigatran allows shorter time to cardioversion for atrial fibrillation than warfarin, and appears to be an effective and safe alternative treatment strategy to warfarin.

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

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

Comparative safety and effectiveness of rivaroxaban versus VKAs in patients with venous thromboembolism: A Danish nationwide registry-based study

The approval of rivaroxaban has changed the landscape of treatment of venous thromboembolism (VTE). Little is known about the effect of rivaroxaban compared with vitamin K antagonists (VKA), when used in the everyday clinical practice. The aim of this study was to investigate the safety and effectiveness of rivaroxaban compared with VKAs among patients with VTE, using the Danish nationwide registries. All patients diagnosed with VTE and treated with either rivaroxaban or VKAs between 2013 and 2015 were included. A total of 12,318 patients were diagnosed with VTE and treated with VKAs [n=6,907] or rivaroxaban [n=5,411.]. Combined Cox regression analyses showed that the standardised absolute six-month risk of recurrent VTE was 3.03 % [95 % CI: 2.57 % to 3.48 %] in the rivaroxaban group and 3.13 % [95 % CI: 2.70 % to 3.56 %] in the VKA group (absolute risk difference of -0.11 % [95 % CI: -0.76 % to 0.54 %]). The standardised absolute six-months risk of bleeding was 2.28 % [95 % CI: 1.87 % to 2.67 %] for patients in the rivaroxaban group and 2.10 % [95 % CI: 1.78 % to 2.43 %] in the VKA group (absolute risk difference of 0.18 % [95 % CI: -0.34 % to 0.67]). In conclusion, rivaroxaban was associated with similar risk of recurrent VTE and bleeding compared with VKA.

Genetic Predisposition, Clinical Risk Factor Burden, and Lifetime Risk of Atrial Fibrillation

Background: The long-term probability of developing atrial fibrillation (AF) considering genetic predisposition and clinical risk factor burden is unknown. Methods: We estimated the lifetime risk of AF in individuals from the community-based Framingham Heart Study. Polygenic risk for AF was derived using a score of ≈1000 AF-associated single-nucleotide polymorphisms. Clinical risk factor burden was calculated for each individual using a validated risk score for incident AF comprised of height, weight, systolic and diastolic blood pressure, current smoking status, antihypertensive medication use, diabetes mellitus, history of myocardial infarction, and history of heart failure. We estimated the lifetime risk of AF within tertiles of polygenic and clinical risk. Results: Among 4606 participants without AF at 55 years of age, 580 developed incident AF (median follow-up, 9.4 years; 25th–75th percentile, 4.4–14.3 years). The lifetime risk of AF >55 years of age was 37.1% and was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of AF at 55 years of age, those in low-polygenic and clinical risk tertiles had a lifetime risk of AF of 22.3% (95% confidence interval, 15.4−9.1), whereas those in high-risk tertiles had a risk of 48.2% (95% confidence interval, 41.3−55.1). A lower clinical risk factor burden was associated with later AF onset after adjusting for genetic predisposition (P<0.001). Conclusions: In our community-based cohort, the lifetime risk of AF was 37%. Estimation of polygenic AF risk is feasible and together with clinical risk factor burden explains a substantial gradient in long-term AF risk.

Initiation of anticoagulation in atrial fibrillation: which factors are associated with choice of anticoagulant?

The use of non‐vitamin K antagonist oral anticoagulants (NOACs) for stroke prophylaxis in atrial fibrillation (AF) is increasing rapidly. We compared characteristics of AF patients initiated on NOACs versus vitamin K antagonists (VKAs).