Caroline Sindet-Pedersen

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.

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.

Safety and efficacy of direct oral anticoagulants compared to warfarin for extended treatment of venous thromboembolism -a systematic review and meta-analysis

OBJECTIVE To examine and compare the safety and efficacy of extended treatment with dabigatran, apixaban, rivaroxaban and warfarin in patients with unprovoked venous thromboembolism. METHODS PubMed and Embase were searched for randomized clinical trials reporting on the use of direct oral anticoagulants (DOACs) and warfarin for the extended treatment of VTE. Meta-analysis was performed on studies reporting similar study design and comparator. RESULTS A total of 729 articles were identified and 5 studies covering 6 randomized clinical trials met the eligibility criteria and were included in the study. 5 studies were included in the meta-analysis. Results from the meta-analysis showed that the extended use of DOACs and warfarin significantly decreased the risk of recurrent VTE with 83 % when compared placebo. Warfarin (RR: 0.03, CI: 0.00-0.49) and dabigatran (RR: 0.08, CI: 0.03-0.27) showed the largest relative risk reduction followed by apixaban 2.5mg (RR: 0.19, CI: 0.11-0.33), rivaroxaban (RR:0.19, CI: 0.09-0.40) and apixaban 5mg (RR: 0.20, CI: 0.11-0.34). No significant increased risk of major bleeding was observed with the extended use of any DOACs and warfarin compared to placebo (1.15, CI: 0.40-3.31), but an overall increased risk of non-major clinically relevant bleeding (NMCRB) was observed (RR: 2.12, CI: 1.55-2.90). Apixaban 2.5mg and warfarin was not individually associated with an increased risk of NMCRB. Furthermore, it was found from a study not included in the meta-analysis that dabigatran was non-inferior to VKA for the prevention of recurrent VTE (HR: 1.44, CI: 0.78-2.64, p=0.01 for noninferiority) and decreased the risk of NMCRB compared to VKA (RR: 0.58, CI: 0.43-0.77). CONCLUSION Extended treatment with both warfarin and DOACs are effective in preventing recurrent VTE and does not increase the risk of major bleeding, but increases the risk of NMCRB.

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).

Use of oral anticoagulants in combination with antiplatelet(s) in atrial fibrillation

Objectives To investigate temporal trends in the use of non-vitamin K oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) in combination with aspirin and/or clopidogrel in patients with atrial fibrillation (AF) following acute myocardial infarction (MI) and/or percutaneous coronary intervention (PCI). Methods Using Danish nationwide registries, all patients with AF who survived 30 days after discharge from MI and/or PCI between 22 August 2011 and 30 September 2016 were identified. Results A total of 2946 patients were included in the study population, of whom 1967 (66.8%) patients were treated with VKA in combination with antiplatelet(s) (VKA+aspirin n=477, VKA+clopidogrel n=439, VKA+aspirin+clopidogrel n=1051) and 979 (33.2%) patients were treated with NOAC in combination with antiplatelet(s) (NOAC+aspirin n=252, NOAC+clopidogrel n=218, NOAC+aspirin+clopidogrel n=509). The overall study population had a median age of 76 years [IQR: 69–82] and consisted of 1995 (67.7%) men. Patients with MI as inclusion event accounted for 1613 patients (54.8%). Patients with high CHA2DS2-VASc score(congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, history of stroke/transient ischemic attack/systemic thromboembolism (2 points), vascular disease, age 65-75 years, and female sex) accounted for 132 2814 (95.5%) of patients, and patients with high HAS-BLED score (hypertension, abnormal renal/liver function, history of stroke, history of bleeding, age >65 years, non-steroidal anti-inflammatory drug usages, or alcohol abuse, leaving out labile international normalized ratio (not available), and use of antiplatelets (exposure variable)) accounted for 934 (31.7%) of patients. There was an increase from 10% in 2011 to 52% in 2016 in the use of NOACs in combination with antiplatelet(s). Conclusion From 2011 to 2016, the use of NOAC in combination with antiplatelet(s) increased in patients with AF following MI/PCI and exceeded the use of VKA in combination with antiplatelet(s) by 2016.

Temporal trends in initiation of VKA, rivaroxaban, apixaban and dabigatran for the treatment of venous thromboembolism: A Danish nationwide cohort study

Danish nationwide registries were used to investigate temporal trends in initiation of rivaroxaban or apixaban or dabigatran versus vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Patients treated with one of the NOACs (rivaroxaban, dabigatran, apixaban) or VKA were identified between February 2012 and September 2016. A total of 19,578 patients were included of which 10,844 (55.4%) were treated with VKA and 8,734 (44.6%) were treated with NOACs (rivaroxaban 7,572, apixaban 1,066, and dabigatran 96). Temporal trends showed a decrease in the initiation of VKA (p-value for decreasing trend, p < 0001) and an increase in the initiation of rivaroxaban and apixaban (p-value for increasing trend, p < 0001). By September 2016, 12%, 70%, 16%, and 2% of patients with VTE were initiated on VKA, rivaroxaban, apixaban, and dabigatran. Patients with previous VTE, chronic kidney disease, liver disease, cancer, and thrombophilia were more likely to be initiated on VKA compared with one of the NOACs. In conclusion the initiation of rivaroxaban and apixaban is increasing significantly over time in patients with VTE. Patients with previous VTE, chronic kidney disease, liver disease, cancer, and thrombophilia were more likely to be initiated on VKA compared with rivaroxaban or apixaban.

Risk of Ischemic Stroke, Hemorrhagic Stroke, Bleeding, and Death in Patients Switching from Vitamin K Antagonist to Dabigatran after an Ablation.

Background Safety regarding switching from vitamin K antagonist (VKA) to dabigatran therapy in post-ablation patients has never been investigated and safety data for this is urgently needed. The objective of this study was to examine if switch from VKA to dabigatran increased the risk of stroke, bleeding, and death in patients after ablation for atrial fibrillation. Methods Through the Danish nationwide registries, patients with non-valvular atrial fibrillation undergoing ablation were identified, in the period between August 22nd 2011 and December 31st 2015. The risk of ischemic stroke, hemorrhagic stroke, bleeding, and death, related to switching from VKA to dabigatran was examined using a multivariable Poisson regression model, where Incidence rate ratios (IRR) were estimated using VKA as reference. Results In total, 4,236 patients were included in the study cohort. The minority (n = 470, 11%) switched to dabigatran in the follow up period leaving the majority (n = 3,766, 89%) in VKA treatment. The patients in the dabigatran group were older, were more often males, and had higher CHA2DS2-VASc, and HAS-BLED scores. The incident rates of bleeding and death were almost twice as high in the dabigatran group compared with the VKA group. When adjusting for the individual components included in the CHA2DS2-VASc and HAS-BLED scores, the multivariable Poisson analyses yielded a non-significant IRR (95%CI) of 1.64 (0.72–3.75) for bleeding and of 1.41 (0.66–3.00) for death associated with the dabigatran group, compared to the VKA group. A significant increased risk of bleeding was found in the 110mg bid group with an IRR (95%CI) of 4.49(1.40–14.5). Conclusion Shifting from VKA to dabigatran after ablation was associated with twice as high incidence of bleeding compared to the incidence in patients staying in VKA treatment. The only significant increased risk found in the adjusted analyses was for bleeding with 110mg bid dabigatran and not for 150mg bid. Since there was no dose-response for bleeding, the switch from VKA to dabigatran in itself was not a risk factor for bleeding.

Safety and effectiveness of rivaroxaban and apixaban in patients with venous thromboembolism: a nationwide study

Aims To investigate the risk of all-cause mortality, recurrent venous thromboembolism (VTE), and hospitalized bleeding in patients with VTE treated with either rivaroxaban or apixaban. Methods and results Using Danish nationwide registries, patients with VTE treated with rivaroxaban or apixaban in the period from 1 January 2015 to 30 June 2017 were identified. Standardized absolute risks were estimated based on outcome-specific Cox regression models, adjusted for potential confounders. A total of 8187 patients were included in the study, of which 1504 (18%) were treated with apixaban [50% males, median age 70 years; interquartile range (IQR) 56-80] and 6683 (82%) were treated with rivaroxaban (55% males, median age 67 years; IQR 53-76). The 180 days risk of all-cause mortality was 5.08% [95% confidence interval (95% CI) 4.08% to 6.08%)] in the apixaban group and 4.60% (95% CI 4.13% to 5.18%) in the rivaroxaban group [absolute risk difference: -0.48% (95% CI -1.49% to 0.72%)]. The 180 days risk of recurrent VTE was 2.16% (95% CI 1.49% to 2.88%) in the apixaban group and 2.22% (95% CI 1.89% to 2.52%) in the rivaroxaban group [absolute risk difference of 0.06% (95% CI -0.72% to 0.79%)]. The 180 days risk of hospitalized bleeding was 1.73% (95% CI 1.22% to 2.35%) for patients in the apixaban group and 1.89% (95% CI 1.56% to 2.20%) in the rivaroxaban group [absolute risk difference: 0.16% (95% CI -0.59% to 0.81%)]. Conclusion In a nationwide cohort of 8187 patients with VTE treated with rivaroxaban or apixaban, there were no significant differences in the risks of all-cause mortality, recurrent VTE, or hospitalized bleeding.

Familial Clustering of Venous Thromboembolism - A Danish Nationwide Cohort Study.

Background Identification of risk factors for venous thromboembolism (VTE) is of utmost importance to improve current prophylactic regimes and treatment guidelines. The extent to which a family history contributes to the risk of VTE needs further exploration. Objectives To examine the relative rate of VTE in first-degree relatives compared with the general population. Methods By crosslinking Danish nationwide registries we identified patients with VTE between 1978 and 2012, and their familial relations. The first member in a family to acquire VTE was defined as the proband. All first-degree relatives to probands were followed from the VTE date of the proband and until an event (VTE), death, emigration, 100 year birthday or end of study: 31st of December 2012, whichever came first. The relative rate of VTE was estimated by standardized incidence ratios (SIR) using time-dependent Poisson regression models, with the general population as a fixed reference. Results We identified 70,767 children of maternal probands, 66,065 children of paternal probands, and 29,183 siblings to sibling probands. Having a maternal proband or a paternal proband were associated with a significantly increased VTE rate of 2.15 (CI: 2.00–2.30) and 2.06 (CI: 1.92–2.21), respectively. The highest estimate of VTE was observed among siblings (adjusted SIR of 2.60 [CI: 2.38–2.83]). Noteworthy, the rate of VTE increased for all first-degree relatives when the proband was diagnosed with VTE in a young age (≤ 50 years). Conclusion A family history of VTE was associated with a significantly increased rate of VTE among first-degree relatives compared with the general population.

Stroke and Bleeding Risk in Patients With Atrial Fibrillation With Resumption of Oral Anticoagulation Following Traumatic Injury: A Danish Nationwide Cohort Study

With increasing age, patients with atrial fibrillation (AF) also are at higher risk of falls causing traumatic injury, leading to bleeding risks. We examined the risks of all-cause mortality, stroke, and major bleeding associated with resumption of oral anticoagulation (OAC) after traumatic injury