BACKGROUND: Dabigatran directly inhibits thrombin and is used in primary and secondary stroke prevention in individuals with nonvalvular atrial fibrillation. The prodrug dabigatran etexilate is absorbed by enteral P-glycoprotein (ABCB1) and then activated by hepatic and intestinal carboxylesterases (CES1) to produce active metabolites. Variations in dabigatran metabolism because of genetics may affect concentration levels and clinical outcomes. STUDY QUESTION: We conducted a study to assess how polymorphisms in the CES1 (rs2244613) and ABCB1 (rs4148738) genes affect the through plasma level (c min ) of dabigatran and its correlation to clinical outcomes. STUDY DESIGN: Retrospective multicentric study of consecutive patients on dabigatran therapy. Examination of CES1 rs2244613 and ABCB1 rs4148738 polymorphisms, c min 12 hours after administration, clinical follow-up (ischemic stroke, major or clinically relevant hemorrhage, myocardial infarction, other thromboembolism, and death). MEASURES AND OUTCOMES: A total of 432 patients received treatment for an average of 19.78 months (SD of 20.165). The sex distribution of the patients was 56.5% male, and the average age was 67.56 years (SD of 14.7). The ABCB1 variant genotype was present in 67.8% of patients, whereas 37.5% carried the CES1 polymorphism. RESULTS: Compared with wild-type patients, patients with the CES1 variant had significantly lower dabigatran plasma levels (with a mean difference of 16.986; 95% confidence interval, 5.794-28.178 ng/mL, P = 0.003). We also found a significant risk of major bleeding in patients carrying the ABCB1 rs4148738 allele (hazard ratio = 1.99, confidence interval 95% 1.10 to 3.59, P = 0.024). CONCLUSIONS: The CES1 variant genotype rs2244613 is closely linked with reduced c min of dabigatran. Carriers of the ABCB1 rs4148738 polymorphism exhibit a tendency toward higher plasma levels of dabigatran, which leads to a significantly increased risk of bleeding.

• MeSH
• antitrombiny * škodlivé účinky   krev   farmakokinetika   aplikace a dávkování   MeSH
• dabigatran * škodlivé účinky   farmakokinetika   krev   aplikace a dávkování   MeSH
• fibrilace síní farmakoterapie   genetika   komplikace   krev   MeSH
• ischemická cévní mozková příhoda * prevence a kontrola   genetika   krev   MeSH
• jednonukleotidový polymorfismus MeSH
• karboxylesterhydrolasy * genetika   krev   MeSH
• krvácení * chemicky indukované   krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• P-glykoproteiny * genetika   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• antitrombiny * MeSH
• CES1 protein, human MeSH Prohlížeč
• dabigatran * MeSH
• karboxylesterhydrolasy * MeSH
• P-glykoproteiny * MeSH

The management of patients with atrial fibrillation (AF) has rapidly changed with increasing use of non-vitamin K antagonist oral anticoagulants (NOACs) and changes in the use of rhythm control therapy. The prevention of thromboembolic events European Registry in Atrial Fibrillation Prolongation Registry (PREFER Prolongation) enrolled consecutive patients with AF on NOACs between 2014 and 2016 in a multicentre, prospective, observational study with one-year follow-up, focusing on the time of introduction of NOACs. Overall, 3783 patients were enrolled, with follow-up information available in 3223 (85%). Mean age was 72.2 ± 9.4 years, 40% were women, mean CHA2DS2VASc score was 3.4 ± 1.6, and 2587 (88.6%) had a CHA2DS2VASc score ≥ 2. Rivaroxaban was used in half of patients, and dabigatran and apixaban were used in about a quarter of patients each; edoxaban was not available for use in Europe at the time. Major cardiovascular event rate was low: serious events occurred in 74 patients (84 events, 2%), including 24 strokes (1%), 62 major bleeds (2%), of which 30 were life-threatening (1%) and 3 intracranial (0.1%), and 28 acute coronary syndromes (1%). Mortality was 2%. Antiarrhythmic drugs were used in about 50% of patients, catheter ablation in 5%. Adverse events were low in this contemporary European cohort of unselected AF patients treated with NOACs already at the time of their first introduction, despite high thromboembolic risk.

• Klíčová slova
• Anticoagulants, Atrial fibrillation, Bleeding, Major cardiac or cerebrovascular events, NOAC, Registry,
• MeSH
• aplikace orální MeSH
• dabigatran aplikace a dávkování   MeSH
• fibrilace síní farmakoterapie   mortalita   MeSH
• inhibitory faktoru Xa aplikace a dávkování   MeSH
• lidé MeSH
• prospektivní studie MeSH
• pyrazoly aplikace a dávkování   MeSH
• pyridony aplikace a dávkování   MeSH
• registrace MeSH
• rivaroxaban aplikace a dávkování   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH
• Názvy látek
• apixaban MeSH Prohlížeč
• dabigatran MeSH
• inhibitory faktoru Xa MeSH
• pyrazoly MeSH
• pyridony MeSH
• rivaroxaban MeSH

Background and Purpose- The RE-SPECT ESUS trial (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) tested the hypothesis that dabigatran would be superior to aspirin for the prevention of recurrent stroke in patients with embolic stroke of undetermined source. This exploratory subgroup analysis investigates the impact of age, renal function (both predefined), and dabigatran dose (post hoc) on the rates of recurrent stroke and major bleeding. Methods- RE-SPECT ESUS was a multicenter, randomized, double-blind trial of dabigatran 150 or 110 mg (for patients aged ≥75 years and/or with creatinine clearance 30 to <50 mL/minute) twice daily compared with aspirin 100 mg once daily. The primary outcome was recurrent stroke. Results- The trial, which enrolled 5390 patients from December 2014 to January 2018, did not demonstrate superiority of dabigatran versus aspirin for prevention of recurrent stroke in patients with embolic stroke of undetermined source. However, among the population qualifying for the lower dabigatran dose, the rate of recurrent stroke was reduced with dabigatran versus aspirin (7.4% versus 13.0%; hazard ratio, 0.57 [95% CI, 0.39-0.82]; interaction P=0.01). This was driven mainly by the subgroup aged ≥75 years (7.8% versus 12.4%; hazard ratio, 0.63 [95% CI, 0.43-0.94]; interaction P=0.10). Stroke rates tended to be lower with dabigatran versus aspirin with declining renal function. Risks for major bleeding were similar between treatments, irrespective of renal function, but with a trend for lower bleeding rates with dabigatran versus aspirin in older patients. Conclusions- In subgroup analyses of RE-SPECT ESUS, dabigatran reduced the rate of recurrent stroke compared with aspirin in patients qualifying for the lower dose of dabigatran. These results are hypothesis-generating. Aspirin remains the standard antithrombotic treatment for patients with embolic stroke of undetermined source. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

• Klíčová slova
• anticoagulants, atrial fibrillation, cardiovascular disease, risk factors, secondary prevention,
• MeSH
• Aspirin * aplikace a dávkování   farmakokinetika   MeSH
• cévní mozková příhoda * krev   farmakoterapie   MeSH
• dabigatran * aplikace a dávkování   farmakokinetika   MeSH
• dvojitá slepá metoda MeSH
• fibrinolytika * aplikace a dávkování   farmakokinetika   MeSH
• intrakraniální embolie * krev   farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci ledvin * krev   farmakoterapie   MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• Aspirin * MeSH
• dabigatran * MeSH
• fibrinolytika * MeSH

OBJECTIVE: We evaluated atrial fibrillation (AF) patients' perceptions of anticoagulation treatment with dabigatran or a vitamin K antagonist (VKA) for stroke prevention, according to accepted indications. METHODS: The RE-SONANCE observational, prospective, multicentre, international study used the validated Perception on Anticoagulant Treatment Questionnaire (PACT-Q) to assess patients with AF already taking a VKA who were switched to dabigatran (cohort A), and newly diagnosed patients initiated on either dabigatran or a VKA (cohort B). Visit 1 (V1) was at baseline, and visit 2 (V2) and visit 3 (V3) were at 30-45 and 150-210 days after baseline, respectively. Primary outcomes were treatment satisfaction and convenience in cohort A at V2 and V3 versus baseline, and in cohort B for dabigatran and a VKA at V2 and V3. RESULTS: The main analysis set comprised 4100 patients in cohort A and 5365 in cohort B (dabigatran: 3179; VKA: 2186). In cohort A, PACT-Q2 improved significantly (p<0.001 for all) for treatment convenience (mean change V1 vs V2=20.72; SD=21.50; V1 vs V3=24.54; SD=22.85) and treatment satisfaction (mean change V1 vs V2=17.60; SD=18.76; V1 vs V3=21.04; SD=20.24). In cohort B, mean PACT-Q2 scores at V2 and V3 were significantly higher (p<0.001 for all) for dabigatran versus a VKA for treatment convenience (V2=18.38; SE =0.51; V3=23.34; SE=0.51) and satisfaction (V2=15.88; SE=0.39; V3=19.01; SE=0.41). CONCLUSIONS: Switching to dabigatran from long-term VKA therapy or newly initiated dabigatran is associated with improved patient treatment convenience and satisfaction compared with VKA therapy.

• Klíčová slova
• atrial fibrillation, quality of care and outcomes, stroke,
• MeSH
• antikoagulancia aplikace a dávkování   škodlivé účinky   MeSH
• antitrombiny aplikace a dávkování   škodlivé účinky   MeSH
• aplikace orální MeSH
• časové faktory MeSH
• cévní mozková příhoda diagnóza   etiologie   prevence a kontrola   MeSH
• dabigatran aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• fibrilace síní komplikace   diagnóza   farmakoterapie   MeSH
• krvácení chemicky indukované   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• náhrada léků MeSH
• ochranné faktory MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spokojenost pacientů * MeSH
• vitamin K antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• zdraví - znalosti, postoje, praxe * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Izrael MeSH
• Názvy látek
• antikoagulancia MeSH
• antitrombiny MeSH
• dabigatran MeSH
• vitamin K MeSH

OBJECTIVES: The aim of this study was to assess if prior oral anticoagulant agent (OAC) use modifies the lower bleeding risk observed with dabigatran dual therapy (dabigatran twice daily plus a P2Y12 inhibitor) versus warfarin triple therapy (warfarin plus a P2Y12 inhibitor plus aspirin) in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI). BACKGROUND: In the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, the primary outcome of major bleeding or clinically relevant nonmajor bleeding was lower with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation who underwent PCI. METHODS: A total of 2,725 patients were randomized to dual therapy with dabigatran (110 or 150 mg twice daily) plus clopidogrel or ticagrelor or triple therapy with warfarin plus aspirin and clopidogrel or ticagrelor. Subgroup analysis compared risk for major bleeding or clinically relevant nonmajor bleeding and a composite thromboembolic endpoint in patients with prior OAC use and in those who were OAC treatment naive. RESULTS: Risk for major bleeding or clinically relevant nonmajor bleeding was reduced with both dabigatran dual therapies compared with warfarin triple therapy in both the prior OAC use group (hazard ratios: 0.58 [95% confidence interval (CI): 0.42 to 0.81] and 0.61 [95% CI: 0.41 to 0.92] with 110 and 150 mg dabigatran, respectively) and the OAC-naive group (hazard ratios: 0.49 [95% CI: 0.38 to 0.63] and 0.76 [95% CI: 0.59 to 0.97] with 110 and 150 mg dabigatran) (p for interaction = 0.42 and 0.37, 110 and 150 mg dabigatran, respectively). The risk for thromboembolic events seemed similar with dabigatran dual therapy (both doses) and warfarin triple therapy across subgroups. CONCLUSIONS: Bleeding risk was reduced with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation after PCI, regardless of whether they were prior OAC users or OAC treatment naive. These results suggest that it is also safe to switch patients on OAC pre-PCI to dabigatran dual therapy post-PCI.

• Klíčová slova
• OAC, atrial fibrillation, bleeding event, dabigatran dual therapy, oral anticoagulant agents, switching OACs,
• MeSH
• antikoagulancia aplikace a dávkování   škodlivé účinky   MeSH
• aplikace orální MeSH
• Aspirin aplikace a dávkování   MeSH
• časové faktory MeSH
• dabigatran aplikace a dávkování   MeSH
• fibrilace síní diagnóza   farmakoterapie   mortalita   MeSH
• inhibitory agregace trombocytů aplikace a dávkování   škodlivé účinky   MeSH
• klopidogrel aplikace a dávkování   MeSH
• kombinovaná farmakoterapie MeSH
• koronární angioplastika * škodlivé účinky   mortalita   MeSH
• krvácení chemicky indukované   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• náhrada léků * škodlivé účinky   MeSH
• nemoci koronárních tepen diagnostické zobrazování   mortalita   terapie   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ticagrelor aplikace a dávkování   MeSH
• výsledek terapie MeSH
• warfarin aplikace a dávkování   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antikoagulancia MeSH
• Aspirin MeSH
• dabigatran MeSH
• inhibitory agregace trombocytů MeSH
• klopidogrel MeSH
• ticagrelor MeSH
• warfarin MeSH