Use Of Dabigatran In Patients Research Articles

Efficacy and safety of oral factor Xa inhibitors versus vitamin-K antagonists in the early phase after acute ischemic stroke or TIA in the real-world setting: The PRODAST study.

Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37-1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53-1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33-2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65-1.41) were not substantially different. This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates.

Treatment of dabigatran intoxication in critically ill patients with Acute Kidney Injury: The role of Sustained Low-Efficiency Dialysis.

The use of dabigatran in patients with non-valvular atrial fibrillation (AF) has widely increased in the last decades, due to its positive effects in terms of safety/efficacy. However, because of the risk of major bleeding, a great degree of attention has been suggested in elderly patients with multiple comorbidities. Notably, dabigatran mainly undergoes renal elimination and dose adjustment is recommended in patients with Chronic Kidney Disease (CKD). In this regard, the onset of an abrupt decrease of kidney function may further affect dabigatran pharmacokinetic profile, increasing the risk of acute intoxication. Idarucizumab is the approved antagonist in the case of dabigatran-associated major bleeding or concomitant need of urgent surgery, but its clinical use is limited by the lack of data in patients with Acute Kidney Injury (AKI). Thus, the early start of Extracorporeal Kidney Replacement Therapy (EKRT) could be indicated to remove the drug and to reverse the associated excess anticoagulation. Sustained Low-Efficiency Dialysis (SLED) could represent an effective therapeutic option to reduce the dabigatran plasma levels rapidly while avoiding post-treatment rebound. We present here a case series of three AKI patients with acute dabigatran intoxication, effectively and safely resolved with a single SLED session.

The place of dabigatran in the treatment of patients with atrial fibrillation in the light of modern recommendations

This review is devoted to the aspects of anticoagulant therapy in patients with atrial fibrillation in the light of the modern understanding of this type of arrhythmia as a polymorbid continuously developing syndrome. According to experts, the management strategy of this category of patients is based on an integrated assessment, including the risk of stroke, the presence of symptoms, assessment of structural heart disease and mandatory accounting of concomitant pathology. In this approach, the appointment of anticoagulant therapy as a prevention of stroke in a patient with atrial fibrillation is put in the first place. At the same time, experts emphasize the need for a dynamic reassessment of risks, as well as the use of a multidisciplinary team of specialists to make a complex decision. The review summarizes the basic concepts of the integrated approach, describes various variants of clinical scenarios, including aspects of anticoagulant maintenance of cardioversion and catheter ablation, multicomponent therapy after percutaneous coronary intervention. A separate chapter is devoted to modern algorithms of perioperative management of a patient receiving oral anticoagulants, which is based on the stratification of interventions according to the risk of perioperative bleeding and the characteristics of the anticoagulant prescribed to the patient. The place of dabigatran in the primary and secondary prevention of stroke and systemic embolism in patients with atrial fibrillation is described, studies that served as the basis of the evidence base for the use of dabigatran in patients with atrial fibrillation are presented. The data of register observations, meta-analyses devoted to the evaluation of the efficacy and safety of dabigatran in certain categories of patients (elderly patients, patients with chronic heart failure, diabetes mellitus) are presented, which form the basis of decision-making in real clinical practice.

Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study.

The optimal timing of initiating or resuming anticoagulation after acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with atrial fibrillation (AF) is debated. Dabigatran, a non-vitamin K oral anticoagulant (NOAC), has shown superiority against vitamin K antagonists (VKA) regarding hemorrhagic complications. In this registry study, we investigated the initiation of dabigatran in the early phase after AIS or TIA. PRODAST (Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA) is a prospective, multicenter, observational, post-authorization safety study. We recruited 10,039 patients at 86 German stroke units between July 2015 and November 2020. A total of 3,312 patients were treated with dabigatran or VKA and were eligible for the analysis that investigates risks for major hemorrhagic events within 3 months after early (⩽ 7 days) or late (> 7 days) initiation of dabigatran or VKA initiated at any time. Further endpoints were recurrent stroke, ischemic stroke, TIA, systemic embolism, myocardial infarction, death, and a composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. Major bleeding event rates per 10,000 treatment days ranged from 1.9 for late administered dabigatran to 4.9 for VKA. Early or late initiation of dabigatran was associated with a lower hazard for major hemorrhages as compared to VKA use. The difference was pronounced for intracranial hemorrhages with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval (CI): 0.10-2.21) for early dabigatran use versus VKA use and an adjusted HR of 0.09 (95% CI: 0.00-13.11) for late dabigatran use versus VKA use. No differences were found between early initiation of dabigatran versus VKA use regarding ischemic endpoints. The early application of dabigatran appears to be safer than VKA administered at any time point with regards to the risk of hemorrhagic complications and in particular for intracranial hemorrhage. This result, however, must be interpreted with caution in view of the low precision of the estimate.

Assessment of the efficiency and safety of anti-coagulation therapy in patients with liver cirrhosis and atrial fibrillation.

Currently, there are insufficient scientific data regarding the efficacy and safety of direct oral anticoagulants (DOACs) compared to warfarin in patients with both liver cirrhosis (LC) and atrial fibrillation (AF). The aim of the study was to analyze the frequency and risk factors for the development of thrombotic and hemorrhagic complications in patients with LC and AF after DOAC treatment compared to warfarin. A randomized clinical trial was conducted including 56 patients with both LC and AF treated with dabigatran (n = 30) and warfarin (n = 26). The frequency and risk factors of hemorrhagic and thrombotic complications were evaluated after 3 months of observation. The overall frequency of bleeding was significantly higher after treatment with warfarin (p = 0.038). The frequency of major and minor bleeding events did not differ statistically significantly between the two groups (p > 0.05). Factors which significantly increased the risk of bleeding were: glomerular filtration rate (GFR) < 60 ml/min/1.73 m2 (adjusted hazard ratio (AHR) = 0.82, CI: 0.69-0.96, p = 0.02), constant of thrombin activity (CTA) < 25 units of low-frequency piezoelectric thromboelastography (AHR = 0.66, CI: 0.46-0.92, p = 0.017) and prior history of bleeding (AHR = 108, CI: 8.78-134, p < 0.001). The use of dabigatran in patients with Child-Pugh class A and B of LC and AF has advantages over warfarin, as it is clinically associated with a lower incidence of bleeding. An increased risk of bleeding is observed in patients with LC classes A and B according to the Child-Pugh scale and AF, who have a reduced GFR < 60 ml/min/1.73 m2, CTA < 25 units and a prior history of bleeding.

Rationale, Design and Methods of the Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) Study.

BackgroundThe optimal timing of anticoagulation following acute ischaemic stroke or TIA in patients with atrial fibrillation (AF) is a frequent challenge. Early initiation of anticoagulation can reduce the risk for recurrent ischaemic events, but may lead to an increased risk for intracerebral haemorrhage.AimThe Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study was initiated to investigate outcome events under antithrombotic therapy after ischaemic stroke or TIA in patients with AF. The main objective is to compare the three-month rates of major haemorrhagic events between early (≤ 7 days) versus late (> 7 days) administration of dabigatran or treatment with vitamin-K antagonists started at any time. Occurrences of ischaemic and major haemorrhagic events will be evaluated to determine the optimal time point for initiation or resumption of anticoagulation.Design and MethodsPRODAST is a prospective, multicenter, observational, non-interventional post-authorization safety study. 10,000 patients with recent (≤ 1 week from index event) ischaemic stroke or TIA and non-valvular AF were recruited at 86 German sites starting in July 2015. The observational plan includes a baseline visit, documentation of data during hospitalization and a telephone-based, central follow-up at three months after the index event. The primary endpoint is the major bleeding rate within three months. Secondary endpoints include rates of recurrent ischaemic or haemorrhagic stroke, TIA, systemic embolism, myocardial infarction and death.SummaryPRODAST will provide important real-world data on safety and efficacy of antithrombotic therapy after acute stroke and TIA in patients with AF.

Clinical outcomes of dabigatran use in patients with non-valvular atrial fibrillation and weight >120 kg

BackgroundPatients with obesity were underrepresented in studies evaluating the safety and effectiveness of direct oral anticoagulants (DOAC) in patients with non-valvular atrial fibrillation (NVAF). This study compared clinical outcomes in patients with NVAF and weighing >120 kg and ≤120 kg who were receiving dabigatran. Materials and methodsThis retrospective, matched, longitudinal cohort study included patients from three integrated healthcare delivery systems. Patients ≥18 years of age with NVAF were included if between September 1, 2016 and June 30, 2019 they received dabigatran. Patients >120 kg and ≤120 kg were matched up to 1:6 on age, sex, and CHA2DS2-VASc score. Data were extracted from administrative databases. The primary outcome was a composite of ischemic stroke, clinically-relevant bleeding, systemic embolism, and all-cause mortality. Multivariable regression analyses were performed. Results777 and 3522 patients >120 kg and ≤120 kg, respectively, were matched. The >120 kg group tended to be younger with a higher burden of chronic disease. There was no difference between groups in the composite outcome (adjusted hazard ratio [AHR] 1.10, 95% confidence interval 0.89–1.37) or individual components of the composite. A subanalysis of clinically-relevant bleeding identified that patients >120 kg were at a greater risk of gastrointestinal bleeding (AHR 1.44, 95% CI 1.01–2.05). ConclusionsIn patients with NVAF and >120 kg, dabigatran use was associated with a small increased risk of gastrointestinal bleeding but no differences in stroke, mortality or clinically-relevant bleeding. These findings suggest that dabigatran use is reasonable in patients with NVAF and weight >120 kg.

Effectiveness and Safety of Dabigatran Compared to Vitamin K Antagonists in Non-Asian Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Real-life data about the use of dabigatran in patients with non-valvular atrial fibrillation are warranted. The objective of this systematic review and meta-analysis was to assess the effectiveness and safety of dabigatran, globally and stratified by dose (110/150 mg twice daily), vs vitamin K antagonists in non-Asian patients with non-valvular atrial fibrillation from "real-world" studies. A systematic review was performed according to Cochrane methodological standards. The results were reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement) statement. The ROBINS-I tool was used to assess bias risk.MEDLINE and EMBASE, from inception up to May 2021, using appropriate controlled vocabulary and free search terms, were searched. RESULTS: A total of 34 studies, corresponding to 37 articles involving 1,600,722 participants (1,154,283 exposed to vitamin K antagonists and 446,439 to dabigatran) were eligible for this review. Dabigatran 150 mg reduced the risk of ischemic stroke compared with vitamin K antagonists, with a 14% risk reduction (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.74-0.98). Globally, dabigatran reduced the risk of all-cause mortality compared with vitamin K antagonists (HR 0.76, 95% CI 0.69-0.84), with a greater effect observed with dabigatran 150 mg (HR 0.65, 95% CI 0.58-0.73). There was a trend towards a lower risk of myocardial infarction with dabigatran 150 mg (HR 0.86, 95% CI 0.71-1.04). Regarding the primary safety outcomes, dabigatran (either at a dose of 150 mg or 110 mg) reduced the risk of major bleeding compared with vitamin K antagonists (HR 0.77, 95% CI 0.70-0.83), as well as the risk of intracranial bleeding (HR 0.44, 95% CI 0.39-0.50) and fatal bleeding (HR 0.76, 95% CI 0.60-0.95), but with a slight increase in gastrointestinal bleeding risk (HR 1.16, 95% CI 1.08-1.26). Dabigatran has a favorable impact on effectiveness and safety outcomes compared with vitamin K antagonists in real-world populations.

Aspects of anticoagulant therapy in patients with atrial fibrillation in the light of updated guidelines of the European society of cardiology 2020: the position of dabigatran

This review focuses on some aspects of anticoagulant therapy in the updated clinical guidelines for atrial fibrillation of the European society of cardiology, published in 2020. Atrial fibrillation is a polymorbid continuously developing syndrome, and therefore the treatment strategy is based on a comprehensive assessment of the patient, including the risk of stroke, the presence and severity of symptoms, and an assessment of structural heart disease and comorbidities. The review describes the principles of the proposed integrated approach, abbreviated “ABC pathway”, as reflecting the three main directions of the treatment strategy. According to experts, the clinical picture of AF (i.e. first detected, paroxysmal, persistent, long-term persistent or permanent) should not determine the indications for the appointment of anticoagulant therapy. The CHA2DS2-VASc scale continues to be the basis for stratification of thromboembolic risk. The role of dabigatran in primary and secondary prevention of stroke and systemic embolism in patients with atrial fibrillation is described. Changes in the position of experts regarding the assessment of bleeding risk are highlighted in order to help identify unmodified and eliminate modifiable risk factors for bleeding, as well as to identify AF patients who are potentially at high risk of bleeding for more frequent monitoring and monitoring of their condition. Questions about the use of direct oral anticoagulants in the choice of rhythm control tactics are highlighted separately. The use of dabigatran in patients undergoing cardioversion and catheter ablation is justified. Practical questions about the continuous strategy of anticoagulant therapy during ablation are highlighted separately. Changes related to multicomponent therapy after percutaneous coronary intervention are highlighted. The main measure to improve the safety of combined antithrombotic therapy is to minimize the duration of triple therapy. The updated recommendations supportlimiting the duration of triple antithrombotic therapy to 1 month, and also provide for early discontinuation of aspirin (≤1 week) and continuation of double antithrombotic therapy in cases of uncomplicated stenting and low risk of thrombosis, or when the risk of bleeding exceeds the risk of thrombotic events.

The Risk of Myocardial Infarction in Patients with Atrial Fibrillation Taking a Direct Thrombin Inhibitor: Myths and Reality

The purpose of this review is to analyze the results of randomized clinical trials, meta-analyses of cohort and observational studies in real clinical practice on the influence of dabigatran etexilate on the risk of myocardial infarction in patients with atrial fibrillation. A pivotal RE-LY study on dabigatran use in patients with atrial fibrillation did not show statistically significant differences in the frequency of myocardial infarction between any of the doses of dabigatran and warfarin, and the risk of coronary events did not depend on the presence of coronary heart disease or myocardial infarction in the patient's history. Subsequently, a number of meta-analyses have reported an increased risk of myocardial infarction when dabigatran was administered to patients with atrial fibrillation. In general, these studies were characterized by conflicting data, which did not allow to draw any definite conclusions regarding the use of dabigatran in relation to the risk of myocardial infarction. Two FDA cohort observational studies were published in 2014 and 2017, and the former was significantly criticized by experts, and the results of the second study did not provide a definitive answer to the question about the importance of the effect of dabigatran on the development of myocardial infarction in patients with atrial fibrillation. Even more "confusing" the problem arose after the publication of meta-analyses of randomized trials, which showed that the risk of myocardial infarction was increased in patients treated with direct oral anticoagulants compared to patients treated with warfarin. This review provides high quality evidence for the efficacy of dabigatran in preventing myocardial infarction and other vascular complications in patients with atrial fibrillation.

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation

The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown. To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF. Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016. Dabigatran or warfarin use during the study period. Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated. Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 [95% CI, -0.38 to -0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 [95% CI, -2.40 to -3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 [95% CI, 0.67 to -0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001). Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a lower risk of osteoporotic fracture. Additional study, perhaps including randomized clinical trials, may be warranted to further understand the relationship between use of dabigatran vs warfarin and risk of fracture.

Abstract 75: Bleeding and Ischemic Stroke Risk in Patients with Atrial Fibrillation Standard or Low Dose Dabigatran and Concomitant P-gp Inhibitors

Background: Guidelines for dabigatran in patients with atrial fibrillation (AF) recommend dose reduction in patients with impaired renal function and concomitant use of strong P-gp inhibitors. However, there are limited data regarding the safety and efficacy of concomitant use of dabigatran and p-gp inhibitors. We evaluated risk of major bleeding and stroke in patients with AF taking low (75 mg) or standard (150 mg) dose dabigatran with concomitant use of strong or moderate p-gp inhibitors and no history or renal disease. Methods: We identified Medicare beneficiaries age 66 and older with new AF diagnoses during 2011-2013 who received dabigatran within 90 days of AF diagnosis and had concurrent use of a P-gp inhibitor (droneradarone, amiodarone, ketoconazole, quinidine, verapamil, and clarithromycin). We excluded patients with existing renal disease, based on ICD-9-CM codes. We also excluded patients with recent hip surgery or recent embolism, to ensure that the purpose of dabigatran was long term stroke prevention. Of the 7,077 patients meeting inclusion criteria, 1,125 (16%) received dabigatran 75 mg; the remaining received 150 mg. We matched each patient taking low dose dabigatran to a single patient taking standard dose using an optimal propensity matching algorithm. Proportional hazards regression further controlled for patient attributes that may confound the relationship between dose and likelihood of stroke or bleeding. Matching and modeling steps were repeated 1000 times using bootstrapping. We then calculated the mean (and 95% confidence intervals) risk-adjusted stroke and bleeding rates per person-year. Results: There was a significant reduction in bleeding risk with use of low dose dabigatran, compared to standard dose, with an absolute reduction in bleeding risk of 23 per 1000 patient-years (95% CI, 1 to 45 per 1000 patient years). In contrast, the risk of stroke did not differ significantly among patients taking low or standard dose dabigatran (2 more strokes per 1000 patient-years with low dose dabigatran; 95% CI, -7 to 10). Conclusions: Use of low dose dabigatran in patients taking a P-gp inhibitor may result in fewer bleeding events compared to standard dose, without compromising the protective effect against ischemic stroke.

The Need for a Coagulation Assay after Initiation of New Oral Anticoagulants in Patients with Renal Dysfunction: A Case Report.

BackgroundDabigatran etexilate, a new oral anticoagulant, was recently approved as an efficacious alternative to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular atrial fibrillation. Limited data are available for dabigatran use in patients with a creatinine clearance rate (CrCL) of 15-30 mL/min. Furthermore, current guidelines do not recommend frequent blood monitoring after dabigatran use. We report herein a patient with severe renal dysfunction who exhibited profound coagulopathy after 2 days of dabigatran use.Case ReportAn 87-year-old woman was admitted for altered mental status and left-side weakness. She was diagnosed with right middle cerebral artery infarction. The baseline assessment revealed a serum creatinine concentration of 1.29 mg/dL and a CrCL of 27.2 mL/min. Dabigatran therapy was started 5 weeks after admission at a dosage of 110 mg twice daily. After 2 days of dabigatran use, the patient developed multiple bruises and evidence of upper-gastrointestinal bleeding. Laboratory tests demonstrated a severe coagulopathy, with a prothrombin time of 85.9 sec, an international normalized ratio of 11.36, an activated partial thromboplastin time of 119.2 sec, and a thrombin time of 230.8 sec. Serial assessment of the patient's renal function revealed substantial fluctuation of the CrCL (range, 17.9-26.5 mL/min).ConclusionsThe present case emphasizes the need for frequent checking of renal function and assessment using coagulation assays after commencing dabigatran therapy in patients with moderate-to-severe renal impairment.

The peri-procedural use of dabigatran in patients undergoing left atrial ablation for atrial fibrillation.

Pulmonary vein isolation is an effective strategy in patients with atrial fibrillation (AF). The peri-procedural use of anticoagulation is routinely employed to reduce thromboembolic risk. The aim of this study was to compare the use of Dabigatran to the other 2 strategies involving the use of Warfarin. Single centre observational study comparing 3 anticoagulation strategies: Group 1 consisted of patients maintained on Warfarin (5.15±2.52mg) with a therapeutic INR of 2-3. Group 2 comprised patients initially treated with Warfarin (6.98±3.17mg), which was discontinued 1week prior to LA ablation, during which time patients were bridged with a therapeutic dose of Dalteparin. Group 3 included patients anticoagulated with Dabigatran (40 patients received 150mg BID, 3 patients received 110mg BID), which was discontinued 24-30h prior to the procedure. A total of 207 patients were included in the study. There were no significant differences in age, sex, LA volume, CHADS2 score or proportion of patients with persistent AF. There were no significant differences in the number of patients with intra-cardiac thrombus found at TOE (Group 1: 2.3% vs. Group 2: 1.5% vs. Group 3: 0%; P=0.37). Furthermore, there were no differences in the rate of groin hematoma (2.2% vs. 1.5% vs. 2.3%; P=0.8) or the development of pericardial effusion (5.4% vs. 8.8% vs. 2.3%; P=0.54). No thromboembolic events were seen. Peri-procedural use of Dabigatran during AF ablation procedures is safe, with no significant difference when compared to conventional anticoagulation with either Warfarin bridged with Dalteparin or uninterrupted Warfarin.

Relation between frequency of activated partial prothrombin time measurements and clinical outcomes in patients after initiation of dabigatran: A two-center cooperative study

BackgroundAlthough activated partial prothrombin time (aPTT) has often been used as a biomarker for evaluating the safety of dabigatran use in patients with non-valvular atrial fibrillation (NVAF), the optimal frequency of aPTT measurements is unclear. This study aimed to identify the frequency distribution of aPTT measurements in clinical practice and its clinical significance. MethodsThis was a retrospective cooperative study conducted in 2 sites. All NVAF patients who underwent aPTT measurements before and after dabigatran treatment were included (n=380). The patients were divided into 2 groups according to the frequency of aPTT measurements during the first 3 months after drug prescription: Group A: infrequent group with only 1 measurement; and Group B: frequent group with ≥2 measurements. The clinical characteristics and outcomes were compared between the groups. ResultsThe frequency of aPTT measurements in the 3 months after dabigatran initiation varied: 240 patients underwent 1 measurement (Group A), and the remaining 140 patients underwent repeated measurements (Group B). There were significant differences in age and creatinine clearance (Ccr) between the groups (Group A vs. Group B: age 64.0±11.7 vs. 67.0±11.1 years, p=0.01; Ccr 83.8±30.3 vs.76.7±31.1mL/min, p=0.03). During the mean follow-up period of 310 days, there were no significant differences in the discontinuation rate and incidence of bleeding (17% vs. 15% and 5% vs. 3%, respectively; both not significant). In Group B, the aPTT rarely increased beyond twice the upper normal limit within the 3 months (2.1%), although the correlation between the initial and subsequent aPTT measurements was low (r=0.366). ConclusionsIn this retrospective study, the frequency of aPTT measurements after dabigatran initiation might have been dependent on patient characteristics. However, frequent aPTT measurements did not lead to a reduction in adverse clinical events.

Dabigatran Use in Mechanical Heart Valve Patients

Current guidelines have no recommendations on the utilization of novel oral anticoagulants, such as dabigatran, for the prevention of thromboembolic events in patients with mechanical heart valves. However, recent studies on the use of dabigatran in patients with atrial fibrillation and animal studies have suggested a new potential role for dabigatran in patients with mechanical heart valves. The study by Eikelboom et al. investigates this important clinical question in a prospective, randomized controlled Phase II clinical trial. The authors randomly assigned 252 patients from 39 centers in ten countries to receive dabigatran or warfarin in a 2:1 ratio. The objective of the study was to validate a dosing regimen for use of dabigatran in patients with mechanical heart valves. The trial was prematurely terminated after a recommendation by the data and safety monitoring board. The composite of stroke, systemic embolism, myocardial infarction and death was 8% in the dabigatran group and 2% in the warfarin group (hazard ratio: 3.37; 95% CI: 0.76–14.95; p = 0.11). There were significantly higher bleeding rates of any type in the dabigatran group (27%) compared with the warfarin group (12%; hazard ratio: 2.45; 95% CI: 1.23–4.86; p = 0.01). These results demonstrated a higher risk and no additional benefits in using dabigatran compared with warfarin in patients with mechanical heart valves.

Initial experience with rivaroxaban in mechanical valve prosthesis in an animal model

Warfarin, first synthesized in 1940, and its derivatives like coumadin were the only available oral anticoagulant agents until recently. Even though it has immense efficacy as an anticoagulant, warfarin is universally acknowledged as a cumbersome agent to use. It has a delayed onset of action, unpredictable efficacy affected by genetics, race and ethnicity, co-administered drugs and diet, body weight and age of the patient [1]. It requires periodic monitoring to ensure therapeutic levels and despite careful follow-up, only 50% of the patients are able to achieve therapeutic levels as defined by the international normalized ratio. In the last decade, new oral anticoagulants, like dabigatran and rivaroxaban have proved useful in preventing thromboembolic events in patients with non-valvular atrial fibrillation or in preventing deep vein thrombosis. They are administered orally at a fixed dose and do not require periodical blood test to assess efficacy. Recently, the preliminary results of the RE-ALIGN study have been published [2]. This Phase 2 dose-validation study evaluated the use of dabigatran in patients with mechanical heart valves. The study terminated prematurely because of an excess of thromboembolic and bleeding events. Authors concluded that the use of dabigatran in patients with mechanical heart valves showed no benefit and an excess risk. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin and eventually dabigatran. In the ROCKET AF trial [3], in patients with atrial fibrillation, rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Pivotal clinical trials in the prophylaxis against venous thromboembolism (VTE) in orthopaedic patients following primary total hip and total knee arthroplasty have demonstrated the superior efficacy of rivaroxaban in reducing total VTE in comparison with standard regimens of enoxaparin. The safety of the drug was found to be excellent, with no demonstrable cardiovascular or hepatic effects and no statistically significant increase in major bleeding. A pooled analysis of data collected on the patients from the four RECORD trials revealed rivaroxaban to be the first antithrombotic agent to demonstrate superiority over another antithrombotic agent (enoxaparin) in reducing symptomatic VTE and all-cause mortality [4]. The most challenging indication for oral anticoagulation is the prevention of thrombosis after implantation of mechanical heart valve prosthesis. No human studies have been reported assessing the efficacy of rivaroxaban in preventing mechanical valve thrombosis. Greiten et al. [5] report in this issue of the Journal the use of rivaroxaban in an animal model implanted with mechanical bileaflet aortic valve prosthesis. They implanted a heterotopic valve conduit in 30 swine which were assigned to enoxaparin, rivaroxaban or no treatment (10 swine in each group). They measured valve thrombosis and platelet deposition. Rivaroxaban resulted superior to enoxaparin or no treatment in preventing thrombus or platelet deposition in mechanical valves, although a small amount of visible thrombosis was seen in 4 of 10 animals. The authors suggest that further investigations are required with a higher dose in order to safely evaluate the effects of rivaroxaban in this animal model. Noteworthy, safety of rivaroxaban was excellent with no evidence of haemorrhage or peripheral emboli on post-mortem examination.

Experiencia inicial del uso de dabigatrán en la ablación de fibrilación auricular

ObjectiveTo determine the safety of a new protocol for oral anticoagulation with dabigatran in patients undergoing atrial fibrillation ablation. Material and methodsA single-centre, descriptive and prospective study was conducted on 69patients undergoing pulmonary vein isolation. The occurrence of bleeding or thromboembolic events in patients having dabigatran compared to those with acenocoumarol were analysed. ResultsAcenocoumarol was used in 56patients and dabigatran in 13patients. After a mean follow-up of 2.7±0,89 months there were 3 cases of minor bleeding and 4cases of peri-procedural complications in the acenocoumarol group and none in the dabigatran group. There was no incidence of stroke, death, major bleeding, or admissions due to heart failure. ConclusionNo bleeding or thromboembolic events were found with the use of dabigatran in patients undergoing atrial fibrillation ablation.

Dabigatran versus Warfarin in Patients with Mechanical Heart Valves

BackgroundDabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves.MethodsIn this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran.ResultsThe trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding.ConclusionsThe use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.)

“Blue letter effects”: Changes in physicians’ attitudes toward dabigatran after a safety advisory in a specialized hospital for cardiovascular care in Japan

BackgroundA blue letter (safety advisory) for dabigatran was issued by the Japanese Ministry of Health, Labour and Welfare in August 2011. Changes in physicians’ attitudes toward dabigatran use before and after the blue letter have not been previously reported. Methods and resultsBetween March 2011 and July 2012, dabigatran was prescribed to 404 Japanese patients with nonvalvular atrial fibrillation at The Cardiovascular Institute (Tokyo, Japan). Patients were divided into three groups according to the first prescription date: phase I (before the blue letter, n=135); phase II (after the blue letter and before permission for longer-term prescriptions, n=112); and phase III (after permission for longer-term prescriptions, n=157). In phase II, dabigatran use tended to be avoided for patients with older age, renal dysfunction, receiving antiplatelet medication, or p-glycoprotein inhibitors. Measurement of activated partial thromboplastin time significantly increased from phase I to III. In phase III, the tendencies seen in phase II were reversed: dabigatran use in patients with older age and renal dysfunction tended to increase, but decreased or remained the same in patients receiving antiplatelet medications or p-glycoprotein inhibitors. ConclusionsWe described the changes in the attitudes of attending physicians toward dabigatran prescription after the blue letter in a specialized hospital for cardiovascular care in Japan, which, we believe, involve useful information for safe use of dabigatran in a real-world clinical setting. However, a true impact or effect of the blue letter should be ascertained in a nationwide, multicenter study.