Safety Of Dabigatran Research Articles

A Review of the Clinical Subgroup Analyses From the RE-LY Trial

Dabigatran was the first direct-acting oral anticoagulant approved by the US Food and Drug Administration for prevention of stroke and systemic embolism in people with atrial fibrillation, based on data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Over 18,000 patients with nonvalvular atrial fibrillation and a moderate-to-high risk of thromboembolic stroke were randomized to warfarin or dabigatran. With respect to the primary endpoints for efficacy and safety, dabigatran was superior to warfarin in the prevention of stroke and thromboembolism and noninferior with respect to major bleeding. Although unified by a common arrhythmia and a similar thromboembolic stroke risk, this large patient population is also significantly heterogeneous with respect to other demographics and comorbidities that raise important questions about the efficacy and safety of dabigatran in specific patient populations. Furthermore, there were significant differences between the warfarin and dabigatran groups with respect to several important secondary endpoints. Understanding the differences in outcomes between specific patient subgroups from the RE-LY trial can better inform the practicing clinician's ability to offer the best anticoagulation options to individual patients.

非弁膜症性心房細動患者におけるダビガトラン長期投与下での安全性に関する調査研究

非弁膜症性心房細動患者におけるダビガトラン長期投与下での安全性に関する調査研究

Global Thrombosis Test - a possible monitoring system for the effects and safety of dabigatran.

BackgroundDabigatran is an alternative to warfarin (WF) for the thromboprophylaxis of stroke in patients with non-valvular atrial fibrillation (NVAF). The advantage of dabigatran over WF is that monitoring is not required; however, a method to monitor the effect and the safety of dabigatran is not currently available. The Global Thrombosis Test (GTT) is a novel method to assess both clot formation and lysis activities under physiological conditions.ObjectiveThe aim of this study was to evaluate whether treatment with dabigatran might affect shear-induced thrombi (occlusion time [OT], sec) by the GTT, and to investigate the possibility that the GTT could be useful as a monitoring system for dabigatran.Patients/MethodsThe study population consisted of 50 volunteers and 43 NVAF patients on WF therapy, who were subsequently switched to dabigatran. Using the GTT, the thrombotic status was assessed one day before and 1 month after switching anticoagulation from WF to dabigatran.ResultsThe OT was 524.9 ± 17.0 sec in volunteers whereas that of NVAF patients on WF therapy was 581.7 ± 26.3 sec. The switch from WF to dabigatran significantly prolonged OT (784.5 ± 19.3 sec). One patient on WF therapy and 12 patients on dabigatran therapy were shown to have OT > 900 sec.ConclusionThe GTT could be used to assess the risk of dabigatran-related bleeding complications.

Abstract 17137: Safety and Effectiveness of Dabigatran Relative to Warfarin in Routine Clinical Practice - New Interim Results of Long-term Study Program

Background: Dabigatran etexilate is a newer oral anticoagulant developed as an alternative to warfarin for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Although the efficacy and safety of dabigatran were established in a randomized trial, evaluation of its effects in routine clinical practice is ongoing. Objectives: Quantification of the comparative safety and effectiveness of dabigatran in routine care within two large US commercial health insurance databases (Truven MarketScan and Optum Clinformatics) Methods: Cohort design with propensity score (PS) matching to compare new initiators of dabigatran with warfarin between October 2010 and June 2013. Primary outcomes were stroke and major bleeding. Proportional hazards regression of time to outcome was conducted separately within each data source and results were pooled. Results: There were 22,736 PS matched dabigatran and warfarin initiators with NVAF pooled across data sources (MarketScan 18,726; Optum 4,010). The matching resulted in well balanced cohorts with no individual characteristic (including stroke and bleeding risk factors) having a standardized difference of greater than 0.1. The average follow-up for the as-treated analyses was 5 months for dabigatran and 4 months for warfarin. There were 69 strokes amongst dabigatran initiators and 84 strokes amongst warfarin initiators for a pooled HR of 0.71 (95% CI 0.51 – 0.98) (MarketScan HR = 0.65, 95% CI=0.45-0.93, Clinformatics HR = 1.05, 95% CI = 0.50-2.19). For the outcome of major hemorrhage, there were 429 events amongst dabigatran initiators and 480 events amongst warfarin initiators for a pooled HR of 0.77, 95% CI = 0.68 – 0.88) (MarketScan HR = 0.80, 95% CI = 0.70 - 0.92, Clinformatics HR = 0.55, 95% CI = 0.37 - 0.82). Pooled results in the full cohort were fairly consistent across numerous subgroup and sensitivity analyses, however, comparative conclusions within some subgroups are limited by small numbers and limited follow-up time. Conclusions: Analyses from this ongoing sequential long-term study program suggest a reduced risk of both stroke and major hemorrhage for dabigatran relative to warfarin. Continued follow-up will increase the sample size, permitting greater precision in effect estimates.

Abstract 17126: Efficacy and Safety of Dabigatran Compared With Warfarin in Patients With Atrial Fibrillation and Normal Renal Function Over Time: Insights From the RE-LY Trial

Background: In patients with atrial fibrillation (AF) and normal renal function it has been reported that one oral factor-Xa inhibitor is associated with decreased efficacy compared to warfarin. In the RE-LY trial of patients with AF dabigatran, with approximately 80% renal elimination, was superior to warfarin for prevention of stroke and systemic embolism (SEE) with the 150 mg dose and non-inferior with the 110 mg dose and associated with significantly less major bleeding with the 110 mg dose. This is a post hoc analysis of the efficacy and safety of dabigatran vs. warfarin treatment in patients with normal renal function during the study. Methods: In the RE-LY trial among patients who received at least one dose of study medication, 17882 had creatinine measurements available at baseline, out of which 91% also had measurements after randomization. There were a total of 382 stroke/SEE, 280 ischemic strokes, and 1018 major bleed events during median follow-up of 1.8 years. The relations between outcomes, treatment, and renal function (Cockcroft-Gault estimated glomerular filtration rate (eGFR)) during follow-up were evaluated using Cox regression including treatment, eGFR as a continuous time dependent covariate, fitted using restricted cubic splines, and interaction. Hazard ratios (95% CI) comparing treatment effects were analyzed according to eGFR level. Results: In patients with normal renal function the relative risk of stroke/SEE was consistently lower in those treated with dabigatran as compared with warfarin. The patterns were similar for major bleeding with a trend of greater relative risk reduction with dabigatran as compared to warfarin at normal renal function. Conclusions: In patients with AF and normal renal function during treatment the efficacy of dabigatran compared to warfarin was consistent with the overall result of the RELY study. Both dabigatran doses were associated with lower risk of major bleeding in patients with normal renal function.

Critical appraisal of dabigatran in the treatment of deep vein thrombosis and pulmonary embolism.

ObjectiveTo compare the safety and efficacy of dabigatran to warfarin for the treatment of deep vein thrombosis and pulmonary embolism.BackgroundVenous thromboembolism (VTE) is a disease comprised of two conditions: deep vein thrombosis and pulmonary embolism. VTE is a major cause of morbidity and mortality worldwide with an annual incidence estimated at 1–3 cases per 1,000 individuals. This incidence increases with age from 0.1 per 1,000 in adolescence to eight per 1,000 in those 80 years of age and older. As the proportion of patients 65 years of age and older expands, the number of patients presenting with VTE will also increase. Anticoagulation remains the cornerstone of VTE treatment. Traditionally, vitamin K antagonists have been used to minimize the risk of thrombus extension and for secondary prevention. Unpredictable pharmacokinetics and pharmacodynamics, routine monitoring, drug–food and drug–drug interactions, and potentially severe adverse events have all been cited as barriers to optimal care. Dabigatran has been proposed as a suitable alternative to warfarin therapy in the treatment of VTE. Therefore, a critical appraisal of dabigatran’s safety and efficacy is necessary to determine its role in therapy.ConclusionDabigatran remains an alternative to warfarin therapy for the treatment of VTE. However, dabigatran also has distinct disadvantages that warrant consideration. Clinicians must ensure that drug characteristics align with patient characteristics to optimize patient outcomes.

Safety of dabigatran in an elderly population: single center experience in Italy.

In clinical practice, adherence to drugs and their safety may differ from randomised controlled trial settings. This study was undertaken to investigate the adherence to dabigatran, a direct thrombin inhibitor, and its safety in a real-world setting. We studied a prospective cohort of 114 elderly consecutive patients with non valvular atrial fibrillation (AF) who were treated with dabigatran 150 mg twice-daily (N=39) or 110 mg twice-daily (N=76). These patients were studied at baseline and after an average of 6 months. Mean age was 80 years and 53% were women. At entry, the average CHA2DS2VASc score was 4 and the HAS-BLED score was 2. AF was permanent in 49% of patients, persistent in 30%, paroxysmal in 12% and new-onset in 24%. In the follow-up clinical visit we ascertained vital status, adherence to treatment according to refill prescription orders, and side effects. Adherence was ≥80% in 76.5% of patients. Heartburn, the most frequent adverse effect, was reported by 25 patients (22%). Major and minor bleedings were experienced by 2 (1.8%) and 9 (7.9%) patients, respectively. Permanent discontinuation occurred in 18 patients (16%). The most frequent cause of permanent discontinuation was heartburn (10 patients). This real-life study suggests that safety of dabigatran and adherence to this drug in an elderly cohort of AF patients at high or very high risk of thromboembolism are generally good. Heartburn is the main cause of treatment discontinuation.

The Use of Dabigatran for Prevention of Thromboembolic Complications in Patients Underwent Atrial Fibrillation Catheter Ablation

The aim of the study was to estimate the efficacy and safety of dabigatran in comparison with warfarin after atrial fibrillation (AF) catheter ablation (CA). 228 consecutive patients, having undergone AF CA, were enrolled in retrospective trial. In group I (n=170) warfarin was administered by modified interrupted scheme, in group II (n=58) dabigatran was administered by 150 mg twice a day. The main clinical efficacy and safety indicators were evaluated during the procedure and within 12 months after the procedure. There was no statistically significant difference between patients taking warfarin and dabigatran (p>0,1) in all of the investigated parameters, including the amount of bleeding and thromboembolic events. Side effects of mild dyspepsia were observed in the dabigatran group in 2.7% of the observations and in the warfarin group in 2.4% (p = 0,589). None of them required discontinuation of the therapy. Dabigatran can be considered as an alternative to warfarin for anticoagulation in patients undergoing AF CA.

Safety of dabigatran or rivaroxaban for thoracoscopic ablation in patients with atrial fibrillation

Safety of dabigatran or rivaroxaban for thoracoscopic ablation in patients with atrial fibrillation

<b>非弁膜症心房細動患者におけるダビガトラン投与時の活性化部分トロンボプラスチン時間(APTT)延長に関わる危険因子の検討</b>

Background: There is no established surrogate indicator for the efficacy and safety of dabigatran. Although activated partial thromboplastin time (APTT) may be an index of safety for dabigatran, the risk factors for the development of prolonged APTT while taking dabigatran is unclear. The purpose of this study was to find risk factors contributing to prolonged APTT.Methods and Results: 394 plasma samples from 108 patients (67±9 years of age, 70 men) with non-valvular atrial fibrillation (NVAF) at our hospital were analyzed. Median APTT in patients taking dabigatran 220 mg/day was 39.4 seconds (range 19.9-88.6), with a positive correlation between APTT and age (R2=0.04, p<0.01) and a negative correlation between APTT and creatinine clearance (Ccr) (R2=0.07, p<0.01). Median APTT in patients taking dabigatran 300 mg/day was 39.8 seconds (range 24.8-66.6), with a negative correlation between APTT and Ccr (R2=0.09, p<0.01). In multivariable analysis, significant associations were found between APTT and the following risk factors: age ≥70 years, gender, weight, Ccr, and dose of dabigatran. Twelve patients (11%) developed bleeding complication. In receiver operating characteristic analysis, the cut-off value of APTT for bleeding-related adverse effects was 50.4 seconds. In multivariate analysis, Ccr and P-glycoprotein inhibitor were significant risk factors associated with prolongation of APTT to 50 seconds.Conclusions: We identified the risk factors contributing to prolonged APTT during dabigatran treatment in NVAF patients.

Effectiveness and Safety of Dabigatran and Warfarin in Real-World US Patients With Non-Valvular Atrial Fibrillation: A Retrospective Cohort Study

Effectiveness and Safety of Dabigatran and Warfarin in Real-World US Patients With Non-Valvular Atrial Fibrillation: A Retrospective Cohort Study

A systematic review and adjusted indirect comparison of oral anticoagulants.

EDUCATIONAL OBJECTIVES As a result of reading this article, physicians should be able to: 1. Recognize the high risk of postoperative venous thromboembolism (VTE) in patients undergoing major orthopedic surgery. 2. Distinguish the different pharmacological mechanisms of VTE prophylaxis drugs. 3. Delineate the advantages and disadvantages of each VTE prophylaxis drug. 4. Recognize that rivaroxaban is as efficacious as apixaban but can increase the risk of hemorrhage. Patients undergoing major orthopedic surgery are at high risk for developing postoperative venous thromboembolism (VTE). The authors analyzed the available evidence on the efficacy and safety of dabigatran, apixaban, and rivaroxaban vs low-molecular-weight heparins (LMWHs) as VTE prophylaxis in major orthopedic surgery. Outcomes evaluated included total VTE, deep venous thrombosis (DVT), pulmonary embolism (PE), death, and major bleeding. Rivaroxaban and apixaban are more efficacious than dabigatran and are as safe as dabigatran. Rivaroxaban is as efficacious as apixaban but can increase the risk of hemorrhage.

Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants

Increasing age and renal impairment are risk factors for venous thrombosis but also for anticoagulant-induced bleeding. In large-scale phase III trials, non-VKA oral anticoagulants (NOACs) were at least as effective and safe for the treatment of acute venous thromboembolism as warfarin. Here, we review the efficacy and safety of dabigatran, rivaroxaban, apixaban and edoxaban in the subgroups of elderly patients (≥75 years) and patients with impaired renal function (creatinine clearance ≤50 ml/min). In all phase III trials, the efficacy of NOACs in the prevention of recurrent VTE was conserved both in the elderly subgroup and in the subgroup with impaired renal function. In a meta-analysis of the pooled results, NOACs reduced VTE recurrence compared with warfarin in elderly patients. In elderly patients and patients with impaired renal function, the safety of NOACs was in line with the results of the overall study.NOACs may offer an effective, safer and more convenient alternative for VKAs also in the elderly. However, the efficacy/safety profile of NOACs in the aged population needs to be confirmed in real-life.

The use of dabigatran for prevention of ischemic stroke in patiets with atrial fibrillation: special features of treatment in different clinical situations

Atrial fibrillation (AF) is extremely highly prevalent both in Russia and in the world. Ischemic stroke is a severe complication of AF often resulting in disability or death. Therefore important role is given to conduct of primary and secondary prevention of development of thromboembolic complications which is realized by means of administration of antithrombotic therapy. For a long time warfarin has been used for this purpose. However compliance of physicians to its prescription remains unsatisfactory. Recently novel oral anticoagulants (NOAC) have been elaborated. Among them dabigatran has longest period of use and has been recommended as the drug of choice for patients with non-valvular AF. At present time wide use of dabigatran is limited because of lack of clear understanding of some practical questions of the use of this drug. Aim of this review--to analyze available data on efficacy and safety of dabigatran, to study special features of its administration in various clinical situations.

The Safetyof Dabigatran Versus Warfarin in Patients Undergoing Atrial Fibrillation Ablation.

The safety and optimal strategy of the use of dabigatran versus uninterrupted warfarin in atrial fibrillation ablation is currently unclear. We performed a retrospective analysis between July 2011-October 2012 of all patients undergoing an AF ablation who received uninterrupted warfarin therapy (199) and the routine cessation of Dabigatran therapy (126) 4 days pre-ablation. Major safety endpoints included: pericardial effusion (requiring pericardiocentesis), peripheral thromboembolism, CVA, and groin hematoma requiring blood transfusion. Minor endpoints included pericardial effusion and groin hematoma. Dabigatran was restarted the following day after ablation. The warfarin group was older, had a higher CHADS2, CHA2DS2VASc and HASBLED scores and greater prevalence of aortic plaque. The major complication rate was 2.0% in the warfarin group and 2.4% in the dabigatran group (P= 0.83). The minor complication rate was 2.5% in the warfarin group and <1% in the dabigatran group (P= 0.27). In the dabigatran group, there was one renal thromboembolic event 4 days post-ablation. All patients in the warfarin group who suffered a major complication required a blood transfusion. Cessation of dabigatran therapy 4 days pre AF ablation has a comparable safety profile to uninterrupted warfarin therapy.

Meta-Analysis of Risk of Stroke or Transient Ischemic Attack With Dabigatran for Atrial Fibrillation Ablation

Dabigatran is a novel oral anticoagulant and may be useful during atrial fibrillation (AF) ablation for prevention of thromboembolic events. However, the benefits and adverse effects of periprocedural dabigatran therapy have not been thoroughly evaluated. A meta-analysis was performed to evaluate the efficacy and safety of dabigatran for anticoagulation in AF ablation. PubMed, The Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 01, 2001 through July 30, 2013. Two reviewers reviewed the studies for inclusion and extracted data from studies comparing dabigatran with warfarin for AF ablation. A total of 5,513 patients undergoing catheter ablation were included in 17 observational studies and 1 randomized trial. Fourteen events of stroke or transient ischemic attacks were reported in the dabigatran group and 4 in the warfarin group (Peto's odds ratio 3.94, 95% confidence interval [CI] 1.54 to 10.08, number needed to harm=284 patients). The risk of all thromboembolic complications was also higher in the dabigatran group compared with the warfarin group (Peto's odds ratio 2.81, 95% CI 1.23 to 6.45). No major differences were observed for the risk of major bleeding (odds ratio 0.99, 95% CI 0.55 to 1.78), pericardial tamponade, and groin hematoma. A lower risk of minor bleeding was observed with dabigatran (odds ratio 0.60, 95% CI 0.41 to 0.87). In conclusion, periprocedural use of dabigatran for AF ablation was related to a higher risk of thromboembolic complications including stroke and transient ischemic attack.

Increased risk of myocardial infarction with dabigatran

Dabigatran is a direct, competitive inhibitor of thrombin recently approved for the prophylaxis of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In some of the clinical trials evaluating the efficacy and safety of dabigatran in different clinical settings [i.e., prevention of venous thromboembolism (VTE) after orthopedic surgery, secondary prevention of VTE, and acute coronary syndromes (ACS)], a trend toward an increase in acute coronary events among patients receiving dabigatran has been reported, thus raising concerns of a possible relationship between dabigatran and myocardial infarction, especially in high-risk patients. However, as shown in our article, current evidence is inconclusive on this topic; more data are needed to detail this hypothetical association, and other considerations, such as the well-known protective effect of warfarin against ACS, should be taken into account as a possible explanation.

Dabigatran Use in the Real World

Dabigatran etexilate, an oral direct thrombin inhibitor, was approved by the Food and Drug Administration to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation based on the outcomes of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) study. Although this study provides robust data on the efficacy and safety of dabigatran, there may be differences in the drug use and outcomes in routine clinical practice following drug approval. In this retrospective chart review study, we describe the use of dabigatran in 160 patients in 4 adult hospitals (1 academic and 3 community), including appropriate prescribing for indication, starting dose, concomitant anticoagulant and antiplatelet use, and clinical outcomes such as bleeding, myocardial infarction, and stroke. The study revealed appropriate indication of nonvalvular atrial fibrillation in 145 (91%) of the 160 patients. The dose of dabigatran was appropriate in 90% of the patients, with the most common cause of inappropriate dosing due to perceived bleeding risk. Over a follow-up period of 6 months, bleeding complications were noted in 6 patients still taking dabigatran, 5 of which were gastrointestinal bleeding. Our study underscores the importance of prescriber education regarding the appropriate indication, dosage, and safety of dabigatran with active participation of pharmacists in this process.

Dabigatran etexilate for thromboembolic prophylaxis in non-valvular atrial fibrillation: the RE-LY study and substudies with commentary

In 2010, dabigatran etexilate, a direct thrombin inhibitor, was the first new oral anticoagulant to be approved for thromboembolic prophylaxis in atrial fibrillation in over 50 years. Dabigatran, unlike warfarin, has a short half-life with a rapid onset of anticoagulant effect, does not require dose adjustment or monitoring, and does not interact with food. The RE-LY trial compared two doses of dabigatran (110 and 150 mg twice daily) with adjusted dose warfarin in patients with non-valvular atrial fibrillation and at least 1 stroke risk factor. Compared with warfarin, dabigatran 150 mg twice daily was superior in reducing the risk of stroke or systemic embolism and was associated with a similar rate of major bleeding, while dabigatran 110 mg twice daily was equally effective in reducing stroke or systemic embolism and was associated with less major bleeding. Despite these favorable results, there remains disagreement regarding the optimal dose and overall safety of dabigatran in certain patient populations including the elderly and those with renal dysfunction.

Real life efficacy and safety of rivaroxaban for stroke prevention in atrial fibrillation: updated results of the prospective NOAC registry (NCT01588119)

Background: In the RELY trial, the novel oral anticoagulant (NOAC) dabigatran has been found to be at least as effective and safe as warfarin for stroke prevention in atrial fibrillation (SPAF). As a consequence, dabigatran has become approved in many countries. However, patients in RCT's present a selected population which is treated under a strict protocol and followed for a short period of time. Consequently, efficacy and safety of dabigatran need to be confirmed in unselected patients in daily care. Objectives: To evaluate the efficacy, safety and management issues of dabigatran anticoagulation in AF in daily care. Patients and methods: In the prospective, non-interventional Dresden NOAC registry a network of more than 230 physicians enrol eligible patients. Up to 2000 patients receive prospective follow up by phone visits by the registry office. All events are centrally adjudicated using standard definitions. Results: Until December 31th 2012, 1665 patients were registered. Of these, 303 patients received dabigatran for SPAF (50.5% male, mean age 74.5 years, mean CHADS-Score 2.6; 61.4% newly anticoagulated). Treatment adherence was acceptable with 73.6% of patients still taking dabigatran at 9 month. 18.4% of patients were switched to other anticoagulants (side effects, incompliance, costs). In total, 9 major cardiovascular events were observed (5.8 per 100 patient years; 4 TIA, 1 stroke, 2 ACS, 1 limb ischemia, see table 1). Furthermore, 84 bleeding events occurred, of which only 5 events were major bleedings (3.2 per 100 patient years). No fatal bleeding was observed. 2 patients died (1.3 per 100 patient years), both of sudden cardiac death. View this table: Table 1. Real-life efficacy and safety of dabigatran in SPAF Conclusion: In unselected patients in daily care, dabigatran is effective and safe with low rates of cardiovascular or major bleeding events. However, about 25% of patients are switched to other anticoagulants within 9 months. Data on bleeding pattern and management will be presented.