Dabigatran Group Research Articles

A comparison of bleeding complications post-ablation between warfarin and dabigatran

Although warfarin has traditionally been used for reducing risk of stroke in patients with atrial fibrillation, over the past year, the direct thrombin inhibitor dabigatran has become an accepted alternative. No study has conclusively investigated bleeding risks of patients treated with dabigatran immediately following radiofrequency catheter ablation (RFCA) procedures. We evaluated 156 consecutive patients referred for RFCA of atrial arrhythmias: 31 patients were on dabigatran and 125 patients were on warfarin. The incidence of bleeding complications during the first 48 h and the first week following ablation were recorded and comparisons made using Fisher's exact test. Major complications were defined as hemorrhage requiring blood products or the need for vascular intervention. Minor complications were defined as prolonged bleeding from the catheter insertion site, hematoma formation, or development of ecchymosis. Our study also took into account the intraprocedure activated clotting time (ACT) levels in an effort to describe any differences between both patient groups. There were no differences in age, gender, procedure type, or level of intraprocedural anticoagulation between the warfarin and dabigatran groups. No major bleeding complications were observed in either patient group at either 48 h or 1 week postprocedure. Six of the 31 dabigatran patients and 21 of the 125 warfarin patients had minor bleeding complications. There was no statistically significant difference between the incidence of minor bleeding complications between the two groups (p = 0.7384), although rebleeding was more commonly observed in patients on dabigatran. In regard to the intraprocedure ACT levels, there was more variability in the dabigatran patient group, and it was more difficult to achieve the goal ACT level, yet these results did not affect overall bleeding complications. In our cohort, bleeding-related complications 48 h and 1 week post-ablation were similar for warfarin and dabigatran. Dabigatran is associated with more intraprocedural variability in ACT than warfarin.

Letter by Stöllberger and Finsterer Regarding Article, “Intracranial Hemorrhage in Patients With Atrial Fibrillation During Anticoagulation With Warfarin or Dabigatran: The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial”

To the Editor: We read with interest the article by Hart et al1 on intracranial hemorrhage (IH) in patients with atrial fibrillation undergoing anticoagulation treatment with warfarin or dabigatran. They analyzed retrospectively the clinical spectrum of 154 IHs in 18 113 participants of the Randomized Evaluation of Long-term anticoagulant therapY (RE-LY) trial and found that the rates of IHs were lower in dabigatran-treated patents than in those treated with warfarin. However, several points need to be addressed by the authors before one can accept the conclusion that dabigatran is indeed safer than warfarin with respect to the most feared complication of anticoagulant therapy, cerebral bleeding. In particular, the following questions need to be answered: How was it ascertained in the RE-LY study that the patients randomly chosen for the dabigatran group actually …

Dabigatran versus Warfarin after Mechanical Mitral Valve Replacement in the Swine Model

ABSTRACTBackground: Mechanical heart valve replacement is an absolute indication for anticoagulation. We report our experience comparing dabigatran to warfarin as thromboembolic prophylaxis after mechanical mitral valve replacement in the swine model. Methods: Nineteen swine underwent mitral valve replacement with a regulatory approved, 27 mm mechanical valve. Two control groups consisted of three animals receiving no anticoagulation and five animals receiving warfarin (5 mg once a day [QD], adjusted to maintain international normalized ratio [INR] from 2.0 to 2.5). The experimental group consisted of 11 animals receiving dabigatran (20 mg/kg twice a day [BID]). The study period was 90 days. The primary outcome was animal mortality; secondary outcomes included presence of thrombus and bleeding complications. Results: The experimental group had four full-term survivors (40.0%); there were no full-term survivors in either control group. The average length of survival was 50.3 days in the experimental group compared with 18.7 and 15.6 days for the no anticoagulation and warfarin groups, respectively (p = .017). Valve thrombus was observed in all study groups. Hemorrhagic complications were present in 40% of the warfarin group and 27% of the dabigatran group. Conclusions: There was a significant mortality benefit to the use of dabigatran as thromboembolic prophylaxis when compared with warfarin in the setting of mechanical heart valve replacement in the swine model. There was also a decreased incidence of bleeding complications in the dabigatran group compared with the warfarin group. Valve thrombus was observed in all study groups. Any conclusions regarding the rate of thrombus formation are outside the scope of this study and merit further investigation.

Feasibility and Safety of Dabigatran Versus Warfarin for Periprocedural Anticoagulation in Patients Undergoing Radiofrequency Ablation for Atrial Fibrillation: Results From a Multicenter Prospective Registry

The purpose of this study was to evaluate the feasibility and safety of periprocedural dabigatran during atrial fibrillation (AF) ablation. AF ablation requires optimal periprocedural anticoagulation for minimizing bleeding and thromboembolic complications. The safety and efficacy of dabigatran as a periprocedural anticoagulant for AF ablation are unknown. We performed a multicenter, observational study from a prospective registry including all consecutive patients undergoing AF ablation in 8 high-volume centers in the United States. All patients receiving dabigatran therapy who underwent AF ablation on periprocedural dabigatran, with the dose held on the morning of the procedure, were matched by age, sex, and type of AF with an equal number of patients undergoing AF ablation with uninterrupted warfarin therapy over the same period. A total of 290 patients, including 145 taking periprocedural dabigatran and an equal number of matched patients taking uninterrupted periprocedural warfarin, were included in the study. The mean age was 60 years with 79% being male and 57% having paroxysmal AF. Both groups had a similar CHADS(2) score, left atrial size, and left ventricular ejection fraction. Three thromboembolic complications (2.1%) occurred in the dabigatran group compared with none in the warfarin group (p = 0.25). The dabigatran group had a significantly higher major bleeding rate (6% vs. 1%; p = 0.019), total bleeding rate (14% vs. 6%; p = 0.031), and composite of bleeding and thromboembolic complications (16% vs. 6%; p = 0.009) compared with the warfarin group. Dabigatran use was confirmed as an independent predictor of bleeding or thromboembolic complications (odds ratio: 2.76, 95% confidence interval: 1.22 to 6.25; p = 0.01) on multivariate regression analysis. In patients undergoing AF ablation, periprocedural dabigatran use significantly increases the risk of bleeding or thromboembolic complications compared with uninterrupted warfarin therapy.

Risks for Stroke, Bleeding, and Death in Patients With Atrial Fibrillation Receiving Dabigatran or Warfarin in Relation to the CHADS_2 Score: A Subgroup Analysis of the RE-LY Trial

CHADS(2) is a simple, validated risk score for predicting the risk for stroke in patients with atrial fibrillation not treated with anticoagulants. There are sparse data on the risk for thrombotic and bleeding complications according to the CHADS(2) score in patients receiving anticoagulant therapy. To evaluate the prognostic importance of CHADS(2) risk score in patients with atrial fibrillation receiving oral anticoagulants, including the vitamin K antagonist warfarin and the direct thrombin inhibitor dabigatran. Subgroup analysis of a randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00262600) SETTING: Multinational study setting. 18 112 patients with atrial fibrillation who were receiving oral anticoagulants. Baseline CHADS(2) score, which assigns 1 point each for congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for stroke. Distribution of CHADS(2) scores were as follows: 0 to 1-5775 patients; 2-6455 patients; and 3 to 6-5882 patients. Annual rates of the primary outcome of stroke or systemic embolism among all participants were 0.93% in patients with a CHADS(2) score of 0 to 1, 1.22% in those with a score of 2, and 2.24% in those with a score of 3 to 6. Annual rates of other outcomes among all participants with CHADS(2) scores of 0 to 1, 2, and 3 to 6, respectively, were the following: major bleeding, 2.26%, 3.11%, and 4.42%; intracranial bleeding, 0.31%, 0.40%, and 0.61%; and vascular mortality, 1.35%, 2.39%, and 3.68% (P < 0.001 for all comparisons). Rates of stroke or systemic embolism, major and intracranial bleeding, and vascular and total mortality each increased in the warfarin and dabigatran groups as CHADS(2) score increased. The rates of stroke or systemic embolism with dabigatran, 150 mg twice daily, and of intracranial bleeding with dabigatran, 150 mg or 110 mg twice daily, were lower than those with warfarin; there was no significant heterogeneity in subgroups defined by CHADS(2) scores. These analyses were not prespecified and should be deemed exploratory. Higher CHADS(2) scores were associated with increased risks for stroke or systemic embolism, bleeding, and death in patients with atrial fibrillation receiving oral anticoagulants. Boehringer Ingelheim.

Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II)

SummaryThis trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28–35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) –1.1% (95%CI –3.8 to 1.6%); p&lt;0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD –1.9% (-3.6% to –0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as sub-cutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.

Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial

In the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, dabigatran reduced occurrence of both stroke and haemorrhage compared with warfarin in patients who had atrial fibrillation and were at increased risk of stroke. We aimed to assess the effects of dabigatran compared with warfarin in the subgroup of patients with previous stroke or transient ischaemic attack. In the RE-LY trial, 18,113 patients from 967 centres in 44 countries were randomly assigned to 110 mg or 150 mg dabigatran twice daily or to warfarin dose adjusted to international normalised ratio 2·0 to 3·0. Median follow-up was 2·0 years (IQR 1·14-2·86), and the primary outcome was stroke or systemic embolism. The primary safety outcome was major haemorrhage. Patients and investigators were aware of whether patients received warfarin or dabigatran, but not of dabigatran dose, and event adjudicators were masked to treatment. In a predefined analysis, we investigated the outcomes of the RE-LY trial in subgroups of patients with or without previous stroke or transient ischaemic attack. RE-LY is registered with ClinicalTrials.gov, NCT00262600. Within the subgroup of patients with previous stroke or transient ischaemic attack, 1195 patients were from the 110 mg dabigatran group, 1233 from the 150 mg dabigatran group, and 1195 from the warfarin group. Stroke or systemic embolism occurred in 65 patients (2·78% per year) on warfarin compared with 55 (2·32% per year) on 110 mg dabigatran (relative risk 0·84, 95% CI 0·58-1·20) and 51 (2·07% per year) on 150 mg dabigatran (0·75, 0·52-1·08). The rate of major bleeding was significantly lower in patients on 110 mg dabigatran (RR 0·66, 95% CI 0·48-0·90) and similar in those on 150 mg dabigatran (RR 1·01; 95% CI 0·77-1·34) compared with those on warfarin. The effects of both doses of dabigatran compared with warfarin were not significantly different between patients with previous stroke or transient ischaemic attack and those without for any of the outcomes from RE-LY apart from vascular death (110 mg group compared with warfarin group, interaction p=0·038). The effects of 110 mg dabigatran and 150 mg dabigatran twice daily in patients with previous stroke or transient ischaemic attack are consistent with those of other patients in RE-LY, for whom, compared with warfarin, 150 mg dabigatran reduced stroke or systemic embolism and 110 mg dabligatran was non-inferior. [corrected] Most effects of both dabigatran doses were consistent in patients with versus those without previous stroke or transient ischaemic attack. Boehringer Ingelheim.

The Evolving Field of Stroke Prevention in Patients With Atrial Fibrillation

Vitamin K antagonists have been the standard in stroke prophylaxis in patients with atrial fibrillation for decades, but several limitations make it difficult for patients to tolerate chronic anticoagulation treatment. New drugs are under evaluation in clinical trials, including direct thrombin inhibitors and factor Xa inhibitors. Antiplatelet agents such as clopidogrel and aspirin are alternatives to warfarin for stroke prevention but have proven less efficacious in trials. The only drug to have completed a Phase III trial successfully thus far is dabigatran. The 150-mg twice-a-day dose was superior to warfarin in efficacy and similar for major bleeding, whereas the 110-mg twice-a-day dose was noninferior for efficacy and reduced major bleeding. Both doses reduced intracranial hemorrhages substantially compared with warfarin. Dabigatran-assigned patients had a higher incidence of discontinuation due to gastrointestinal symptoms. Clinically apparent myocardial infarction rates were slightly higher in the dabigatran groups than the warfarin group. Dabigatran is the first agent to show superiority over warfarin for stroke prevention in atrial fibrillation, raising the standard for newer agents.

Abstract 4629: Long-Term Open Label Extension of the Prevention of Embolic and Thrombotic Events on Dabigatran in Atrial Fibrillation (PETRO- Ex study)

Dabigatran is an oral direct thrombin inhibitor (DTI), which has a rapid onset of action and can be given twice daily (b-i-d) without anticoagulation monitoring. To determine the long term safety and efficacy of dabigatran in patients with atrial fibrillation (AF). AF patients (n=502) from 53 centers in Denmark, the Netherlands, Sweden and the United States were enrolled in the PETRO study, a 12 week comparison between dabigatran (50, 150, and 300 mg b-i-d) and warfarin (INR 2–3). 361 dabigatran patients were rolled over into a long term extension trial (PETRO-Ex). The warfarin patient arm (n=70) was discontinued. All patients were initially maintained on the same dabigatran doses as in PETRO except the 50 mg b-i-d dose group who were switched to 150 mg once daily (qd). At entry, patients were 70 years old (mean age), 19% female, median AF duration of 4.2 years, and had a median of 3 stroke risk factors. Maximum and mean follow-up times were 51 and 29 months respectively. Due to higher frequency of major bleeding events in 300 mg b-i-d group and thromboembolic events in 150 mg qd group, they were switched to dabigatran 300 mg qd or 150 mg b-i-d groups. PETRO and PETRO-Ex results: Events reported as absolute number of patients (per 100 patient-years) Thromboembolic event rates were lowest in the dabigatran 150 and 300 mg b-i-d groups. Major bleeding was most frequent in the 300 mg b-i-d group. No significant liver function abnormalities were noted in any of the dabigatran groups. The balance between stroke and bleeding risk supported dabigatran doses between 100 and 150 mg b-i-d for the ongoing phase 3 Randomized Evaluation of Longterm anticoagulation therapY (RELY) trial.

Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation (PETRO Study)

This is the first evaluation of dabigatran, an oral direct thrombin inhibitor, in patients with atrial fibrillation (AF). Patients (n = 502) were randomized to receive blinded doses of 50-, 150-, or 300-mg dabigatran twice daily alone or combined with 81- or 325-mg aspirin or open-label warfarin administered to achieve an international normalized ratio of 2 to 3 for 12 weeks. Dabigatran plasma concentrations, activated partial thromboplastin time, D-dimer, urinary 11-dehydrothromboxane B(2) (DTB2), and liver function were measured at baseline and at 1, 2, 4, 8, and 12 weeks. Clinical end points were assessed according to the treatment received at the time of the event. Overall, 92% of patients completed the study. Major hemorrhages were limited to the group treated with 300-mg dabigatran plus aspirin (4 of 64), and the incidence was significant versus 300-mg dabigatran alone (0 of 105, p <0.02). Total bleeding events were more frequent in the 300-mg (39 of 169, 23%) and 150-mg (30 of 169, 18%) dabigatran groups compared with the 50-mg groups (7 of 107, 7%; p = 0.0002 and p = 0.01, respectively). Thromboembolic events were limited to the 50-mg dabigatran dose groups (2 of 107, 2%). The mean trough d-dimer measurements were suppressed for the 2 highest doses of dabigatran and warfarin (international normalized ratio of 2 to 3). Aminotransferase levels >3 times the upper limit of normal were observed in 0.9% of the dabigatran recipients and in none of the warfarin recipients. Two dabigatran recipients had aminotransferase levels >5 times the upper limit of normal as a result of gallstones, which resolved. Trough activated partial thromboplastin time values were 1.2, 1.5, and 1.8 times the baseline level for the 50-, 150-, and 300-mg dabigatran groups, respectively. DTB2 concentrations after 12 weeks of 50-, 150-, and 300-mg dabigatran treatment were increased by 31%, 17%, and 23%, respectively, versus baseline (p = 0.02, p = 0.03, and p = 0.0004). In conclusion, major bleeding events were limited to patients treated with dabigatran 300 mg plus aspirin and thromboembolic episodes were limited to the 50-mg dabigatran groups. The 2 highest doses of dabigatran suppress D-dimer concentrations. Serious liver toxicity was not seen. The significance of the increase of DTB2 concentrations in dabigatran-treated patients needs resolution.