Randomized Evaluation Of Long-Term Anticoagulation Therapy Research Articles

RE-LY: dabigatran in cardioversion

Cardioversion in atrial fibrillation (AF) is associated with an increased risk of thromboembolism. Current recommendations advise therapy with the anticoagulant warfarin both before and after cardioversion. A new post hoc analysis of data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial shows that the novel anticoagulant dabigatran is a safe alternative to warfarin in patients with AF who undergo cardioversion.

Dabigatran Versus Warfarin in Patients With Atrial Fibrillation

Background– The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial compared dabigatran 110 mg BID (D110) and 150 mg BID (D150) with warfarin for stroke prevention in 18 113 patients with nonvalvular atrial fibrillation. Methods and Results– Cardioversion on randomized treatment was permitted. Precardioversion transesophageal echocardiography was encouraged, particularly in dabigatran-assigned patients. Data from before, during, and 30 days after cardioversion were analyzed. A total of 1983 cardioversions were performed in 1270 patients: 647, 672, and 664 in the D110, D150, and warfarin groups, respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for ≥3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P <0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P =0.71; D150 versus warfarin, P =0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P =0.06; D150 versus warfarin, P =0.99). Conclusions– This study is the largest cardioversion experience to date and the first to evaluate a novel anticoagulant in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance. Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Clinical Trial Registration– URL: http://www.ClinicalTrials.gov . Unique identifier: NCT00262600.

Advances in Emerging Therapies 2010

In 2010, there were significant advancements in stroke prevention, whereas there were fewer studies that unearthed new ground on treatment of acute stroke and rehabilitation. We first discuss important pivotal studies in stroke prevention followed by acute treatment and rehabilitation. ### Prevention #### Homocysteine, Folic Acid, and B Vitamins Approximately 90% of all strokes are attributable to vascular risk factors.1 Homocysteine has also been identified as another risk factor for stroke. VITAmins TO Prevent Stroke (VITATOPS) aimed to assess whether daily administration of folic acid, vitamin B6, and vitamin B12 in patients with recent stroke or transient ischemic attack lowers homocysteine and reduces major vascular events. The data overall and pooled analysis of individual patient data showed that B vitamins have no or at most a marginal positive effect on reducing vascular events.2 #### Blood Pressure There is a correlation between blood pressure levels and risk of stroke. Data from Rothwell and colleagues now show that not only blood pressure levels, but also blood pressure variability account for stroke risk. A meta-analysis of antihypertensive drug trials found that calcium channel blockers and nonloop diuretic drugs were more effective than other antihypertensive agents to reduce blood pressure variability.3 Drug-class effects on interindividual variation in blood pressure can explain differences in effects of antihypertensive drugs on risk of stroke independently of their effects on mean systolic blood pressure. This means that the ideal antihypertensive agent should lower both blood pressure levels and variation in blood pressure to reduce stroke risk; however, we currently do not have such agents in our pharmacopeia for stroke prevention. #### Antithrombotic Drugs and Cerebrovascular Diseases New data have emerged on some age old questions about carotid dissection and intracranial stenosis. The use of aspirin or anticoagulation in spontaneous carotid artery dissection is a matter of debate with little data to guide decision-making. Data within a nonrandomized study suggest that the frequency …

Efficacy and Safety of Dabigatran vs. Warfarin in Patients With Atrial Fibrillation - Sub-Analysis in Japanese Population in RE-LY Trial -

RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) is an international multicenter study (18,113 patients from 967 centers in 44 countries) that demonstrated the ability of dabigatran to reduce the occurrence of both stroke and hemorrhage in patients who had atrial fibrillation (AF) with high risks of stroke compared with patients who received warfarin. From Japan, 326 patients were randomized in RE-LY. RE-LY was designed to compare 2 fixed doses (110 mg or 150 mg, twice daily) of dabigatran, each administered in a blinded manner, with open-label use of warfarin. There were no major differences in patient demographic information among the overall study population and Japanese patients. However, in Japanese patients, the proportion of prior stroke was higher but prior myocardial infarction was lower than in the overall. The yearly rate for the primary endpoints (stroke and systemic embolism) was 1.38, 0.67 and 2.65%/year for 110 mg and 150 mg dabigatran twice daily and warfarin, respectively. These results were similar to the overall results (1.54, 1.11 and 1.71%/year for each group, respectively). For any bleeding, the relative risk of dabigatran at 110 mg and 150 mg twice daily over warfarin was 0.79 and 1.06, respectively, which was similar to the findings overall (dabigatran 110 mg twice daily: 0.78; 150 mg twice daily: 0.91). In RE-LY, the efficacy and safety profiles of dabigatran for Japanese AF patients at high risk of stroke were essentially the same as for the study population overall.

Newly Identified Events in the RE-LY Trial

To the Editor: We wish to update our article about the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial (Sept. 17, 2009, issue).1 After the database was locked on August 15, 2009, we identified several additional primary efficacy and safety outcome events during routine clinical site closure visits. These events included two systemic embolic events and nine major hemorrhages. Subsequently, after discussions with the Food and Drug Administration, the primary and secondary efficacy and safety data were checked for consistency, and the study database was reevaluated for possible underreporting of events. To achieve this, all free text, outcomes, and adverse . . .

Cost-Effectiveness of Dabigatran Compared With Warfarin for Stroke Prevention in Atrial Fibrillation

Warfarin reduces the risk for ischemic stroke in patients with atrial fibrillation (AF) but increases the risk for hemorrhage. Dabigatran is a fixed-dose, oral direct thrombin inhibitor with similar or reduced rates of ischemic stroke and intracranial hemorrhage in patients with AF compared with those of warfarin. To estimate the quality-adjusted survival, costs, and cost-effectiveness of dabigatran compared with adjusted-dose warfarin for preventing ischemic stroke in patients 65 years or older with nonvalvular AF. Markov decision model. The RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial and other published studies of anticoagulation. The cost of dabigatran was estimated on the basis of pricing in the United Kingdom. Patients aged 65 years or older with nonvalvular AF and risk factors for stroke (CHADS₂ score ≥1 or equivalent) and no contraindications to anticoagulation. Lifetime. Societal. Warfarin anticoagulation (target international normalized ratio, 2.0 to 3.0); dabigatran, 110 mg twice daily (low dose); and dabigatran, 150 mg twice daily (high dose). Quality-adjusted life-years (QALYs), costs (in 2008 U.S. dollars), and incremental cost-effectiveness ratios. The quality-adjusted life expectancy was 10.28 QALYs with warfarin, 10.70 QALYs with low-dose dabigatran, and 10.84 QALYs with high-dose dabigatran. Total costs were $143 193 for warfarin, $164 576 for low-dose dabigatran, and $168 398 for high-dose dabigatran. The incremental cost-effectiveness ratios compared with warfarin were $51 229 per QALY for low-dose dabigatran and $45 372 per QALY for high-dose dabigatran. The model was sensitive to the cost of dabigatran but was relatively insensitive to other model inputs. The incremental cost-effectiveness ratio increased to $50 000 per QALY at a cost of $13.70 per day for high-dose dabigatran but remained less than $85 000 per QALY over the full range of model inputs evaluated. The cost-effectiveness of high-dose dabigatran improved with increasing risk for stroke and intracranial hemorrhage. Event rates were largely derived from a single randomized clinical trial and extrapolated to a 35-year time frame from clinical trials with approximately 2-year follow-up. In patients aged 65 years or older with nonvalvular AF at increased risk for stroke (CHADS₂ score ≥1 or equivalent), dabigatran may be a cost-effective alternative to warfarin depending on pricing in the United States. American Heart Association and Veterans Affairs Health Services Research & Development Service.

Drug Betters Aspirin for Stroke of A Fib

Drug Betters Aspirin for Stroke of A Fib

Does dabigatran improve stroke‐prevention in atrial fibrillation? Reply to a rebuttal

We agree with Stöllberger and Finsterer that physicians and patients alike are keenly awaiting a new oral anticoagulant that is more effective, safer and more convenient than the vitamin K antagonists. The Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) trial demonstrated that dabigatran compared with warfarin offers superior protection against stroke and systemic embolism and reduces the risk of life‐threatening and intracranial bleeding [1]. Unlike warfarin, dabigatran has a low potential for clinically important food and drug interactions and can be administered in fixed doses without routine coagulation monitoring [2].

Another oral thrombin inhibitor for stroke prevention in atrial fibrillation?

Atrial fibrillation (AF), the most common arrhythmia, is associated with a five-fold increase in the risk of stroke (1). Furthermore, cardio-embolic strokes in AF patients tend to be severe, and are often fatal or associated with serious morbidity. Vitamin K antagonists, such as warfarin, produce about a 64% reduction in the risk of stroke in AF patients (2), but have numerous limitations that curtail their uptake and diminish their effectiveness. These limitations include a slow onset of action, a variable dose requirement, reflecting common genetic polymorphisms that influence their metabolism, and an unpredictable anticoagulant response because of differences in dietary vitamin K intake and numerous drug-drug interactions, which increase or decrease the anticoagulant effect (3). With the anticoagulant response so variable, routine monitoring is necessary to ensure that the international normalised ratio (INR) is therapeutic because overanticoagulation is associated with an increased risk of haemorrhage, whereas under-anticoagulation increases the risk of thrombosis. Such monitoring is inconvenient for patients and physicians and costly for the healthcare system. Because of the complexity of management, only about one-half of eligible patients with AF receive warfarin, and among those who receive such treatment, the INR is frequently outside of the therapeutic range (4). The large unmet need caused by the limitations of warfarin has prompted the development of new oral anticoagulants with potential advantages over existing agents. Ximelagatran, the first oral thrombin inhibitor, was effective for stroke prevention in patients with AF, but was withdrawn in 2006 because of potential hepatic toxicity (5). The effectiveness of ximelagatran prompted development of a second generation of oral thrombin inhibitors. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial demonstrated the effectiveness of dabigatran etexilate, the first of this new generation, for stroke prevention in AF, endorsing thrombin as an appropriate target for new anticoagulants. Two doses of dabigatran etexilate were compared with warfarin in this trial; the higher dose regimen (150 mg twice-daily) was associated with significantly fewer intracranial bleeds and strokes compared with warfarin, whereas the lower dose (110 mg twice-daily) was associated with significantly less major bleeding than warfarin and similar efficacy (6). AZD0837 is the second of the new generation of oral thrombin inhibitors. A follow-up of ximelagatran, AZD0837 is a prodrug of AR-H067637, a selective and reversible inhibitor of free and fibrin-bound thrombin (7). Cytochrome P450 isoenzymes in the liver convert AZD0837 to AR-H069927, an intermediate that undergoes further metabolism to AR-H067637, the active form. In healthy individuals, AR-H067637 has a plasma half-life of 9–14 hours and the drug is cleared in the urine and faeces. An immediate-release preparation was the first formulation of AZD0837 evaluated in clinical trials; a more recent extended-release formulation enables once-daily dosing. In this issue of Thrombosis and Haemostasis, Olsson et al. (8) report the results of a phase II, randomised, controlled, dosefinding study evaluating the safety and tolCorrespondence to: Dr. Jeffrey Weitz Henderson Research Centre 711 Concession Street Hamilton, Ontario L8V 1C3, Canada Tel.: +1 905 574 8550, Fax: +1 905 575 2646 E-mail: jweitz@thrombosis.hhscr.org

Stroke: more protection for patients with atrial fibrillation

Progress in the prevention of stroke in patients with atrial fibrillation (AF) dominated advances in the area of cerebrovascular disorders in 2009. The most significant advance was the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study,1 which compared warfarin with a new oral antithrombin, dabigatran, in patients with AF. Vitamin K antagonists, such as warfarin, are the most effective drugs available for protection against stroke in patients with AF who are at increased stroke risk.

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.