Evaluation Of Long-Term Anticoagulation Therapy Research Articles

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.

Prognostic Usefulness of Left Ventricular Hypertrophy by Electrocardiography in Patients With Atrial Fibrillation (from the Randomized Evaluation of Long-Term Anticoagulant Therapy Study)

It is unknown whether left ventricular hypertrophy (LVH) diagnosis by electrocardiography improves risk stratification in patients with atrial fibrillation (AF). We investigated the prognostic impact of LVH diagnosis by electrocardiography in a large sample of anticoagulated patients with AF included in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Study. We defined electrographic LVH (ECG-LVH) by strain pattern or Cornell voltage (R wave in aVL plus S wave in V3) >2.0 mV (women) or >2.4 mV (men). LVH prevalence was 22.7%. During a median follow-up of 2.0 years, 303 patients developed a stroke, 778 died (497 from cardiovascular causes), and 140 developed a myocardial infarction. LVH was associated with a greater risk of stroke (1.99% vs 1.32% per year, hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.18 to 1.93, p <0.001), cardiovascular death (4.52% vs 1.80% per year, HR 2.56, 95% CI 2.14 to 3.06, p <0.0001), all-cause death (6.03% vs 3.11% per year, HR 1.95, 95% CI 1.68 to 2.26, p <0.0001), and myocardial infarction (1.11% vs 0.55% per year, HR 2.07, 95% CI 1.47 to 2.92, p <0.0001). In multivariate analysis, the prognostic value of LVH was additive to CHA2DS2-VASc score and other covariates. The category-free net reclassification index and integrated discrimination improvement increased significantly after adding LVH to multivariate models. In conclusion, our study demonstrates for the first time that ECG-LVH, a simple and easily accessible prognostic indicator, improves risk stratification in anticoagulated patients with AF.

Causes of Death and Influencing Factors in Patients With Atrial Fibrillation

Background— Atrial fibrillation is associated with increased mortality, but the specific causes of death and their predictors have not been described among patients on effective anticoagulant therapy. Methods and Results— The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial randomized 18 113 patients (age, 71.5±9 years; male, 64%; CHADS 2 score, 2.1±1) to receive dabigatran or warfarin. Median follow-up was 2 years, and complete follow-up was achieved in 99.9% of patients. All deaths were categorized by the investigators using prespecified definitions followed by central adjudication. Overall, 1371 deaths occurred (annual mortality rate, 3.84%; 95% confidence interval [CI], 3.64–4.05). Cardiac deaths (sudden cardiac death and progressive heart failure) accounted for 37.4% of all deaths, whereas stroke- and hemorrhage-related deaths represented 9.8% of the total mortality. An examination of the causes of death according to dabigatran or warfarin showed that dabigatran significantly reduced vascular (embolism and hemorrhage-related) mortality (relative risk, 0.63; 95% CI, 0.45–0.88; P =0.007), whereas other causes of death were similar between treatments, including cardiac mortality (relative risk, 0.96; 95% CI, 0.80–1.15; P =0.638). The two strongest independent predictors of cardiac death in this population were heart failure (hazard ratio, 3.02; 95% CI, 2.45–3.73; P &lt;0.0001), and prior myocardial infarction (hazard ratio, 2.05; 95% CI, 1.61–2.62; P &lt;0.0001). Conclusions— The majority of deaths are not related to stroke in a contemporary anticoagulated atrial fibrillation population. These results emphasize the need to identify interventions beyond effective anticoagulation to further reduce mortality in atrial fibrillation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00262600.

Thromboembolism in a Patient With a Mechanical Mitral Valve During Anticoagulation With Dabigatran Etexilate

Recently, several new anticoagulants have been used instead of warfarin for preventing thromboembolism. In the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, the direct thrombin inhibitor dabigatran etexilate was as an effective and safe as dose-adjusted warfarin for prevention of stroke in high-risk patients with atrial fibrillation. However, the safety and efficacy of thromboprophylaxis after mechanical valve replacement is uncertain. We report a 57-year-old man with a mechanical heart valve who experienced acute upper limb thromboembolism during dabigatran intake. Dabigatran might be inadequate for thromboprophylaxis after mechanical valve replacement.

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Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: apopulation-based descriptive analysis.

The clinical armamentarium for anticoagulation has expanded substantially since the recent approval of dabigatran, rivaroxaban and apixaban for the prevention of stroke in atrial fibrillation. However, patients in the general population often differ from participants in clinical trials. In this study, we assessed the uptake of these novel oral anticoagulants in Ontario, Canada, within the first 2 years after dabigatran's approval for this indication. Using data on province-wide prescription volumes, we conducted a time-series analysis of prescription trends between October 2010 and September 2012 for all orally administered anticoagulants (warfarin, dabigatran and rivaroxaban) that were available in this period. We stratified dabigatran prescription rates by age group (20-39, 40-59, 60-64, 65-84 and ≥ 85 yr). We compared the proportion of dabigatran prescriptions to patients aged 65 or older with similar data from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. Over the 24-month study period, we found that prescriptions for the novel anticoagulants rose more than 20-fold, to represent 21.1% of all prescriptions of oral anticoagulants by September 2012. The rise in prescriptions was due primarily to an increase in dabigatran use. Prescription rates of dabigatran were highest among people aged 85 years or more, a group at increased risk of bleeding who are markedly older than the average participant in the clinical trial in which the drug was tested (71 yr). In September 2012, most of the dabigatran prescriptions were for the lower-dose formulation (110 mg) in the older groups (58.8% of dabigatran prescriptions in the 65-84 age group and 93.6% in the oldest group). We observed rapid growth in the uptake of the novel oral anticoagulants since their approval for use in patients with atrial fibrillation, especially among those aged 85 years or more. This increase in use in the oldest group, a population at high risk of bleeding, signals the need to evaluate outcomes of use of novel oral anticoagulants in the clinical setting.

The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy)

The goal of this study was to analyze the impact of dabigatran plasma concentrations, patient demographics, and aspirin (ASA) use on frequencies of ischemic strokes/systemic emboli and major bleeds in atrial fibrillation patients. The efficacy and safety of dabigatran etexilate were demonstrated in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, but a therapeutic concentration range has not been defined. In a pre-specified analysis of RE-LY, plasma concentrations of dabigatran were determined in patients treated with dabigatran etexilate 110 mg twice daily (bid) or 150 mg bid and correlated with the clinical outcomes of ischemic stroke/systemic embolism and major bleeding using univariate and multivariate logistic regression and Cox regression models. Patient demographics and ASA use were assessed descriptively and as covariates. Plasma concentrations were obtained from 9,183 patients, with 112 ischemic strokes/systemic emboli (1.3%) and 323 major bleeds (3.8%) recorded. Dabigatran levels were dependent on renal function, age, weight, and female sex, but not ethnicity, geographic region, ASA use, or clopidogrel use. A multiple logistic regression model (c-statistic 0.657, 95% confidence interval [CI]: 0.61 to 0.71) showed that the risk of ischemic events was inversely related to trough dabigatran concentrations (p = 0.045), with age and previous stroke (both p < 0.0001) as significant covariates. Multiple logistic regression (c-statistic 0.715, 95% CI: 0.69 to 0.74) showed major bleeding risk increased with dabigatran exposure (p < 0.0001), age (p < 0.0001), ASA use (p < 0.0003), and diabetes (p = 0.018) as significant covariates. Ischemic stroke and bleeding outcomes were correlated with dabigatran plasma concentrations. Age was the most important covariate. Individual benefit-risk might be improved by tailoring dabigatran dose after considering selected patient characteristics. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600).

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A review of apixaban for stroke prevention in atrial fibrillation: insights from ARISTOTLE

Atrial fibrillation (AF) is associated with significant mortality and morbidity, and stroke represents the most-feared complication. Consequently, AF treatment has focused on thromboprophylaxis, with warfarin as the mainstay of therapy. However, concerns over ease of use and safety have limited its use. Three novel oral anticoagulants have been approved for use in stroke prevention in AF based on randomized data: 1) dabigatran, studied in Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY); 2) rivaroxaban, studied in Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF); and 3) apixaban, studied inApixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE). In this review, we focus on apixaban and discuss subgroup analyses that have been performed in the three trials comparing novel oral anticoagulants with warfarin. We conclude with recommendations regarding further investigations.

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Medical Costs of Oral Anticoagulants vs Warfarin for Atrial Fibrillation Patients with Different Stroke Risks.

IntroductionThe Apixaban for the Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trials demonstrated that the oral anticoagulants (OACs), apixaban, dabigatran, and rivaroxaban, respectively, are efficacious for stroke prevention among nonvalvular atrial fibrillation (NVAF) patients. Based on clinical trial results this study evaluated medical costs of clinical events associated with use of individual OACs relative to those of warfarin in NVAF patients with moderate and high stroke risk.MethodsRates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients with CHADS2 = 2 and ≥3 were determined from the three OAC trials. One-year incremental costs among patients with clinical events from a US payer perspective were obtained from the literature and inflation adjusted to 2010 costs. Medical costs for clinical events associated with each OAC vs. warfarin were estimated and compared.ResultsFor NVAF patients with moderate stroke risk (CHADS2 = 2) differences in clinical event medical costs vs. warfarin were −$298, −$143, and +$117 per patient year for apixaban, dabigatran (150 mg), and rivaroxaban, respectively (negative numbers indicate cost reduction). For NVAF patients with high stroke risk (CHADS2 ≥ 3) differences in clinical event medical costs vs. warfarin were −$697, +$2, and −$100 for apixaban, dabigatran (150 mg), and rivaroxaban, respectively.ConclusionsMedical cost differences associated with OACs vs. warfarin vary according to stroke risk. Of the three OACs, apixaban demonstrated consistent medical cost reductions vs. warfarin for NVAF patients with moderate and high stroke risks.

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The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study

During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses. Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE-eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69-1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04-1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80-1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y. During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death.

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Dabigatran: Is There a Role for Coagulation Assays in Guiding Therapy?

To determine the usefulness of coagulation assay monitoring for dabigatran etexilate in certain high-risk clinical situations. Literature retrieval was accessed through MEDLINE (1948-February 2013), Web of Science (1980-February 2013), International Pharmaceutical Abstracts (1977-February 2013), and Google Scholar using the terms dabigatran, dabigatran etexilate, BIBR 1048, BIBR 953, direct thrombin inhibitor, therapeutic monitoring, and atrial fibrillation. In addition, abstracts presented at the 2011-2012 American Society of Hematology, American College of Cardiology, International Society of Thrombosis and Haemostasis, and European Society of Cardiology annual meetings were reviewed. A search of Clinicaltrials.gov was performed to identify relevant ongoing or completed research. All English-language articles identified from the data sources were evaluated for inclusion. Priority was placed on all data derived from controlled clinical studies. Of the 6 published Phase 3 studies, only the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial evaluated the safety and efficacy of dabigatran for the prevention of stroke in patients with nonvalvular atrial fibrillation. Post hoc analyses of the RE-LY trial have provided additional information in special situations. Several published reports highlight the potential for complications with dabigatran, the importance of determining the most optimal candidates, and the need for therapeutic monitoring. Activated partial thromboplastin time and thrombin time are effective qualitative assays for dabigatran. Ecarin clotting time and the dilute thrombin time (ie, Hemoclot direct thrombin inhibitor) assays are suitable for quantitative measurement. The correlation between coagulation-based assays and clinical out comes among dabigatran-treated patients has not been definitively established. However, coagulation-based assays may be useful in the management of several clinical scenarios.

Modeling of the Impact on Health Outcomes of the Use of Dabigatran in Patients with Atrial Fibrillation

Background: Atrial fibrillation (AF) is the main direct cause of stroke. Prevention by anticoagulation or antithrombotic treatment is required, vitamin K antagonists (VKAs) and aspirin being the main agents. Dabigatran etexilate is a novel oral direct thrombin inhibitor. The RE-LY study demonstrated that in patients with AF, the rates of stroke and systemic embolism were similar (at a dose of 110 mg) or lower (at a dose of 150 mg) than those observed in patients treated with warfarin, a VKA. The aim of the present study was to estimate, through modeling, the number of severe events avoided with dabigatran at dosages of 110 mg (D110) or 150 mg (D150) twice daily compared to warfarin, when prescribed in the French population for patients with AF who meet the inclusion criteria of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study. Methods: We used a decision tree type model to simulate the outcome at 5 years in a cohort of patients eligible for treatment with dabigatran. We compared 3 hypothetical cohorts: all AF patients are treated with D110, D150 and warfarin. Based on the probabilities of occurrence of the different outcomes observed in the RE-LY study and in the Dijon Stroke Registry, we simulated for each year during 5 years the evolution of the 3 cohorts. The model allows to simulate a prevalent cohort of 461,392 patients at year zero, with a follow-up of 5 years (‘constant prevalence model'), and it can also take into account incident patients during 5 years (‘dynamic prevalence model'). The different events taken into account were: major hemorrhages (excluding hemorrhagic strokes), myocardial infarctions, hemorrhagic strokes, ischemic strokes, recurrence of strokes (without differentiating the mechanism) or deaths. Results: Considering the constant prevalence model, the use of D110 instead of warfarin for the whole target population in France would permit to avoid 10,012 events and to save 18,879 years of life in a period of 5 years. These figures are 13,484 and 27,736 for D150 instead of warfarin. Considering the dynamic prevalence model, the use of D110 for the whole target population in France would permit to avoid 13,620 events and to save 22,674 years of life in a period of 5 years. These figures are 18,186 and 33,091 for D150. Conclusion: The use of dabigatran would lead to a significant reduction of strokes and deaths attributable to AF in France.

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Response to Letters Regarding Article, “Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin: Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial”

RE-LY is the largest randomized experience reporting outcomes after interruption of anticoagulant therapy.1 There was no excess of bleeding in patients taking dabigatran, including those having major or urgent surgery.1 David and colleagues correctly state that the majority of procedures performed during the RE-LY trial were minor. Nonetheless, our analysis included 1482 major procedures that had a 6% to 8% rate of major bleeding,1 which was numerically lower among dabigatran-treated patients.1 Hjemdahl et al opine that the high rate of major bleeding in RE-LY patients assigned to dabigatran 150 mg twice daily who had interruption for >72 hours before surgery suggests accumulation of dabigatran in patients with renal impairment. However, data from RE-LY do not support this interpretation, because the same pattern …

Letter by David et al Regarding Article, “Periprocedural Bleeding and Thromboembolic Events With Dabigatran Compared With Warfarin: Results From the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) Randomized Trial”

To the Editor: We read with interest the article recently published by Healey et al1 on the subgroup analysis of periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin. Interestingly, the rate of bleeding was similar in patients taking dabigatran as compared with those taking warfarin. It is also noteworthy that the majority of interventional procedures in this study were procedures with a low bleeding risk. We believe that these observations may limit the conclusion of the study. The authors suggested that the delay for surgery might be shorter with dabigatran than with warfarin. However, we feel that further analysis would have been required to …