Safety Of Novel Oral Anticoagulants Research Articles

Abstract P255: Use of Novel Oral Anticoagulants Among Patients With Atrial Fibrillation Increased Even in Those With Severely Impaired Kidney Function

Novel oral anticoagulants (NOACs) are increasingly prescribed as substitutes for warfarin in patients with atrial fibrillation (AF). All of the NOACs are at least partially renally cleared, but most trials excluded patients with severe kidney dysfunction. Despite this, labels include dosing for creatinine clearance 15-30 ml/min. The objective of the study was to estimate the prevalence of NOAC use over time among people with AF, stratified by stage of chronic kidney disease (CKD). Study population included 17,280 patients with AF and at least one prescribed anticoagulant (warfarin, dabigatran, rivaroxaban, or apixaban) between 2010 and 2016 in the Geisinger Health System, a large rural health care system in Pennsylvania. Medication information was obtained from both medication orders and records. Average age of the study population was 73.6 years, 46.6% (N=8,044) were women, 98.4% (N=17,009) were Non-Hispanic White, and average estimated glomerular filtration rate (eGFR) was 70.2 ml/min/1.73 m 2 . Over the course of 2010-2016, 3.0% (N=513), 6.9% (N=1,184) and 4.6% (N=792) received at least one prescription for dabigatran, rivaroxaban, or apixaban. NOAC ever-users (N=2,392) were younger (69.1 vs. 74.3 years, P <0.001) and had a higher eGFR (77.7 vs. 69.9 ml/min/1.73 m 2 ) than warfarin-only users (N=14,888). Prescription of NOACs increased from 0% to 14.7% from 2010 to 2016 ( P <0.001). Prescription of NOACs increased in each category of CKD (G1-2, G3 and G4-5, all P <0.001) (Figure 1). The most frequently prescribed NOAC in 2016 was rivaroxaban (8.2%) among those with eGFR>60 ml/min/1.73 m 2 and apixaban (5.9% and 4.9%) among those with eGFR 30-60 ml/min/1.73 m 2 and eGFR<30 ml/min/1.73 m 2 , respectively. Among the 22 patients prescribed apixaban with eGFR<30 ml/min/1.73 m 2 in 2016, 22.7% (5 of 22) had eGFR<15 ml/min/1.73 m 2 . In conclusion, NOAC prescriptions increased among patients with AF in all stages of CKD. Further studies to quantify the effectiveness and safety of NOACs compared to warfarin by stage of CKD are warranted.

Efficacy and Safety of Novel Oral Anticoagulants in Patients With Atrial Fibrillation and Heart Failure: A Meta-Analysis

ObjectivesThis study investigated the efficacy and safety of novel oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and heart failure (HF) by a meta-analysis. BackgroundAF is quite prevalent in patients with HF. MethodsFour phase III clinical trials comparing NOACs to warfarin in patients with AF were included. Each patient was defined as affected by HF according to the criteria of the trial in which the patient was enrolled. Pre-specified outcomes were the composite of stroke/systemic embolism (SSE); major, intracranial, and any bleeding; and cardiovascular (CV) and all-cause death. ResultsA total of 55,011 patients were enrolled, 26,384 (48%) with HF, and 28,627 (52%) without HF; 27,518 receiving NOACs and 27,493 receiving warfarin (median, 70 years of age; 36% females; follow-up: 1.5 to 2.8 years). Rates of SSE (relative risk [RR]: 0.98; 95% confidence interval [CI]: 0.90 to 1.07]; p = 0.68) and major bleeding (RR: 0.95; 95% CI: 0.88 to 1.03; p = 0.21) were comparable in patients with and without HF. HF patients had reduced rates of any (RR: 0.86; 95% CI: 0.81 to 0.91; p < 0.01) and intracranial (RR: 0.74 95% CI: 0.63 to 0.88; p < 0.01) bleeding but increased rates of all-cause (RR: 1.70 95% CI: 1.31 to 2.19; p < 0.01) and CV death (RR: 2.05 95% CI: 1.66 to 2.55; p < 0.01). NOACs, compared with warfarin significantly reduced SSE and major, intracranial, and any bleeding, regardless of the presence or absence of HF (pinteraction > 0.05 for each). ConclusionsPatients with AF and HF had increased mortality but reduced rates of intracranial and any bleeding compared with the no-HF patients, with no differences in rates of SSE and major bleeding. NOACs significantly reduced SSE, major bleeding, and intracranial hemorrhage in HF patients. No interactions in efficacy and safety of NOACs were observed between AF patients with and without HF.

Efficacy and Safety of Novel Oral Anticoagulants for Atrial Fibrillation Ablation: An Updated Meta-Analysis.

IntroductionNovel oral anticoagulants (NOACs) have been approved for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). A large number of patients are on NOACs when they present for AF ablation. We intended to evaluate the safety and efficacy of NOACs for AF ablation during the periprocedural period by performing a meta-analysis of trials comparing NOACs with warfarin.MethodsStudies comparing NOACs (dabigatran and rivaroxaban) with warfarin as periprocedural anticoagulants for AF ablation were identified using an electronic search. Primary outcomes were: (1) a composite endpoint of stroke, transient ischemic attack (TIA), peripheral arterial embolism, or silent cerebral lesions on magnetic resonance imaging (MRI) and (2) major bleeding complications. A random effects model was used to pool the safety and efficacy data across all included trials.ResultsWhen compared to warfarin, there was an increased risk of the composite endpoint of stroke, TIA, peripheral arterial embolism, or silent cerebral lesions on MRI with NOACs as periprocedural anticoagulants for AF ablation [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.06–2.68]. Sub-group analysis revealed a higher risk of composite endpoint with dabigatran as a periprocedural anticoagulant for AF ablation (OR: 2.01, 95% CI: 1.19–3.39) whereas the risk was similar with rivaroxaban (OR: 0.90, 95% CI: 0.34–2.41). Sensitivity analysis after excluding silent cerebral lesions on MRI showed there was no increased risk of thromboembolic events with either dabigatran (OR: 1.69, 95% CI: 0.81–3.51) or rivaroxaban (OR: 0.70, 95% CI: 0.12–4.04). Risk of bleeding with NOACs was similar to warfarin (OR: 0.91, 95% CI: 0.62–1.34).ConclusionNOACs are comparable to warfarin in terms of bleeding complications. However, dabigatran therapy is potentially associated with a higher risk of silent cerebral lesions on MRI. The results of this study should be considered as hypothesis-generating and assessed further in prospective randomized clinical studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s40119-016-0061-7) contains supplementary material, which is available to authorized users.

Abstract 2: Comparative Effectiveness and Safety of Anticoagulant Therapy With Warfarin, Dabigatran, Apixaban, or Rivaroxaban in Patients With Nonvalvular Atrial Fibrillation

Background: The efficacy and safety of novel oral anticoagulants (NOACs) as alternatives to warfarin therapy in nonvalvular atrial fibrillation (NVAF) patients have been studied in randomized trials. Given the increasing use of NOACs, additional data is required to assess the relative effectiveness and safety of anticoagulation with warfarin, dabigatran, apixaban, or rivaroxaban therapy in real-world settings in the United States (U.S). Methods: A retrospective cohort study design was used to analyze data from a U.S. commercial claims database of &gt; 38 million members. Study population included new users of warfarin, dabigatran, apixaban, or rivaroxaban aged ≥ 18 years with ≥ 2 diagnoses of NVAF from November 2010 to February 2015. The primary effectiveness outcome was a composite of thromboembolic event or stroke; the primary safety outcome was major bleeding event requiring hospitalization. Cox proportional hazards models with inverse probability of treatment weighting (IPTW) were used to compare event rates between NOAC and warfarin users, and among NOAC users. Results: In the final NVAF cohort studied, there were 23,431 warfarin, 8,539 dabigatran, 3,689 apixaban, and 8,398 rivaroxaban users. A total of 7,022 primary outcome events and 3,264 safety events were identified. Warfarin users were older than dabigatran, apixaban, or rivaroxaban users (mean: 73 vs 66 vs 69 vs 67 years). After IPTW, all treatment groups were balanced on all baseline risk factors including stroke and bleeding risk. Compared to warfarin, NOAC users had fewer thromboembolic events or strokes: dabigatran (hazard ratio HR, 0.77 [95% CI: 0.72 - 0.82]), apixaban (HR, 0.73 [CI: 0.65 - 0.82]), and rivaroxaban (HR, 0.80 [CI: 0.75 - 0.86]). Additionally, dabigatran ([HR], 0.67 [CI: 0.60 - 0.76]), and apixaban users (HR, 0.52 [CI: 0.41 - 0.67) experienced fewer major bleeding events compared to warfarin users. No significant difference was found in major bleeding risk between rivaroxaban (HR, 1.00 [CI: 0.89 - 1.12]) and warfarin users. All three NOAC groups had similar risks for thromboembolic event or stroke: dabigatran vs rivaroxaban (HR, 0.96 [CI: 0.88 - 1.05]); apixaban vs rivaroxaban (HR, 0.91 [CI: 0.80 - 1.04]); dabigatran vs apixaban (HR, 1.05 [CI: 0.93 - 1.19]). However, compared to rivaroxaban users, major bleeding risk was 33% and 48% lower in dabigatran and apixaban users respectively (HR, 0.67[CI: 0.58 - 0.78]) and HR, 0.52 [CI: 0.40 - 0.68]). Conclusions: Our results demonstrated a lower risk of a thromboembolic event or stroke among dabigatran, apixaban, or rivaroxaban users compared to warfarin users. Among NOACs, risks of a thromboembolic event or stroke were similar. Further studies are needed to clarify the finding of a higher major bleeding risk in warfarin and rivaroxaban users.

Clinical Experience of Dabigatran and Rivaroxaban in Electrical Cardioversion of Atrial Fibrillation

&lt;p&gt;Patients scheduled for atrial fibrillation (AF) cardioversion were excluded from clinical trials of novel oral anticoagulants (NOACs).&lt;/p&gt;&lt;p&gt;We evaluated efficacy and safety of NOACs in patients undergoing electrical cardioversion for AF.&lt;/p&gt;&lt;p&gt;We performed a monocentric study of all patients on NOACs who underwent elective electrical cardioversion for non-valvular AF between January 2012 and December 2014. We analyzed incidence of stroke and bleeding at 30 days.&lt;/p&gt;&lt;p&gt;Fifty patients were included, 28 receiving dabigatran, 22 rivaroxaban. Mean age was 65 ± 12 years. Mean CHADS2-VA2SC and HASBLED scores were 3 ± 1.8 and 2.2 ± 1.1 respectively. Transoesophageal echocardiography was performed in 41 (79%) patients, revealing a thrombus in 2 (5%). No clinical evidence of stroke occurred in the 30 days, 1 major gastrointestinal bleeding (2%) in patient on rivaroxaban (led to premature discontinuation) and 3 minor bleedings.&lt;/p&gt;&lt;p&gt;NOACs seem to be safe in daily practice of electrical cardioversion in our population.&lt;/p&gt;

The Use of Oral Anticoagulants for the Treatment of Venous Thromboembolism in Cancer Patients

Background: Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer, second to death caused by cancer itself. Guidelines from the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) support the use of low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) for treatment of VTE in cancer patients. The novel oral anticoagulants (NOACs) are increasingly being used for all types of VTE, but their safety and efficacy in cancer-associated VTE has not been established. In the CLOT trial of LMWH in cancer-associated VTE, the rate of recurrent VTE was 9.0%, compared to 5.1% among the subgroup of cancer patients who received rivaroxaban in the EINSTEIN trial; bleeding rates among cancer patients in the CLOT and EINSTEIN trials were 14% and 15.2%, respectively. Due to a paucity of data, at this point neither the NCCN nor ASCO supports the use of NOACs for treatment of cancer-associated VTE.Objective: Evaluate the efficacy and safety of NOACs in cancer-associated VTE.Methods: We performed a retrospective chart review of all patients with a diagnosis of active malignancy who received a prescription for a NOAC for treatment of VTE at Yale Cancer Center between February 1, 2012, and December 31, 2014. Patients with a heritable thrombophilia or bleeding disorder were excluded. Data collected included patient demographics, body mass index (BMI), cancer type and stage, type of VTE event (deep venous thrombosis (DVT), pulmonary embolism (PE), or both), type of NOAC, compliance with NOAC therapy, appropriate NOAC dose, and potential drug-drug interactions (DDI) with NOACs. Primary outcomes were recurrent VTE, defined as the finding of new or progressive DVT or PE on imaging with or without symptoms, and clinically relevant bleeding (CRB), defined as a decrease in hemoglobin of at least 2 g/dL in a 24-hour period, a requirement for red blood cell transfusion, any critical site bleeding event, or any type of bleeding event requiring increased physician monitoring. Fisher's exact test was used to calculate p-values where appropriate.Results: 75 patients met inclusion criteria; rivaroxaban was the only NOAC used in all cases. The incidence of recurrent VTE and CRB was 7.0% (n = 5) and 25.3% (n = 19), respectively. There were two fatal events, one due to recurrent VTE and one due to major gastrointestinal bleed; in neither case was NOAC compliance, dosing, or DDIs implicated in the fatality. Over half (n = 39) of all study patients were on a concomitant medication with a known DDI with NOAC therapy; the most common such agents were ciprofloxacin, fluconazole, azithromycin and voriconazole. In only one of the 80 DDI cases was anticoagulation therapy changed. NOAC dosing was inappropriate in 20 instances, mostly due to patients not receiving the recommended loading dose prior to beginning maintenance dosing. Among the 19 occurrences of CRB, advanced stage solid tumor emerged as a statistically significant (p = 0.0151) risk factor for bleeding while on rivaroxaban.Conclusion: Treatment of cancer-associated VTE with NOAC therapy is effective, but the risk of bleeding in our cohort was higher than in other published studies. Patients with advanced stage solid tumors may be at a particularly high risk of bleeding. Prescriber practices with NOACs may require modification based on high utilization of concomitant medications with DDIs and failure to prescribe appropriate loading doses of NOACs in treatment of VTE. DisclosuresNo relevant conflicts of interest to declare.

Abstract 16326: Safety and Efficacy of Novel Oral Anticoagulants in Subjects With Atrial Fibrillation in Relation to Renal Function: Meta-analysis of Randomized Clinical Trials

Introduction: The efficacy and safety of novel oral anticoagulants (NOACs) has not been assessed in subjects with renal impairment. Methods: We performed a meta-analysis of RCTs comparing NOACs with warfarin in patients with atrial fibrillation (AF), in relation to renal function estimated by glomerular filtration rate (GFR): normal (GFR&gt;80 ml/min/1.73m2), mild (50-80 mL/min/1.73m2), and moderate (&lt;50 mL/min/1.73m2) impairment. MEDLINE, Embase, Web of Science and the Cochrane Library were searched to identify articles published up to the third week of January 2015. Data were supplemented with FDA data. Data on stroke or systemic embolism (S/SE) and major bleeding according to renal function were collected and extracted. We estimated the pooled relative risk (RR) of S/SE and major bleeding, for NOACs compared to warfarin. Results: We retrieved four randomized clinical trials (each randomizing dabigatran, rivaroxaban, apixaban, or endoxaban versus warfarin) enrolling a total of 58338 subjects, 29123 randomized to NOACs and 29123 randomized to warfarin; 21132 had normal renal function, 13126 had mild and 11027 had moderate renal impairment. In subjects with moderate renal impairment, compared to warfarin, NOACs reduced the risk of S/SE (RR 0.8; 95% CI 0.68-0.94) and major bleeding (RR 0.80; 95% CI 0.71-0.91). In subjects with mild renal impairment NOACs were associated with a reduced risk of S/SE (RR 0.75; 95% CI 0.66-0.85) and major bleeding (RR 0.87; 95% CI 0.79-0.95). In subjects with normal renal function no difference in the risk of S/SE was observed, while the risk of major bleeding was slightly less for subjects taking NOACs (RR 0.87; 95% CI 0.76-0.99). The test for interaction among groups of renal function was borderline significant for S/SE, but not for major bleeding. Conclusions: The use of NOACs was associated with a reduced risk of S/SE in subjects with mild or moderate renal impairment; while the risk of bleeding was reduced by NOACs compared to warfarin.

Efficacy and safety of novel oral anticoagulants in patients with bioprosthetic valves.

Prosthetic valve replacement is performed in several hundred thousand patients worldwide annually, and many of these patients have or will ultimately develop atrial fibrillation or flutter (AF). Novel oral anticoagulants (NOACs) are not recommended in patients with AF and mechanical valves but have not been evaluated in patients with bioprosthetic valves. This study sought to evaluate the efficacy and safety of NOACs in patients with AF and bioprosthetic valves. A retrospective single-center cohort study was performed on all patients with bioprosthetic valve implantation, for whom a NOAC was prescribed for the indication of AF. Patients were evaluated for thromboembolic events including imaging confirmed ischemic stroke, clinically suspected transient ischemic attack, and major bleeding events (according to International Society on Thrombosis and Hemostasis definition). In total, 73 patients (26 female, 35.6 %) were identified. NOAC therapy began, on average, 990.0 ± 1029.1 days after bioprosthetic valve implantation for an average duration of 511.8 ± 400.8 days. Aspirin was used concomitantly in a majority of patients (72.6 %). There were no ischemic strokes identified (0.0 %) and one possible TIA (1.4 %). There were 6 (8.2 %) minor and 5 (6.9 %) major bleeding events. The use of NOAC therapy for AF in patients with bioprosthetic valves appears safe and effective in the occurrence of thromboembolic events, however, at the expense of increased bleeding. Larger studies are necessary to confirm these findings.

Comparative efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation: A network meta-analysis with the adjustment for the possible bias from open label studies

BackgroundThis study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date. MethodWe performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002–2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed. ResultsA systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban. ConclusionsOur indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system.

We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS). We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications. DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively). The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.

New oral anticoagulants versus vitamin K antagonists for treatment of acute venous thromboembolism: do they really increase the incidence of myocardial infarction?

Venous thromboembolism (VTE) is the third commonest cause of cardiovascular disease in the Western countries after coronary artery disease and stroke with 28 days mortality rate of 11 % for all VTE, and 25 % for cancerassociated VTE [1]. It is estimated that up to one-fifth of patients may have a fatal pulmonary embolism before diagnosis, or on the first day after diagnosis [2, 3]. The novel oral anticoagulants (NOACs), which include the direct thrombin inhibitor (DTI) dabigatran and the factor Xa inhibitors (FXaI) rivaroxaban, apixaban and edoxaban, are at least as effective as warfarin for the treatment of acute VTE [4–10]. Loffredo et al. in this issue, have confirmed these findings in their recent meta-analysis of these RCTs, and showed similar rates of recurrent VTE and all-cause mortality, but significantly lower rates of major bleeding with NOACs as compared with warfarin [11]. Their findings are in keeping with other meta-analyses that have examined the efficacy and safety of NOACs for the treatment of acute VTE [12–17]. The authors also found that NOACs increased the risk of MI in this cohort. However, the estimates were not significant when analyzed separately according to the drug class: DTI [risk ratio (RR) 2.49; 95 % CI 0.82–7.55] and FXaI (RR 2.62; 95 % CI 0.82–8.39). Furthermore, these trials were not designed to compare the rates of MI in the NOACs and warfarin treatment arms, and MI was a secondary safety outcome. The majority of the included trials did not describe the baseline cardiovascular disease status and concomitant use of antiplatelet drugs [4–9]. Finally, the event rates for MI were relatively small in these trials. We agree with the authors that their finding of a ‘MI signal’ among NOAC-treated patients with VTE is hypothesisgenerating, but the overall question of an association between NOACs, in particular dabigatran, and MI is debatable. Our objective is to chart the course of this controversy, to summarize past and emerging data, and to discuss planned studies that, taken together, should inform readers about this issue. A possible association between NOACs and MI was first raised in the RE-LY trial, which showed that dabigatran 150 mg b.i.d. was associated with a higher risk for MI in patients with atrial fibrillation (AF) than warfarin [hazard ratio (HR) 1.38; 95 % CI 1.00–1.91). However, a re-analysis of the RE-LY trial that was supplemented by additional data, showed no significant increase in MI risk with dabigatran (RR 1.27; 95 % CI 0.94–1.71) [18], and no significant effect on fatal MI (HR 0.76; 95 % CI 0.31–1.89) [19]. More recently, several meta-analyses have assessed an association between DTIs and MI and, overall, provide conflicting results. Atang et al. in a meta-analysis of 11 trials, showed that DTIs (dabigatran, ximelagatran, and AZD0837) significantly increase MI risk [odds ratio (OR) 1.35; 95 % Cl 1.10–1.66] [20]. Mak showed a significant increase composite risk of unstable angina, MI or cardiac death with dabigatran as compared with either placebo, enoxaparin or warfarin (OR 1.30; 95 % CI 1.04–1.63) [21]. Loffredo et al. in a separate meta-analysis, found that, compared with warfarin, the MI rate was significantly & James Douketis jdouket@mcmaster.ca

Abstract 215: Efficacy and Safety of Novel Oral Anticoagulants (NOACs) in Asian population with Non-Valvular Atrial Fibrillation (NVAF) - A Meta-Analysis

Background and purpose: Asians have higher risk of intracranial hemorrhage (ICH) compared to non-Asians. Although recent clinical trials have shown non-vitamin K antagonist oral anticoagulants (NOACs) were favorable in preventing ICH as well as thrombotic events among patients with non-valvular atrial fibrillation (NVAF), it is unclear whether the efficacy and safety of NOACs are consistent among Asians. The purpose of this study is to assess the efficacy and safety of NOACs in Asians with NVAF. Methods: PubMed, Embase, Cochrane Central, Web of Science, the Western Pacific Index Medicus, Clinicaltrials.Gov and supplemented with conference abstracts were searched up to June 2014. Phase III randomized control trials that reported efficacy and safety of NOACs vs. warfarin in Asians and non-Asians with NVAF were identified. Each study was reviewed by two reviewers and differences were resolved by consensus. The end points analyzed were all stroke or systemic embolism, ischemic and hemorrhagic stroke, major or clinically relevant non major bleeding events (CRNM), and ICH. The hazard ratio (HR) with 95% confidence interval (CI) of each endpoint in NOACs compared to warfarin was extracted separately among Asians and non-Asians. Random-effects models were used to calculate pooled HR and 95% CI. Results: 5 eligible studies were identified. Total of 8928 Asians and 64023 non-Asians were included. All stroke or systemic embolism were significantly reduced with NOACs in Asians (HR: 0.72 [95% CI: 0.59-0.88], p=0.002) but not in non-Asians (HR: 0.82 [0.66-1.01], p=0.097). The risk of ischemic stroke was not decreased in Asians (HR: 0.88 [0.64-1.21], p=0.43) or non-Asians (HR: 0.98 [0.80-1.12], p=0.73), whereas the risk of hemorrhagic stroke was significantly decreased in both groups (HR: 0.28 [0.17-0.47], p&lt;0.001 for Asians, HR: 0.37 [0.24-0.55], p&lt;0.001, respectively). The risk of major bleeding or CRNM was significantly reduced in Asians (HR: 0.68 [0.56-0.83], p&lt;0.001) but not in non-Asians (HR: 0.78 [0.60-1.0], p=0.21). The risk of ICH was significantly decreased in both groups (HR: 0.30 [0.21-0.42], p&lt;0.001, HR: 0.41 [0.34-0.48], p&lt;0.001, respectively). Conclusions: The efficacy and safety of NOACs in Asians with NVAF is consistent with the overall results.

Efficacy and safety of novel oral anticoagulants in clinical practice: a report from three centers in Sweden.

IntroductionIn clinical trials new oral anticoagulants (NOAC) have proved to be as effective as warfarin for thromboprophylaxis in atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of these drugs in clinical practise.Methods and resultsAll patients treated with new oral anticoagulants at Skåne University hospital and Halland County Hospital Halmstad between 2009 and September 2013 was identified in the Swedish national quality registry for atrial fibrillation and anticoagulation (AuriculA). Medical records were reviewed to identify thromboembolism and major bleeding and compared to a warfarin cohort with a time in therapeutic range (TTR) of 76%. There were 826 patients, mean age 70.6, follow up 591 years, with atrial fibrillation treated with NOAC. Dabigatran was the initial drug in 79% of the cohort. The incidences of ischemic stroke/ TIA and major bleeding were 1.9 (95% CI; 1.0-3.2) and 2.0 (95% CI; 1.1-3.5) per 100 patient-years respectively. The corresponding incidences for warfarin were 1.5 (95% CI; 1.0-2.2) and 2.5 (95% CI; 1.8-3.3), with no statistical significance between the groups. Two subdural hematomas occurred 0.4 (95% CI; 0.06-1.1) per 100 patient-years. Mean age of patients with complications was 77.9 (±5.9) and 69.3 (±11.3) for those without (p < 0.001). The discontinuation rate was 6.5% and 1.7% was due to dyspepsia for dabigatran, lower than the RE-LY trial.ConclusionThis study, largely based on dabigatran shows that treatment is efficient and safe in everyday clinical practice and not significantly different compared to a warfarin cohort with tight anticoagulation control.Electronic supplementary materialThe online version of this article (doi:10.1186/s12959-014-0029-6) contains supplementary material, which is available to authorized users.

Efficacy and Safety of Novel Oral Anticoagulants in Patients with Cervical Artery Dissections

Background: American and European guidelines support antiplatelet agents and anticoagulants as reasonable treatments of cervical artery dissection (CAD), though randomized clinical trials are lacking. The utility of novel oral anticoagulants (NOAC), effective in reducing embolic stroke risk in non-valvular atrial fibrillation (NVAF), has not been reported in patients with CAD. We report on the use, safety, and efficacy of NOACs in the treatment of CAD. Methods: We retrospectively identified patients diagnosed with CAD at a single academic center between January 2010 and August 2013. Patients were categorized by their antithrombotic treatment at hospital discharge with a NOAC (dabigatran, rivaroxaban, or apixaban), traditional anticoagulant (AC: warfarin or treatment dose low-molecular weight heparin), or antiplatelet agent (AP: aspirin, clopidogrel, or aspirin/extended-release dypyridamole). Using appropriate tests, we compared the baseline medical history, presenting clinical symptoms and initial radiographic characteristics among patients in the 3 treatment groups. We then evaluated for the following outcomes: recurrent stroke, vessel recanalization, and bleeding complications. p values <0.05 were considered significant. Results: Of the 149 included patients (mean age 43.4 years; 63.1% female; 70.5% vertebral artery CAD), 39 (26.2%), 70 (47.0%), and 40 (26.8%) were treated with a NOAC, AC, and AP, respectively. More patients with severe stenosis or occlusion were treated with NOAC than with AC or AP (61.8 vs. 60.0 vs. 22.5%, p = 0.002). Other baseline clinical and radiographic findings, including the presence of acute infarction and hematoma, did not differ between the 3 treatment groups. One hundred and thirty-five (90.6%) patients had clinical follow-up (median time 7.5 months) and 125 (83.9%) had radiographic follow-up (median time 5 months) information. There were 2 recurrent strokes in the NOAC group and 1 in each of the AC and AP groups (p = 0.822). There were more major hemorrhagic events in the AC group (11.4%) compared to the NOAC (0.0%) and AP (2.5%) groups (p = 0.034). Three patients treated with NOAC and none treated with AC or AP had a worsened degree of stenosis on follow-up imaging (8.6 vs. 0.0 vs. 0.0%, p = 0.019). Conclusion: Compared to traditional anticoagulants for CAD, treatment with NOACs is associated with similar rates of recurrent stroke, fewer hemorrhagic complications, but greater rates of radiographic worsening. These data suggest that NOACs may be a reasonable alternative in the management of CAD. Prospective validation of these findings is needed.

O4.01: Safety of novel oral anticoagulants in very elderly patients with non valvular atrial fibrilation: clinical practice vs clinical trials

O4.01: Safety of novel oral anticoagulants in very elderly patients with non valvular atrial fibrilation: clinical practice vs clinical trials

Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta‐analysis

New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable efficacy to that of vitaminK antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta-analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE. We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random-effects models. Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval [CI]0.74-1.05), 1.02 (95%CI0.39-5.96), and 0.97 (95%CI0.83-1.14), respectively. The RR for major bleeding was 0.60 (95%CI0.41-0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95%CI0.15-0.87) and 1111. A fixed-effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban. NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high.

The efficacy and safety of novel oral anticoagulants for the preventive treatment in atrial fibrillation patients: a systematic review and meta-analysis

Background: Novel oral anticoagulants, including direct factor Xa inhibitors and direct factor IIa inhibitors, have been used to prevent stroke in patients with atrial fibrillation (AF) for a decade. In this study, the efficacy and safety of the novel oral anticoagulants were assessed in AF patients.Methods: No language restrictions were applied. Study selection and data extraction were carried out by searching PubMed, EMBASE, OVID, the BIOSIS, the Web of Science, Clinical Trials Registers, Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. Each database was searched from its inception date to June 2013. Using odds ratio (OR) as an indicator, we systematically evaluated the primary efficacy endpoints and safety endpoints, as well as 10 secondary endpoints.Result: Compared to the control drugs, the novel oral anticoagulants showed an OR decreased by 26% (OR: 0.74, 95% confidence interval (CI): 0.62–0.88) for stroke or systemic embolism, decreased by 24% (OR: 0.76, 95% CI: 0.64–0.90) for major bleeding, decreased by 10% (OR: 0.90, 95% CI: 0.84–0.95) for death from any cause, decreased by 27% for disabling or fatal stroke (OR: 0.73, 95% CI: 0.54–0.97), decreased by 31% (OR: 0.69, 95% CI: 0.60–0.8) for fatal bleeding, and decreased by 8% (OR: 0.92, 95% CI: 0.88–0.95) for serious adverse events. However, there was no significant difference in acute myocardial infarction, systemic embolism, major bleeding or clinically relevant non-major, all bleeding events, all adverse events and liver function disorder, between the novel oral anticoagulants and control drugs (p > 0.05).Conclusions: Compared to the control drugs, the novel oral anticoagulants showed higher efficiency and safety in patients with AF, as evidenced by their superior performance not only in reducing the risk of stroke or systemic embolism with a lower risk of major bleeding but also in decreasing the incidence of death from any cause, disabling or fatal stroke, serious adverse events and fatal bleeding.

POSSIBILITY OF NOVEL ORAL ANTICOAGULANTS USAGE DURING ABLATION IN ATRIAL FIBRILLATION

The review provides the data on contemporary approaches to anticoagulant therapy during catheter radiofrequency ablation of atrial fibrillation. The opportunities are discussed for various types of periprocedural use of warfarin, and the results mentioned for the efficacy and safety of novel oral anticoagulants in catheter ablation.

Design and rationale of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation: A global registry program on long-term oral antithrombotic treatment in patients with atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 1% to 2% of the population and raising the risk of stroke 5-fold. Until recently, the only treatment choices for stroke prevention in patients with AF have been vitamin K antagonists (VKA) or antiplatelet drugs. With approval of novel oral anticoagulants (NOACs) antithrombotic treatment, patterns are changing. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation is designed to investigate patient characteristics influencing choice of antithrombotic treatment of stroke prevention in patients with nonvalvular AF and to collect data on outcomes of antithrombotic therapy in clinical practice. The GLORIA-AF is a large, international, observational registry involving patients with newly diagnosed nonvalvular AF at risk for stroke, enrolling up to 56,000 patients in nearly 50 countries. We will collect and analyze data from routine care using an inception cohort design. Phase I includes patients before approval of NOACs. Phase II, beginning early after approval of dabigatran, monitors dabigatran safety and addresses potential channeling across treatment options based on propensity scoring to assess comparability of baseline characteristics of patients treated with dabigatran or VKA. Phase III entails analysis of large treatment groups, adjusting for differences in propensity score, to provide information about the relative effectiveness and safety of NOACs and VKA in routine clinical care. Novel features of this registry program will add data from clinical practice to those from randomized trials to expand knowledge of antithrombotic treatment in patients with AF.

Comparative efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation: a network meta-analysis with the adjustment for the possible bias from open label studies

Abstract Background This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date. Method We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002–2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed. Results A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150 mg 0.77; edoxaban 60 mg 0.87; rivaroxaban 0.86] except for dabigatran 110 mg and edoxaban 30 mg. Apixaban and edoxaban 30 mg and 60 mg had significantly fewer major bleeding events than dabigatran 150 mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110 mg and 150 mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60 mg, and rivaroxaban. Conclusions Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.