Abstract 18597: Systemic, Non-cerebral, Arterial Embolism in 21,105 Patients with Atrial Fibrillation Randomized to Edoxaban or Warfarin: Results from the ENGAGE AF-TIMI 48 Trial

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Bram J Geller ◽  
Christian T Ruff ◽  
Robert P Giugliano ◽  
Sabina A Murphy ◽  
James J Hanyok ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Primary Endpoint ◽  
Low Dose ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Systemic Embolism ◽  
Arterial Embolism ◽  
Once Daily ◽  
Permanent Atrial Fibrillation ◽  
Multiple Trials

Background: Atrial fibrillation (AF) is widely recognized as a major risk factor for stroke and systemic embolism. Multiple trials comparing warfarin with factor specific oral anticoagulants have demonstrated that the newer agents are at least as effective as and generally safer than warfarin. However, none of these studies has provided a detailed analyses regarding systemic embolism, the less frequent component of the primary endpoint. Methods and Results: We did a prespecified analysis of data from the 21,105 patients with AF enrolled into ENGAGE AF-TIMI 48, a randomized trial comparing two once-daily regimens of edoxaban (high- and low-dose) with warfarin for the prevention of stroke and systemic embolism. Of the 1,016 patients who met the primary endpoint, 67 (6.6%) had a systemic embolic event (SEE) of which 13% were fatal. Risk factors for systemic embolism versus stroke include age (78 versus 74 years; P=0.005), permanent atrial fibrillation (72% versus 54%; P=0.009), and creatinine clearance ≤ 50 mL/min (42% versus 27%; P=0.01). Of the 73 total SEEs (includes multiple events), 62 involved the extremities (85%) and 30 required a surgical or percutaneous intervention (41%). In a meta-analysis of the four major trials comparing novel oral anticoagulants (NOACs) versus warfarin, the NOACs reduce the risk of SEE compared to warfarin (relative risk, 0.63; 95% confidence interval, 0.43 to 0.91; P=0.01), with less bleeding and a better safety profile. Conclusion: Although less frequent than stroke, systemic embolism results in significant morbidity and mortality in patients with AF. In a meta-analysis, NOACs reduce the risk of SEEs compared to warfarin.

scholarly journals Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis

BMJ ◽  
2017 ◽  
pp. j5058 ◽  
Author(s):  
José A López-López ◽  
Jonathan A C Sterne ◽  
Howard H Z Thom ◽  
Julian P T Higgins ◽  
Aroon D Hingorani ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Systematic Review ◽  
Cost Effectiveness ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Randomised Trials ◽  
Systemic Embolism ◽  
Once Daily ◽  
Effectiveness Analysis

Abstract Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation. Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library. Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation. Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin. Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis. Systematic review registration PROSPERO CRD 42013005324.

Abstract 223: Impact of Differences in Once- vs Twice-Daily Medications Adherence on the Risk of Bleed and Stroke in Non-Valvular Atrial Fibrillation: Analysis of Randomized Trials and Claims Data Sources

2017 ◽  
Vol 10 (suppl_3) ◽  
Author(s):  
Colleen A McHorney ◽  
Eric D Peterson ◽  
Mike Durkin ◽  
Veronica Ashton ◽  
François Laliberté ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Stroke Risk ◽  
Claims Data ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Once Daily ◽  
Cardiovascular Medications ◽  
One Year ◽  
The Impact ◽  
Similar Risk

Background: In non-valvular atrial fibrillation (NVAF) patients, those receiving once-daily (QD) versus twice-daily (BID) non vitamin-K antagonist oral anticoagulants (NOACs) may have better medication adherence. The impact on stroke and bleed risk is not known. Objective: To estimate the impact of adherence differences between QD vs BID therapies on bleed and stroke risks in NVAF patients. Methods: The relation between adherence (proportion of days covered [PDC]) for QD vs BID NOACs and one year bleed risk was modeled using claims data from Truven Health Analytics MarketScan databases (7/2012-10/2015). Next, the relation between adherence and bleeding was calibrated to match that seen in the placebo and NOAC arms of previous randomized controlled trials (RCTs). Finally, we used adherence rates for QD (PDC=0.849) and BID (PDC=0.738) cardiovascular medications from a meta-analysis (Coleman et al.). These rates were used in the calibrated model to estimate bleeds. An analogous method was applied to evaluate the impact of QD vs BID adherence on stroke risk. Results: The relation between PDC and risks of bleed and stroke was modeled using claims data (N=65,022) and calibrated using RCTs. In the calibrated model, compared with BID dosing, QD dosing was associated with 81 fewer strokes (34% reduction) and 14 more bleeds (6% more) per 10,000 patients/year (Figure). Conclusion: Among NVAF patients, better adherence to QD dosing was associated with a significantly lower stroke risk of QD but similar risk of bleed.

Edoxaban versus placebo, aspirin, or aspirin plus clopidogrel for stroke prevention in atrial fibrillation

2015 ◽  
Vol 114 (08) ◽  
pp. 403-409 ◽  
Author(s):  
Lars Rasmussen ◽  
Torben Larsen ◽  
Andrew Blann ◽  
Flemming Skjøth ◽  
Gregory Lip
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Trial ◽  
Real World ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Published Data ◽  
Real World Data ◽  
Once Daily ◽  
Increased Risk ◽  
Reduced Risk

SummaryAs non-valvular atrial fibrillation (AF) brings a risk of stroke, oral anticoagulants (OAC) are recommended. In ‘real world’ clinical practice, many patients (who may be, or perceived to be, intolerant of OACs) are either untreated or are treated with anti-platelet agents. We hypothesised that edoxaban has a better net clinical benefit (NCB, balancing the reduction in stroke risk vs increased risk of haemorrhage) than no treatment or anti-platelet agents. We performed a network meta-analysis of published data from 24 studies of 203,394 AF patients to indirectly compare edoxaban with aspirin alone, aspirin plus clopidogrel, and placebo. Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin. Compared to aspirin plus clopidogrel, there was a lower risk of intra-cranial haemorrhage (ICH). Edoxaban 60 mg once-daily had a reduced risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel. Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo. With overall reduced risk of ischemic stroke and ICH, both edoxaban doses bring a NCB of mean (SD) 1.68 (0.15) saved events per 100 patients per year compared to anti-platelet drugs in a clinical trial population. The NCB was demonstrated to be lower, at 0.77 (0.12) events saved (p< 0.01) when modeled to data from a ‘real world’ cohort of AF patients. In conclusion, edoxaban is likely to provide even better protection from stroke and ICH than placebo, aspirin alone, or aspirin plus clopidogrel in both clinical trial populations and unselected community populations. Both edoxaban doses would also bring a positive NCB compared to anti-platelet drugs or placebo/non-treatment based on ‘real world’ data.Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief.

3054Efficacy and safety of non-vitamin K oral anticoagulants in patients with atrial fibrillation and cancer

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
I Cavallari ◽  
G Verolino ◽  
G Patti
Keyword(s):  
Atrial Fibrillation ◽  
Venous Thromboembolism ◽  
Intracranial Hemorrhage ◽  
Major Bleeding ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Efficacy And Safety ◽  
Systemic Embolism ◽  
Patients With Cancer ◽  
All Cause Mortality

Abstract Background Anticoagulation in patients with cancer and atrial fibrillation (AF) is particularly challenging given the higher risk of both thrombotic and bleeding complications in this setting. Data regarding the efficacy and safety of non-vitamin K oral anticoagulants (NOACs) in AF patients with malignancy remain unclear. Purpose In the present meta-analysis we further investigate the efficacy and safety of NOACs compared to warfarin in patients with AF and cancer assuming that available studies may be individually underpowered for endpoints at low incidence, i.e. stroke, major and intracranial bleeding. Methods We performed a systematic review and meta-analysis of studies comparing the use of NOACs vs. warfarin in AF patients with cancer. Efficacy outcome measures included stroke or systemic embolism, venous thromboembolism and mortality. Safety outcome measures were major bleeding and intracranial hemorrhage. Results We pooled data from 6 identified studies enrolling a total of 31,756 AF patients with cancer. Mean follow-up was 1.7 years. Patients with cancer had significantly increased annualized rates of venous thromboembolism (1.38% vs. 0.74%), major bleeding (9.01% vs. 5.13%), in particular major gastrointestinal bleeding (2.38% vs. 1.60%), and all-cause mortality (17.73% vs. 8.50%) vs. those without (all P values <0.001), whereas the incidence of stroke or systemic embolism and intracranial hemorrhage did not differ. Compared with warfarin, treatment with NOACs nominally decreased the risk of stroke or systemic embolism (5.41% vs. 2.70%; odds ratio, OR; 95% confidence intervals, CI 0.51, 0.26–1.01; P=0.05; Figure), mainly of ischemic stroke (OR 0.56; 95% CI 0.35–0.89; P=0.01), and the risk of venous thromboembolism (OR 0.51; 95% CI 0.42–0.61; P<0.001). In cancer patients receiving NOACs there was a significant reduction of major bleeding (3.95% vs. 4.66%; OR 0.66, 95% CI 0.46–0.94; P=0.02; Figure) and intracranial hemorrhage (0.26% vs. 0.66%; OR 0.25, 95% CI 0.08–0.82; P=0.02) vs. warfarin, with no difference in gastrointestinal major bleeding rates. Conclusion AF patients on oral anticoagulation and concomitant cancer are at higher risk of venous thromboembolism, major bleeding and all-cause mortality. NOACs may represent a safer and more effective alternative to warfarin also in this setting of patients.

Efficacy and Safety of Nonvitamin K Oral Anticoagulants in Patients with Atrial Fibrillation and Cancer: A Study-Level Meta-Analysis

2019 ◽  
Vol 120 (02) ◽  
pp. 314-321 ◽  
Author(s):  
Ilaria Cavallari ◽  
Giuseppe Verolino ◽  
Silvio Romano ◽  
Giuseppe Patti
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Venous Thromboembolism ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
Intracranial Bleeding ◽  
Efficacy And Safety ◽  
Systemic Embolism ◽  
Primary Analysis ◽  
Patients With Cancer

Abstract Objectives In this study-level meta-analysis, we evaluated the clinical outcome with nonvitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients with cancer. Background Anticoagulation in AF patients with cancer is challenging given the coexistence of elevated thrombotic and bleeding risk. The efficacy and safety of NOACs in this setting remain unclear. Methods We included three randomized trials in our primary analysis (N = 2,661 patients) and three observational studies in our secondary, confirmatory analysis (N = 21,112 patients). Outcome measures were: the composite of any stroke or systemic embolism, ischemic stroke, venous thromboembolism, major bleeding, intracranial bleeding; and all-cause death. Mean follow-up duration was 2.2 years. Results In the primary analysis, the use of NOACs was associated with similar incidence of stroke/systemic embolism (odds ratio [OR] 0.70, 95% confidence interval 0.45–1.09; p = 0.11), ischemic stroke (OR 0.71, 0.31–1.64; p = 0.42), venous thromboembolism (OR 0.91, 0.33–2.53; p = 0.86), all-cause death (OR 1.02, 0.72–1.42; p = 0.93), and major bleeding (OR 0.81, 0.61–1.06; p = 0.13) compared with VKAs. The occurrence of intracranial bleeding was significantly lower in the NOACs versus VKAs group (OR 0.11, 0.02–0.63; p = 0.01). These results were overall confirmed in the secondary analysis, where there was additionally a significant reduction of stroke/systemic embolism, ischemic stroke, and venous thromboembolism with NOACs. Conclusion In AF patients with malignancy, NOACs appear at least as effective as VKAs in preventing thrombotic events and reduce intracranial bleeding. NOACs may represent a valid and more practical alternative to VKAs in this setting of high-risk patients.

Indirect Comparisons of the New Oral Anticoagulants in Patients with Non-Valvular Atrial Fibrillation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4363-4363 ◽  
Author(s):  
Shabnam Zolfaghari ◽  
Job Harenberg ◽  
Svetlana Marx ◽  
Martin Wehling
Keyword(s):  
Atrial Fibrillation ◽  
Ischemic Stroke ◽  
Conflicts Of Interest ◽  
Controlled Trial ◽  
Meta Analysis ◽  
Oral Anticoagulants ◽  
New Oral Anticoagulants ◽  
Efficacy And Safety ◽  
Systemic Embolism ◽  
Indirect Comparisons

Abstract Abstract 4363 The efficacy and safety of new oral anticoagulants has been demonstrated for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) by dabigatran in the RE-LY trial (150mg and 110mg bid), rivaroxaban in the ROCKET AF trial (20mg od), and apixaban in the ARISTOTLE trial (5mg bid) versus INR-adjusted warfarin. Direct comparisons of the NOACs in this indication are unlikely to be performed. A total of 4 indirect comparisons of these trials on the efficacy and safety of NOACs in patients with NVAF have now been published within only 3 months (Lip et al 2012, Harenberg et al 2012, Mantha et al 2012, Wells et al 2012). Here, we compare the results of these 4 network meta-analysis (NMA). In all 4 NMAs of the 3 new oral anticoagulants dabigatran (150mg bid) showed superior efficacy in preventing ischemic stroke plus systemic embolism to dabigatran (110mg bid, p<0.04) and rivaroxaban (p<0.04). Apixaban had equivalent efficacy with rivaroxaban and dabigatran (either dose). Apixaban was safer (less major bleeding) than dabigatran (150mg bid, p<0.04) or rivaroxaban (p<0.005). Intracerebral haemorrhage occurred with equal frequency for all agents and regimens except for rivaroxaban (higher risk than dabigatran 110mg bid, p<0.005). Myocardial infarction occurred less frequently with rivaroxaban and apixaban compared to either dose of dabigatran (all p<0.05). All-cause mortality was not different for any agent or regimen. Some minor differences between the NMAs may result from the approved doses of dabigatran by the FDA (150mg bid and 75mg bid) and EMA (150mg bid and 110mg bid), as the inclusion of the 110 mg bid dose of dabigatran into the NMA may not be seen relevant in the US. Based on this comparison, doctors and patients have to decide which suggestions of the 4 groups of authors seem more convincing: to change to or to start with one of the NOACs depending on the individual thrombotic or bleeding risk or to wait for the results from a large (and expensive) head-to-head randomised controlled trial which may take years to perform. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Benefits and Harms of Low-Dose Rivaroxaban in Asian Patients With Atrial Fibrillation: A Systematic Review and Meta-analysis of Real-World Studies

2021 ◽  
Vol 12 ◽  
Author(s):  
Jun Qian ◽  
Yi-Dan Yan ◽  
Sheng-Yan Yang ◽  
Chi Zhang ◽  
Wen-Yan Li ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Systematic Review ◽  
Regression Analysis ◽  
Low Dose ◽  
Meta Analysis ◽  
Systemic Embolism ◽  
Asian Patients ◽  
Meta Regression ◽  
Meta Regression Analysis ◽  
Reduced Risk

Background: Low-dose prescription of rivaroxaban was common among patients with atrial fibrillation (AF) in Asia. However, the benefits and harms of rivaroxaban at a low dosage in Asian patients with AF remains unclear. Accordingly, we aimed to collect and summarize all available evidence to fill this important knowledge gap.Methods: In this systematic review and meta-analysis, we systematically searched databases of MEDLINE, EMBASE, and Cochrane Library for relevant studies from inception until February 23, 2021. Eligible retrospective nationwide or health insurance database studies or prospective registration studies that reported efficacy (stroke/systemic embolism), safety (major bleeding, intracranial hemorrhage, gastrointestinal bleeding), or other outcomes (myocardial infarction, death) of low-dose rivaroxaban in comparison with warfarin in AF patients were enrolled. Data extraction and study quality assessment were conducted by two authors independently. Low dosing of rivaroxaban (15/10 mg) was defined as the received dose lower than the recommended dose (20 mg) approved in most districts. Hazard ratio (HR) with 95% confidence intervals (95% CIs) was pooled using a random-effect model. Subgroup analyses were conducted according to different dose regimens. Sensitivity analyses were conducted by sequential elimination of each study from the pool. Since potential effect modifiers (patient demographics, differences of each study, and others) may lead to bias in primacy outcomes, we performed a meta-regression analysis to explore the influence of these factors on the primary efficacy and safety outcomes.Results: Totally, 12 studies involving 292,815 Asian patients with AF were included. All studies were detected as low to moderate risk bias. Low-dose rivaroxaban treatment in Asian AF patients was associated with a reduced risk of stroke/systemic embolism (HR: 0.76, 95% CI: 0.70–0.84, I2: 57.8%), major bleeding (HR: 0.72, 95% CI: 0.62–0.84, I2: 81.5%), and all-cause death (HR: 0.65, 95% CI: 0.58–0.73, I2: 81.7%) when compared with warfarin. Furthermore, consistent results were observed among different dose regimens (10/15/20 mg) in all the clinical outcomes (Pinteraction &gt; 0.05 for each outcome). Meta-regression analysis failed to detect any potential confounding to impact the primacy outcomes.Conclusion: Insights from the present meta-analysis, we found that low-dose rivaroxaban, even at a dosage of 10 mg daily, was associated with a reduced risk of stroke/SE and bleeding than warfarin in Asian AF patients. However, owing to considerable heterogeneity among included studies, further prospective studies are required to confirm these findings.

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