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

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.

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Non–Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Asians With Atrial Fibrillation

Stroke ◽

10.1161/strokeaha.119.026054 ◽

2019 ◽

Vol 50 (10) ◽

pp. 2819-2828 ◽

Cited By ~ 8

Author(s):

Zhengbiao Xue ◽

Hao Zhang

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Major Bleeding ◽

Real World ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Intracranial Bleeding ◽

Systemic Embolism ◽

Real World Data

Background and Purpose— Several randomized trials and real-world studies have reported the efficacy and safety of non–vitamin K antagonist oral anticoagulants (NOACs) in Asian patients with atrial fibrillation; and therefore, this meta-analysis was aimed to compare the effects of NOACs with warfarin for atrial fibrillation stroke prevention in Asians. Methods— The PubMed and Embase databases were searched from January 2009 to February 2019 for studies on comparisons of NOACs versus warfarin in Asians. Risk ratios (RRs) with 95% CIs were pooled using a random-effects model. Results— Five NOAC trials and 21 observational cohorts were included. For the NOAC trials, compared with warfarin, NOACs was associated with reduced risks of stroke or systemic embolism (RR, 0.73; 95% CI, 0.59–0.90), all-cause death (RR, 0.83; 95% CI, 0.73–0.95), major bleeding (RR, 0.59; 95% CI, 0.48–0.72), and intracranial bleeding (RR, 0.36; 95% CI, 0.26–0.49). For the real-world data, compared with warfarin, NOACs was associated with decreased rates of stroke or systemic embolism (RR, 0.75; 95% CI, 0.68–0.82), ischemic stroke (RR, 0.70; 95% CI, 0.59–0.83), myocardial infarction (RR, 0.74; 95% CI, 0.58–0.93), all-cause death (RR, 0.67; 95% CI, 0.59–0.77), major bleeding (RR, 0.63; 95% CI, 0.55–0.73), intracranial bleeding (RR, 0.50; 95% CI, 0.43–0.59), and gastrointestinal bleeding (RR, 0.65; 95% CI, 0.51–0.84). The results did not change in the subgroup analyses based on the type and dose of NOACs. Conclusions— Based on published NOAC trials and real-world studies, the use of NOACs is noninferior to warfarin in Asians with atrial fibrillation irrespective of the NOAC type and dose.

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Safety and efficacy of direct acting oral anticoagulants and vitamin K antagonists in nonvalvular atrial fibrillation – a network meta-analysis of real-world data

VASA ◽

10.1024/0301-1526/a000746 ◽

2019 ◽

Vol 48 (2) ◽

pp. 134-147 ◽

Cited By ~ 8

Author(s):

Mirko Hirschl ◽

Michael Kundi

Keyword(s):

Real World ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Efficacy And Safety ◽

Nonvalvular Atrial Fibrillation ◽

Real World Data ◽

Hazard Ratios ◽

Direct Acting ◽

Event Rates

Abstract. Background: In randomized controlled trials (RCTs) direct acting oral anticoagulants (DOACs) showed a superior risk-benefit profile in comparison to vitamin K antagonists (VKAs) for patients with nonvalvular atrial fibrillation. Patients enrolled in such studies do not necessarily reflect the whole target population treated in real-world practice. Materials and methods: By a systematic literature search, 88 studies including 3,351,628 patients providing over 2.9 million patient-years of follow-up were identified. Hazard ratios and event-rates for the main efficacy and safety outcomes were extracted and the results for DOACs and VKAs combined by network meta-analysis. In addition, meta-regression was performed to identify factors responsible for heterogeneity across studies. Results: For stroke and systemic embolism as well as for major bleeding and intracranial bleeding real-world studies gave virtually the same result as RCTs with higher efficacy and lower major bleeding risk (for dabigatran and apixaban) and lower risk of intracranial bleeding (all DOACs) compared to VKAs. Results for gastrointestinal bleeding were consistently better for DOACs and hazard ratios of myocardial infarction were significantly lower in real-world for dabigatran and apixaban compared to RCTs. By a ranking analysis we found that apixaban is the safest anticoagulant drug, while rivaroxaban closely followed by dabigatran are the most efficacious. Risk of bias and heterogeneity was assessed and had little impact on the overall results. Analysis of effect modification could guide the clinical decision as no single DOAC was superior/inferior to the others under all conditions. Conclusions: DOACs were at least as efficacious as VKAs. In terms of safety endpoints, DOACs performed better under real-world conditions than in RCTs. The current real-world data showed that differences in efficacy and safety, despite generally low event rates, exist between DOACs. Knowledge about these differences in performance can contribute to a more personalized medicine.

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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

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.10.suppl_3.223 ◽

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.

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Real-world adherence to oral anticoagulants in atrial fibrillation patients: a study protocol for a systematic review and meta-analysis

BMJ Open ◽

10.1136/bmjopen-2018-025102 ◽

2018 ◽

Vol 8 (12) ◽

pp. e025102 ◽

Cited By ~ 3

Author(s):

Clara L Rodríguez-Bernal ◽

Aníbal García-Sempere ◽

Isabel Hurtado ◽

Yared Santa-Ana ◽

Salvador Peiró ◽

...

Keyword(s):

Atrial Fibrillation ◽

Systematic Review ◽

Real World ◽

Observational Studies ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Medication Possession Ratio ◽

Essential Element ◽

Study Endpoint ◽

Mortality And Morbidity

IntroductionAtrial fibrillation (AF) is one of the leading causes of cerebrovascular mortality and morbidity. Oral anticoagulants (OACs) have been shown to reduce the incidence of cardioembolic stroke in patients with AF, adherence to treatment being an essential element for their effectiveness. Since the release of the first non-vitamin K antagonist oral anticoagulant, several observational studies have been carried out to estimate OAC adherence in the real world using pharmacy claim databases or AF registers. This systematic review aims to describe secondary adherence to OACs, to compare adherence between OACs and to analyse potential biases in OAC secondary adherence studies using databases.Methods and analysisWe searched on PubMed, SCOPUS and Web of Science databases (completed in 26 September 2018) to identify longitudinal observational studies reporting days’ supply adherence measures with OAC in patients with AF from refill databases or AF registers. The main study endpoint will be the percentage of patients exceeding the 80% threshold in proportion of days covered or the medication possession ratio. Two reviewers will independently screen potential studies and will extract data in a structured format. A random-effects meta-analysis will be carried out to pool study estimates. The risk of bias will be assessed using the Newcastle-Ottawa Scale for observational studies and we will also assess some study characteristics that could affect days’ supply adherence estimates.Ethics and disseminationThis systematic review using published aggregated data does not require ethics approval according to Spanish law and international regulations. The final results will be published in a peer-review journal and different social stakeholders, non-academic audiences and patients will be incorporated into the diffusion activities.PROSPERO registration numberCRD42018095646.

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Non-vitamin K Antagonist Oral Anticoagulants and Cognitive Impairment in Atrial Fibrillation: Insights From the Meta-Analysis of Over 90,000 Patients of Randomized Controlled Trials and Real-World Studies

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2018.00258 ◽

2018 ◽

Vol 10 ◽

Cited By ~ 12

Author(s):

Chi Zhang ◽

Zhi-Chun Gu ◽

Long Shen ◽

Mang-Mang Pan ◽

Yi-Dan Yan ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cognitive Impairment ◽

Randomized Controlled Trials ◽

Vitamin K ◽

Real World ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Controlled Trials ◽

Randomized Controlled

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Oral anticoagulants in atrial fibrillation with valvular heart disease and bioprosthetic heart valves

Heart ◽

10.1136/heartjnl-2019-314767 ◽

2019 ◽

Vol 105 (18) ◽

pp. 1432-1436 ◽

Cited By ~ 7

Author(s):

Aaqib H Malik ◽

Srikanth Yandrapalli ◽

Wilbert S Aronow ◽

Julio A Panza ◽

Howard A Cooper

Keyword(s):

Atrial Fibrillation ◽

Heart Disease ◽

Major Bleeding ◽

Valvular Heart Disease ◽

Heart Valves ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Cardiac Events ◽

Increased Risk ◽

Randomised Controlled

ObjectiveCurrent guidelines endorse the use of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF). However, little is known about their safety and efficacy in valvular heart disease (VHD). Similarly, there is a paucity of data regarding NOACs use in patients with a bioprosthetic heart valve (BPHV). We, therefore, performed a network meta-analysis in the subgroups of VHD and meta-analysis in patients with a BPHV.MethodsPubMed, Cochrane and Embase were searched for randomised controlled trials. Summary effects were estimated by the random-effects model. The outcomes of interest were a stroke or systemic embolisation (SSE), myocardial infarction (MI), all-cause mortality, major adverse cardiac events, major bleeding and intracranial haemorrhage (ICH).ResultsIn patients with VHD, rivaroxaban was associated with more ICH and major bleeding than other NOACs, while edoxaban 30 mg was associated with least major bleeding. Data combining all NOACs showed a significant reduction in SSE, MI and ICH (0.70, [0.57 to 0.85; p<0.001]; 0.70 [0.50 to 0.99; p<0.002]; and 0.46 [0.24 to 0.86; p<0.01], respectively). Analysis of 280 patients with AF and a BPHV showed similar outcomes with NOACs and warfarin.ConclusionsNOACs performed better than warfarin for a reduction in SSE, MI and ICH in patients with VHD. Individually NOACs performed similarly to each other except for an increased risk of ICH and major bleeding with rivaroxaban and a reduced risk of major bleeding with edoxaban 30 mg. In patients with a BPHV, results with NOACs seem similar to those with warfarin and this needs to be further explored in larger studies.

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