Non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis

Caldeira, Daniel; Nunes-Ferreira, A; Rodrigues, Raquel; Vicente, Eunice; Pinto, Fausto J.; Ferreira, Joaquim J.

doi:10.1016/j.archger.2018.12.013

Cited by 52 publications

(39 citation statements)

References 33 publications

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“…Furthermore, besides a significantly lower intracranial bleeding risk and a similar major bleeding risk for both standard and reduced dose NOACs (Ruff et al, 2014;Sadlon and Tsakiris, 2016;Kim et al, 2018;Caldeira et al, 2019;Malik et al, 2019), a similar to significantly higher gastrointestinal bleeding risk for reduced and standard dose NOACs respectively has been illustrated (Kim et al, 2018;Malik et al, 2019). However, substantial heterogeneity was detected in these meta-analyses for the bleeding risk assessment in older patients (I²-value ranging from 84% (Malik et al, 2019) to 94%) (Kim et al, 2018), potentially attributed to differences in the safety profile of individual NOACs (Sadlon and Tsakiris, 2016;Kim et al, 2018;Caldeira et al, 2019;Malik et al, 2019). Indeed, in the individual post hoc analyses of RCTs, an increased bleeding risk for dabigatran and rivaroxaban was observed in older AF patients, as opposed to lower risks for apixaban and edoxaban.…”

Section: Randomized Studiesmentioning

confidence: 96%

“…Several post hoc analyses and meta-analyses of the pivotal phase III RCTs have been performed, illustrating similar stroke/SE and mortality risks with reduced dose NOACs in AF patients ≥75 years old as compared to warfarin, whereas significantly lower stroke/SE and mortality risks with standard dose NOACs were observed (eTable 2) (Ruff et al, 2014;Sadlon and Tsakiris, 2016;Kim et al, 2018;Caldeira et al, 2019;Malik et al, 2019). Furthermore, besides a significantly lower intracranial bleeding risk and a similar major bleeding risk for both standard and reduced dose NOACs (Ruff et al, 2014;Sadlon and Tsakiris, 2016;Kim et al, 2018;Caldeira et al, 2019;Malik et al, 2019), a similar to significantly higher gastrointestinal bleeding risk for reduced and standard dose NOACs respectively has been illustrated (Kim et al, 2018;Malik et al, 2019). However, substantial heterogeneity was detected in these meta-analyses for the bleeding risk assessment in older patients (I²-value ranging from 84% (Malik et al, 2019) to 94%) (Kim et al, 2018), potentially attributed to differences in the safety profile of individual NOACs (Sadlon and Tsakiris, 2016;Kim et al, 2018;Caldeira et al, 2019;Malik et al, 2019).…”

Section: Randomized Studiesmentioning

confidence: 99%

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Effectiveness and Safety of Oral Anticoagulants in Older Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

et al. 2020

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Background and Objective: Atrial fibrillation (AF), the most common cardiac arrhythmia, typically increases with age. Oral anticoagulants (OACs) are the cornerstone of treatment to reduce the associated risk for systemic thromboembolism. Four large randomized controlled trials (RCTs) have shown that non-vitamin K antagonist oral anticoagulants (NOACs) are non-inferior to vitamin K antagonists (VKAs) in preventing stroke and systemic embolism, as well as regarding their risk for major bleeding. However, as vulnerable geriatric patients with AF were largely underrepresented in these trials, physicians are faced with the challenge of choosing the right anticoagulant for geriatric patients in real-life clinical practice. In this vulnerable patient group, NOACs tend to be underused or underdosed due to concerns of excessive fall-related intracranial bleeding, cognitive impairment, multiple drugdrug interactions, low body weight or impaired renal function. As life expectancy continues to rise worldwide, the number of geriatric patients substantially increases. Therefore, there is an urgent need for a critical appraisal of the added value of NOACs in geriatric patients with AF at high thromboembolic and bleeding risk. Methods and Results: This systematic review provides an overview of the literature on the impact of increased age (≥75 years), multimorbidity, polypharmacy, increased falling risk, frailty and dementia on the effectiveness and safety of NOACs as compared to VKAs, after searching the Medline database. Moreover, a meta-analysis on the impact of increased age ≥75 years old was performed after pooling results from 6 post hoc analyses of RCTs and 6 longitudinal observational cohort studies, highlighting the superior effectiveness (hazard ratio (HR) 0.83, 95% confidence interval (CI) [0.74-0.94] for stroke/SE; HR 0.77, 95%CI [0.65-0.92] for mortality) and non-inferior safety (HR 0.93, 95%CI [0.86-1.01] for major bleeding; HR 0.58, 95%CI [0.50-0.67] for intracranial bleeding; HR 1.17, 95%CI [0.99-1.38] for gastrointestinal bleeding) of NOACs versus VKAs in older AF patients.

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Section: Randomized Studiesmentioning

confidence: 96%

Section: Randomized Studiesmentioning

confidence: 99%

Effectiveness and Safety of Oral Anticoagulants in Older Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

et al. 2020

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“…Several previous meta-analyses have demonstrated the superior effectiveness and equivalent safety of DOACs vs. VKAs in elderly AF patients (28)(29)(30)(31). However, the pooled results were mainly drawn from subgroup analysis of phase III clinical trials (RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF-TIMI 48, J-ROCKET AF) and failed to provide therapy choice on individual DOACs.…”

Section: Discussionmentioning

confidence: 99%

Direct Oral Anticoagulants vs. Vitamin-K Antagonists in the Elderly With Atrial Fibrillation: A Systematic Review Comparing Benefits and Harms Between Observational Studies and Randomized Controlled Trials

Shen

Wang

et al. 2020

Front. Cardiovasc. Med.

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Background: The publication of high-quality observational studies (OSs) has fueled reassessment of the treatment effects of direct oral anticoagulants (DOACs) in the elderly with atrial fibrillation (AF). Methods: The MEDLINE, EMBASE, and Cochrane Library databases were systematically searched (through July 1, 2019) for eligible OSs and randomized controlled trials (RCTs) that reported effectiveness outcomes [stroke or systemic embolism (SE)] or safety outcomes [intracranial hemorrhage (ICH), major bleeding, gastrointestinal bleeding (GIB), myocardial infarction (MI), and all-cause mortality] for DOACs and vitamin-K antagonists (VKAs) in elderly AF patients. A random-effects model was applied to calculate adjusted hazard ratios (HRs) for OSs and relative risks (RRs) for RCTs. Interaction analyses and the ratio of HR (RHR) were used to assess and compare OSs and RCTs. Results: A total of 32 studies involving 547,419 patients were included. No significant difference in treatment effect estimates was found between 27 OSs and 5 RCTs [ P interaction > 0.05 for each and all 95% confidence interval (CI) of RHR crossed 1.0]. Compared with VKAs, DOACs significantly reduced risk for stroke/SE (OSs, HR: 0.87, 95% CI: 0.81–0.94; RCT, RR: 0.82, 95% CI: 0.67–0.96), and ICH (OSs: 0.47 [0.37–0.57]; RCTs: 0.47 [0.31–0.63]), without increasing risk for GIB (OSs: 1.21 [0.98–1.43]; RCTs: 1.34 [0.91–1.77]), and all-cause mortality (OSs: 1.01 [0.92–1.11]; RCTs: 0.94 [0.87–1.00]). Among OSs, DOACs significantly decreased risk for major bleeding (0.87 [0.77–0.98]) and MI (0.89 [0.79–0.99]). It was found that dabigatran, but not other DOACs, significantly increased risk for GIB (1.48 [1.23–1.72]). Conclusions: DOACs were demonstrated to be more effective and safer than VKAs in elderly AF patients, whereas dabigatran users had a 48% increase in risk for GIB.

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“…It is remarkable that most older patients used VKA instead of NOAC in this trial, while the superior safety of the NOAC has been proven in different randomized controlled trials [ 14 , 15 , 16 , 17 ]. A recent meta-analysis of NOAC in elderly patients even showed an increased efficacy in elderly patients compared to younger ones [ 18 ]. In addition, the overall risk of major bleeding was similar for NOAC and VKA in the elderly, however apixaban and edoxaban showed a significant reduction in elderly patients’ major bleeding risk.…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor Versus Clopidogrel in Older Patients with NSTE-ACS Using Oral Anticoagulation: A Sub-Analysis of the POPular Age Trial

Gimbel

Tavenier

Bor

et al. 2020

JCM

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There are no randomised data on which antiplatelet agent to use in elderly patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and an indication for oral anticoagulation (OAC). The randomised POPular Age trial, in patients of 70 years or older with NSTE-ACS, showed a reduction in bleeding without increasing thrombotic events in patients using clopidogrel as compared to ticagrelor. In this sub-analysis of the POPular AGE trial, we compare clopidogrel with ticagrelor in patients with a need for oral anticoagulation. The follow-up duration was one year. The primary bleeding outcome was Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding. The primary thrombotic outcome consisted of cardiovascular death, myocardial infarction and stroke. The primary net clinical benefit outcome was a composite of all-cause death, myocardial infarction, stroke, and PLATO major and minor bleeding. A total of 184/1011 (18.2%) patients on OAC were included in this subanalysis; 83 were randomized to clopidogrel and 101 to ticagrelor. The primary bleeding outcome was lower in the clopidogrel group (17/83, 20.9%) compared to the ticagrelor group (33/101, 33.5%; p = 0.051), as was the thrombotic outcome (7/83, 8.4% vs. 19/101, 19.2%; p = 0.035) and the primary net clinical benefit outcome (23/83, 27.7% vs. 49/101, 48.5%; p = 0.003). In this subgroup of patients using OAC, clopidogrel reduced PLATO major and minor bleeding compared to ticagrelor without increasing thrombotic risk. This analysis therefore suggests that, in line with the POPular Age trial, clopidogrel is a better option than ticagrelor in NSTE-ACS patients ≥70 years using OAC.

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Non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis

Cited by 52 publications

References 33 publications

Effectiveness and Safety of Oral Anticoagulants in Older Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

Effectiveness and Safety of Oral Anticoagulants in Older Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

Direct Oral Anticoagulants vs. Vitamin-K Antagonists in the Elderly With Atrial Fibrillation: A Systematic Review Comparing Benefits and Harms Between Observational Studies and Randomized Controlled Trials

Ticagrelor Versus Clopidogrel in Older Patients with NSTE-ACS Using Oral Anticoagulation: A Sub-Analysis of the POPular Age Trial

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