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

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 drug-drug 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. Conclusion Across geriatric subgroups, apixaban was consistently associated with the most favourable benefit-risk profile and should therefore be preferred in geriatric patients with AF. However, research gaps on the impact of increased falling risk, frailty and baseline dementia were identified, requiring careful consideration while awaiting more results.


All-cause mortality (HR [95% CI])
Phase III RCT (worldwide) AF  Overview of included studies investigating the impact of increased age (≥75 years) on the effectiveness and safety of oral anticoagulants.
Bold: significantly lower risk; Italic: significantly higher risk *Rank probability: the rank probabilities reflect the hierarchy of drugs, with a larger first-rank probability value symbolizing that the drug is more likely to be the best.    1 (conclusion that efficacy and safety of rivaroxaban relative to warfarin did not differ with age, while the risk of major or clinically relevant non-major bleeding and gastrointestinal bleeding was significantly increased with rivaroxaban at higher age) Total score: 25/28 (89.3%)

D)
Reference: Hori et al. 2014 (4)  from a Variety of Fields" was used. (51) With this tool, 14 items of each quantitative study, were scored on the study and outcome levels depending on the degree to which the specific criteria were met or reported ("yes" = 2, "partial" = 1, "no" = 0). Items not applicable to a particular study design were marked "n/a" and were excluded from the calculation of the summary score. A percentage was calculated for each paper by dividing the total sum score obtained across rated items by the total possible score. AF: atrial fibrillation; ICD: International Classification of Diseases.

Rationale 3
Describe the rationale for the review in the context of what is already known. 2

Objectives 4
Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

Protocol and registration 5
Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.
Not applicable Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

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Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.
2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. eTable 1 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

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Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

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Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

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Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

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Section/topic # Checklist item Reported on page # Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.
2-3 + Figure 1 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).
14 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 14-15

FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.