The Importance of Appropriate Dosing of Nonvitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation

AbstractPreventing thromboembolic events, while minimizing bleeding risks, remains challenging when managing patients with atrial fibrillation (AF). Several factors contribute to current dosing patterns of nonvitamin K antagonist oral anticoagulants (NOACs), including patient characteristics, comorbidities, and physician judgment. Application of NOAC doses inconsistent with the drug labels may cause patients to receive either subtherapeutic (increasing stroke risk) or supratherapeutic (increasing bleeding risk) anticoagulant levels. In clinical practice, under- or over-dosing of NOACs in patients with AF is not uncommon. This analysis of prospective and retrospective registry and database studies on NOAC use in patients with AF (with at least 250 patients in each treatment arm) showed that under-dosing may be associated with reduced effectiveness for stroke prevention, with similar or even increased bleeding than with the standard dose. This may reflect underlying conditions and patient factors that increase bleeding despite NOAC dose reduction. Such factors could drive the observed overuse of reduced NOAC dosages, often making the prescription of reduced-dose NOAC an intentional label deviation. In contrast, over-dosing more likely occurs accidentally; instead of providing benefits, it may be associated with worse safety outcomes than the standard dose, including increased bleeding risk and higher all-cause mortality rates. This review summarizes the main findings on NOAC doses usually prescribed to patients with AF in clinical practice.

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Edoxaban treatment of elderly patients with atrial fibrillation in routine clinical practice: 1-year results of the non-interventional Global ETNA-AF program

European Heart Journal ◽

10.1093/ehjci/ehaa946.0663 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

T Yamashita ◽

C.C Wang ◽

Y.-H Kim ◽

R De Caterina ◽

P Kirchhof ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Practice ◽

Major Bleeding ◽

Intracranial Haemorrhage ◽

Clinical Care ◽

Oral Anticoagulants ◽

Clinical Event ◽

Funding Source ◽

Private Company ◽

All Cause Mortality

Abstract Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

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Combination of Oral Anticoagulants and Single Antiplatelets versus Triple Therapy in Nonvalvular Atrial Fibrillation and Acute Coronary Syndrome: Stroke Prevention among Asians

International Journal of Angiology ◽

10.1055/s-0040-1708477 ◽

2020 ◽

Vol 29 (02) ◽

pp. 088-097

Author(s):

Anwar Santoso ◽

Sunu B. Raharjo

Keyword(s):

Atrial Fibrillation ◽

Acute Coronary Syndrome ◽

Triple Therapy ◽

Stroke Prevention ◽

Thrombus Formation ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Nonvalvular Atrial Fibrillation ◽

Coronary Syndrome

AbstractAtrial fibrillation (AF), the most prevalent arrhythmic disease, tends to foster thrombus formation due to hemodynamic disturbances, leading to severe disabling and even fatal thromboembolic diseases. Meanwhile, patients with AF may also present with acute coronary syndrome (ACS) and coronary artery disease (CAD) requiring stenting, which creates a clinical dilemma considering that majority of such patients will likely receive oral anticoagulants (OACs) for stroke prevention and require additional double antiplatelet treatment (DAPT) to reduce recurrent cardiac events and in-stent thrombosis. In such cases, the gentle balance between bleeding risk and atherothromboembolic events needs to be carefully considered. Studies have shown that congestive heart failure, hypertension, age ≥ 75 years (doubled), diabetes mellitus, and previous stroke or transient ischemic attack (TIA; doubled)–vascular disease, age 65 to 74 years, sex category (female; CHA2DS2-VASc) scores outperform other scoring systems in Asian populations and that the hypertension, abnormal renal/liver function (1 point each), stroke, bleeding history or predisposition, labile international normalized ratio (INR), elderly (>65 years), drugs/alcohol concomitantly (1 point each; HAS-BLED) score, a simple clinical score that predicts bleeding risk in patients with AF, particularly among Asians, performs better than other bleeding scores. A high HAS-BLED score should not be used to rule out OAC treatment but should instead prompt clinicians to address correctable risk factors. Therefore, the current review attempted to analyze available data from patients with nonvalvular AF who underwent stenting for ACS or CAD and elaborate on the direct-acting oral anticoagulant (DOAC) and antiplatelet management among such patients. For majority of the patients, “triple therapy” comprising OAC, aspirin, and clopidogrel should be considered for 1 to 6 months following ACS. However, the optimal duration for “triple therapy” would depend on the patient's ischemic and bleeding risks, with DOACs being obviously safer than vitamin-K antagonists.

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Stroke prevention in atrial fibrillation: An Asian perspective

Thrombosis and Haemostasis ◽

10.1160/th13-11-0948 ◽

2014 ◽

Vol 111 (05) ◽

pp. 789-797 ◽

Cited By ~ 137

Author(s):

Kang-Ling Wang ◽

Gregory Y. H. Lip ◽

Chern-En Chiang

Keyword(s):

Atrial Fibrillation ◽

Stroke Prevention ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Risk Scores ◽

Asian Patients ◽

History Of ◽

Randomised Controlled ◽

Similar Risk ◽

Selection Of

SummaryAtrial fibrillation (AF) is the most common sustained cardiac arrhythmia. In 2050, it is estimated that there will be 72 million AF patients in Asia, accounting for almost 2.9 million patients suffering from AF-associated stroke. Asian AF patients share similar risk factor profiles as non-Asians, except that more Asians have a history of previous stroke. Clinical challenges are evident in the field of stroke prevention in AF, amongst Asians. Existing stroke and bleeding risk scores have not been well-validated in Asians. Asians are prone to bleeding when treated with warfarin, and the optimal international normalised ratio (INR) for warfarin use is yet to be determined in Asians, though Asian physicians tend to keep it in a lower range (e.g. INR 1.6–2.6) for elderly patients despite limited evidence to justify this. In general, warfarin is ‘difficult’ to use in Asians due to higher risk of bleeding and higher stroke rate in Asians than in non-Asians, as shown in randomised controlled trials. Excess of bleeding was not found in Asians when novel oral anticoagulants (NOACs) were used. Besides, the superiority of NOACs to warfarin in reducing thromboembolism was maintained in Asians. Therefore NOACs are preferentially indicated in Asians in terms of both efficacy and safety. Also, some preliminary data suggest that Asian patients with AF might not be the same. Future prospective randomised trials are needed for the selection of NOACs according to different ethnic background.Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief.

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Gaps in translation from trials to practice: Non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation

Thrombosis and Haemostasis ◽

10.1160/th13-12-1032 ◽

2014 ◽

Vol 111 (05) ◽

pp. 783-788 ◽

Cited By ~ 36

Author(s):

Darae Ko ◽

Christina L. Cove ◽

Elaine M. Hylek

Keyword(s):

Atrial Fibrillation ◽

Clinical Practice ◽

Vitamin K ◽

Stroke Prevention ◽

Current Knowledge ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Major Advance ◽

Single Target ◽

Anticoagulant Drugs

SummaryWorldwide there is a tremendous need for affordable anticoagulants that do not require monitoring. The advent of the non-warfarin oral anticoagulant drugs represents a major advance for stroke prevention in atrial fibrillation (AF). The objectives of this review are to 1) identify gaps in our current knowledge regarding use of these single target anticoagulant drugs; 2) outline the potential implications of these gaps for clinical practice, and thereby, 3) highlight areas of research to further optimise their use for stroke prevention in AF.

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2021 Korean Heart Rhythm Society Guidelines for Stroke Prevention in Atrial Fibrillation

Korean Journal of Medicine ◽

10.3904/kjm.2021.96.4.296 ◽

2021 ◽

Vol 96 (4) ◽

pp. 296-311

Author(s):

Ki Hong Lee ◽

Jin-Bae Kim ◽

Seung Yong Shin ◽

Boyoung Joung

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Stroke Prevention ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Optimal Strategies ◽

Mechanical Valve ◽

Heart Rhythm ◽

Bleeding Risk

Atrial fibrillation (AF) is a strong risk factor for ischemic stroke and systemic embolism. To prevent thromboembolic events in patients with AF, anticoagulation therapy is essential. The anticoagulant strategy is determined after stroke and bleeding risk assessments using the CHA2DS2-VASc and HAS-BLED scores, respectively; both consider clinical risk factors. Vitamin K antagonists (VKAs) are the sole anticoagulant option in AF patients with a prosthetic mechanical valve or moderate-severe mitral stenosis; in all other AF patients VKA or non-vitamin K antagonist oral anticoagulants are therapeutic options. However, antiplatelet therapy should not be used for stroke prevention in AF patients. Anticoagulation is not needed in AF patients with low stroke risk but strongly recommended in those with a with low bleeding risk. Left atrial appendage (LAA) occlusion offers an alternative in AF patients in whom long-term anticoagulation is contraindicated. Surgical occlusion or the exclusion of LAA can be considered for stroke prevention in AF patients undergoing cardiac surgery. In this article, we review existing data for stroke prevention and suggest optimal strategies to prevent stroke in AF patients.

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Exploring patient–provider decision-making for use of anticoagulation for stroke prevention in atrial fibrillation: Results of the INFORM-AF study

European Journal of Cardiovascular Nursing ◽

10.1177/1474515118812252 ◽

2018 ◽

Vol 18 (4) ◽

pp. 280-288 ◽

Cited By ~ 3

Author(s):

Sean D Pokorney ◽

Diane Bloom ◽

Christopher B Granger ◽

Kevin L Thomas ◽

Sana M Al-Khatib ◽

...

Keyword(s):

Atrial Fibrillation ◽

Decision Making ◽

Stroke Prevention ◽

Decision Aids ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Decisional Conflict ◽

Increased Risk ◽

Outpatient Settings ◽

Depth Interviews

Background: Atrial fibrillation is associated with stroke, yet approximately 50% of patients are not treated with guideline-directed oral anticoagulants (OACs). Aims: Given that the etiology of this gap in care is not well understood, we explored decision-making by patients and physicians regarding OAC use for stroke prevention in atrial fibrillation. Methods and results: We conducted a descriptive qualitative study among providers ( N=28) and their patients with atrial fibrillation for whom OACs were indicated ( N=25). We used purposive sampling across three outpatient settings in which atrial fibrillation patients are commonly managed: primary care ( n=14), geriatrics ( n=10), and cardiology ( n=4). Eligible patients were stratified by those prescribed OAC ( n=13) and not prescribed OAC ( n=12). Semi-structured, in-depth interviews assessed decision-making regarding risk and OAC use. Classical content analysis was used to code narratives and identify themes. Results among patients consisted of the overarching theme of trust in provider recommendations. Sub-themes included: awareness of increased risk of stroke with atrial fibrillation; willingness to accept medications recommended by their physician; and low demand for explanatory decision aids. Among physicians, the overarching theme was decisional conflict regarding the balance between stroke and bleeding risk, and the optimal medication to prescribe. Subthemes included: absence of decision aids for communication; and misperceptions around the assessment and management of stroke risk with atrial fibrillation. Conclusions: Patient involvement in decision-making around OAC use did not occur in this study of patients with atrial fibrillation. Improved access to decision aids may increase patient engagement in the decision-making process of OAC use for stroke prevention.

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P4758Label adherence of non-vitamin K antagonist oral anticoagulants and clinical outcomes in patients with atrial fibrillation: A nationwide study

European Heart Journal ◽

10.1093/eurheartj/ehz745.1134 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

H T Yu ◽

P S Yang ◽

E Jang ◽

T H Kim ◽

J S Uhm ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Practice ◽

Clinical Outcomes ◽

Vitamin K ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Systemic Embolism ◽

Increased Risk ◽

All Cause Mortality

Abstract Background Dose adjustment of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in some patients with atrial fibrillation (AF), based on selected patient factors or concomitant medications. Purpose We assessed the frequency of label adherence of NOAC dosing among AF patients and the associations between off-label NOAC dosing and clinical outcomes in real-world clinical practice. Methods We evaluated 53,649 AF patients treated with a NOAC using Korean National Health Insurance Service database during the period from January 2013 to December 2016. NOAC doses were classified as either underdosed or overdosed, consistent with U.S. Food and Drug Administration labeling. Cox proportional hazards regression was performed to investigate the effectiveness and safety outcomes including stroke or systemic embolism, major bleeding, and all-cause mortality. Results Overall, 16,757 NOAC-treated patients (31.2%) were underdosed, 4,492 were overdosed (8.4%), and 32,400 (60.4%) were dosed appropriately according to drug labeling. Compared with patients with label adherence, those who were underdosed or overdosed were older (71±8 and 75±7 years of age vs. 70±9 years of age, respectively; p<0.001), more likely female (39% and 53% vs. 38%, respectively; p<0.001), and had higher CHA2DS2-VASc scores (4.6±1.7 and 5.3±1.7 vs. 4.5±1.8, respectively; p<0.001). NOAC overdosing was associated with increased risk for stroke or systemic embolism (5.76 vs. 4.03 events/100 patient-years, p<0.001), major bleeding (4.77 vs. 2.94 events/100 patient-years, p<0.001), and all-cause mortality (5.43 vs. 3.05 events/100 patient-years, p<0.001) compared with label-adherent use. Figure 1 Conclusion In routine clinical practice, a significant proportion (almost 2 in 5) of AF patients received NOAC doses inconsistent with drug labeling. NOAC overdosing is associated with increased risk for stroke or systemic embolism, major bleeding, and all-cause mortality in Asian patient with AF.

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Efficacy and safety of the target-specific oral anticoagulants for stroke prevention in atrial fibrillation: the real-life evidence

Therapeutic Advances in Drug Safety ◽

10.1177/2042098616673990 ◽

2016 ◽

Vol 8 (2) ◽

pp. 67-75 ◽

Cited By ~ 24

Author(s):

Vincenzo Russo ◽

Anna Rago ◽

Riccardo Proietti ◽

Federica Di Meo ◽

Andrea Antonio Papa ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Practice ◽

Real World ◽

Stroke Prevention ◽

Oral Anticoagulants ◽

Efficacy And Safety ◽

Thromboembolic Stroke ◽

The Real ◽

Concise Review ◽

Real World Setting

The aim of our article is to provide a concise review for clinicians entailing the main studies that evaluated the efficacy and safety of target-specific oral anticoagulants (TSOAs) for thromboembolic stroke prevention in the real-world setting. Atrial fibrillation (AF) is one of the most common supraventricular arrhythmias that requires anticoagulation therapy to prevent stroke and systemic embolism. TSOAs, dabigatran, apixaban and rivaroxaban have become available as an alternative to warfarin anticoagulation in nonvalvular atrial fibrillation (NVAF). Randomized clinical trials showed non-inferior or superior results in efficacy and safety of the TSOAs compared with warfarin for stroke prevention in NVAF patients. For this reason, the 2012 update to the European Society of Cardiology guidelines for the management of AF recommends TSOAs as broadly preferable to vitamin K antagonists (VKAs) in the vast majority of patients with NVAF [Camm et al. 2012]. Although the clinical trial results and the guideline’s indications, there is a need for safety and efficacy data from unselected patients in everyday clinical practice. Recently, a large number of studies testing the efficacy and the safety of TSOAs in clinical practice have been published. The aim of our article is to provide a concise review for clinicians, outlining the main studies that evaluated the efficacy and safety of TSOAs for thromboembolic stroke prevention in the real-world setting.

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Abstract 169: The Role Of Clinical Prediction Factors On Anticoagulant Selection In Atrial Fibrillation

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.7.suppl_1.169 ◽

2014 ◽

Vol 7 (suppl_1) ◽

Author(s):

Julie Lauffenburger

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Stroke Risk ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Patient Characteristics ◽

Treatment Selection ◽

Risk Scores ◽

Treatment Benefit ◽

Risk Treatment

Background: Atrial fibrillation (AF) often benefits from the use of anticoagulants for prevention of stroke or systemic embolism. While novel oral anticoagulants have emerged as possible alternatives to warfarin, it is unknown how treatment selection is determined in practice with clinical guidelines still evolving. This study examined whether and to what extent anticoagulant selection has been driven by clinical predictions of stroke risk (treatment benefit) and bleeding risk (treatment harm) in real-world practice in the US. Methods: A nationwide database of commercial and Medicare Part D supplement claims from 2009-2011 was used to extract a cohort of non-valvular AF patients who were newly-initiating therapy after dabigatran availability in Oct 2010. Patients were excluded if they had claims associated with a reversible AF condition. Risk scores of ischemic stroke (CHADS2 and CHA2DS2-VASc) and bleeding (ATRIA) were used to examine associations with either warfarin or dabigatran use, calculated via claims in the outpatient pharmaceutical, inpatient medical, outpatient, and provider claims files. Baseline demographic and clinical characteristics were also measured as covariates, including concomitant diseases and medications. Multivariable log-binomial regression models assessed the association between each risk score and anticoagulant use, adjusting for the measured covariates. C-statistics were also used to examine the variation in treatment selection explained by inclusion of the risk scores. Results: In total, 37,401 patients were identified with 31% initiating dabigatran. New users of dabigatran were more likely to be younger, male, and have comorbidities. Patients at intermediate stroke risk (CHADS2 or CHA2DS2-VASc =1) were equally likely to receive warfarin and dabigatran (RR, 95% CI: 0.98, 0.93-1.02), while selection for warfarin was significantly associated with high ischemic stroke risk (CHADS2 or CHA2DS2-VASc ≥2) (RR, 95% CI: 0.87, 0.83-0.92). New users of dabigatran were significantly less likely to have high bleeding risk (ATRIA≥5) versus warfarin (RR, 95%: 0.70, 0.66-0.74). The c-statistic of the base model, which included the other measured covariates, was only marginally increased with the addition of any of the risk scores. Conclusions: Despite controlling for other patient characteristics, bleeding risk was strongly associated with the selection of a specific anticoagulant. However, the extent of selection explained by predictions of treatment harm was minimal. Providers appear to base anticoagulant selection on factors other than predictions of treatment benefit, which has implications for studying the anticoagulants’ comparative effectiveness.

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