Clinical Question:

85 year old male with PMHx atrial fibrillation on warfarin for anticoagulation has become less steady when walking and wants to stop taking warfarin. He wants to know if he can safely stop taking the anticoagulant or if there are safer alternatives due to his fall risk.

PICO Question:

Is it safe for the patient to stop warfarin? If not, what safer alternatives than warfarin are available for older patients with a history of atrial fibrillation?

Search Strategy:

P- elderly, male, atrial fibrillation, fall risk

I- safer anticoagulation, NOAC, DOAC, non-vitamin K oral anticoagulation, direct oral anticoagulation

C- warfarin, Coumadin

O- reduced bleeding risk, stroke prevention

Filtered within past 5 years, meta-analysis, systematic review, randomized controlled trials

Pubmed – 367

Google scholar – 2560

Articles Chosen for Inclusion (please copy and paste the abstract with link):

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755244/

Abstract:

Stroke prevention with oral anticoagulants in patients with atrial fibrillation predisposes for bleeding. As a result, in select patient groups anticoagulation is withheld because of a perceived unfavorable risk-benefit ratio. Reasons for withholding anticoagulation can vary greatly between clinicians, often leading to discussion in daily clinical practice on the best approach. To guide clinical decision-making, we have reviewed available evidence on the most frequently reported reasons for withholding anticoagulation: previous bleeding, frailty and age, and an overall high bleeding risk.

Keywords: hemorrhage, frail elderly, age, anticoagulants, atrial fibrillation

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694766/

Abstract:

Atrial fibrillation (AF) is the commonest cardiac rhythm abnormality and has a significant disease burden. Amongst its devastating complications is stroke, the risk of which increases with age. The stroke risk in an older person with AF is therefore tremendous, and oral-anticoagulation (OAC) therapy is central to minimizing this risk. The presence of age-associated factors such as frailty and multi-morbidities add complexity to OAC prescription decisions in older patients and often, OAC is needlessly withheld from them despite a lack of evidence to support this practice. Generally, this is driven by an over-estimation of the bleeding risk. This review article provides an overview of the concepts and controversies in managing AF in older people, with respect to the existing evidence and current practice. A literature search was conducted on Pubmed and Cochrane using keywords, and relevant articles published by the 1st of May 2019 were included. The article will shed light on common misconceptions that appear to serve as rationale for precluding OAC and focus on clinical considerations that may aid OAC prescription decisions where appropriate, to optimize AF management using an integrated, multi-disciplinary care approach. This is crucial for all patients, particularly older individuals who are most vulnerable to the deleterious consequences of this condition.

Keywords: atrial fibrillation, older people, elderly, management, oral anti-coagulation, stroke, frailty, cognitive impairment

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562740/

Abstract:

Stroke prevention in elderly atrial fibrillation patients remains a challenge. There is a high risk of stroke and systemic thromboembolism but also a high risk of bleeding if anticoagulants are prescribed. The elderly have increased chronic kidney disease, coronary artery disease, polypharmacy, and overall frailty. For all these reasons, anticoagulant use is underutilized in the elderly. In this manuscript, the benefits of non-vitamin K antagonist oral anticoagulants compared with warfarin in the elderly patient population with multiple comorbid conditions are reviewed.

Keywords: non-vitamin K antagonist oral anticoagulants, novel oral anticoagulants, warfarin, dabigatran, rivaroxaban, apixaban, edoxaban

4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864792/

Abstract:

Elderly patients with atrial fibrillation are at a higher risk of both ischemic and bleeding events compared with younger patients; therefore, balancing risks and benefits of antithrombotic strategies in this population is crucial. Recent studies have shown that because the risk of stroke increases with age more than the risk of bleeding, the absolute benefit of oral anticoagulation is the highest in elderly patients in whom it outweighs the risk of bleeding. Direct oral anticoagulants (DOACs) have been developed as a treatment for the prevention of cardioembolic stroke to overcome some limitations of warfarin, such as the need for frequent monitoring, labile INR values requiring frequent dose adjustment, dietary and drugs interactions, and increased risk of intracranial bleeding. Despite the better safety profiles of DOACs compared with warfarin, elderly patients often remain undertreated because of the fear of bleeding complications. This review summarizes current evidence regarding the risks of thromboembolisms and bleeding in different antithrombotic strategies in elderly patients (aged ≥75 years) with atrial fibrillation, including data from the warfarin-controlled phase 3 DOACs trials.

Keywords: atrial fibrillation, elderly, anticoagulation

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Seelig et al. 2019   When to withhold oral anticoagulation in atrial fibrillation – an overview of frequent clinical discussion topics.	Systematic review	86 articles to assess and guide clinical decision making regarding when to withhold anticoagulation in patients with atrial fibrillation.	CHADS-VASC scores to evaluate risk for stroke with afib   HAS-BLED to evaluate risk of major bleeding event	Evidence from multiple studies suggests that the clinical benefit of OAC is even greater than the perceived benefits. The current literature shows that OAC is important in patients with very high stroke risk regardless of HAS-BLED scores and risk of major bleed.  The authors conclude that the perceived unfavorable risk-benefit ratio for OAC is often overestimated for elderly patients with atrial fibrillation, and that the benefits of stroke and thromboembolism prevention generally outweigh the risk of major bleeding.	Usefulness is limited because it does not tell us which OAC medication (if any) is safer.
Zafraan et al., 2019   Atrial Fibrillation in Older People: Concepts and Controversies.	Systematic review	154 articles including randomized controlled trials, systemic reviews, meta-analyses, registry studies, and observational studies published on PubMed and Cochrane before May 1st, 2019	CHADS VASC stroke risk with afib   HAS-BLED risk of major bleeding event   Stroke and bleeding events with different AOC medications	The researchers found sufficient evidence to determine that despite the risk of falls, patients benefit from anticoagulation due to the prevention of stroke and that the risk of falls should not be an absolute contraindication to OAC. In fact, patients who were not anticoagulated had significantly more ischemic strokes causing injury and bleeding compared to patients taking OAC. In patient’s over the age of 75, dabigatran 150 mg and apixaban both significantly reduced stroke events while other NOACs shows no significant differences compared to warfarin. Only apixiban had a clinically significant reducation in major bleeding in older patients, the other NOACs had comparable major bleeding risk compared to warfarin.	Its usefulness is limited by not specifically comparing warfarin and other OAC medications, the study is more broad and its aim is to assess the current management practices. There are very few randomized controlled trials that are specifically catered to the older population and as such results from RCTs are mainly referring to younger populations and may have limited applicability to the older population.
Turagam et al., 2015   Stroke prevention in the elderly atrial fibrillation patient with comorbid conditions: focus on non-vitamin K antagonist oral anticoagulants	Systematic review	96 articles in order to evaluate the benefits of non-vitamin K OACs (NOACs) compared to warfarin in elderly patients with multiple comorbidities such as age, CKD, CAD, polypharmacy, and frailty	Stroke/systemic thromboembolism and major bleeding event risks in patients > & < 75 years old while taking different OAC medications   Creatinine Clearance in patients taking different OAC medications   Drug interactions for different DOAC medications	The researchers conclude that for a patient over the age of 75 apixaban is an appropriate alternative for patients who cannot take warfarin.  For patients with CKD, NOACS have similar risk-benefit profile compared to warfarin but it is recommended that kidney function should be monitored routinely and dose should be adjusted based on the results. For patients with CAD, DOACS (specifically factor Xa inhibitors) without aspirin are favored. NOACS and warfarin had comparable rates of MI in this population, and concomitant aspirin may increase the risk of bleeding. For patients with polypharmacy, NOACS are favored over warfarin due to reduced drug interactions. NOACS have advantages for elderly patients in order to prevent stroke, systemic thromboembolism, and bleeding, however there are limitations in patients with multiple comorbidities. The authors recommend that prior to starting OAC therapy in the elderly population that a comprehensive risk assessment is performed in order to optimize therapy.	One of the authors is a consultant for multiple pharm companies including Pfizer and may present a bias. This review was only assessing the use of NOAC medications in patients with comorbidities and does not address the general population. They also do not acknowledge any scenario in which no medication is an appropriate therapy.
Cavallari and Patti, 2018   Efficacy and safety of oral anticoagulation in elderly patients with atrial fibrillation.	Systematic review	33 articles in order to evaluate the risk of thromboembolism and bleeding in elderly patients with atrial fibrillation using different antithrombotic strategies	Stroke/systemic thromboembolism, major bleeding event, and death risks in patients while taking aspirin, Warfarin, apixiban, dabigatran, rivaroxaban, adoxaban, and no medication	The evidence compiled by the researchers shows that for elderly patients, the benefits of vitamin K antagonist outweigh the risks. DOACs such as dabigatran, rivaroxaban, apixaban, and edoxaban, are newer alternatives to warfarin and have shown equal or greater efficacy with lower rates of intracranial hemorrhages. Apixaban and edoxaban are associated with lower risk of major bleeding compared to warfarin. Dagibatran at a lower dose (110 mg BID) has equal risk of bleeding compared to warfarin, while higher dose (150 mg BID) had greater risk of major bleeding. It is important to note that this risk for both doses is for extracranial bleeding, the risk of intracranial bleeding was still lower for both doses compared to warfarin. The authors conclude that DOACs have better safety profile than warfarin and are effective alternative treatments, particularly in elderly patients due to reduced risk of major bleeding compared to warfarin.	limited by its size, only 33 articles reviewed which is much less than the other articles that I have come across and summarized previously

Conclusion(s):

Elderly patients with afib are at greater risk for both stroke and bleeding events. Seelig et al evaluated when it is appropriate to withhold OAC therapy. They determined that the perceived risk of bleed is often overestimated and that the perceived benefit of OAC is often underestimated (Seelig et al, 2019). Zafraan et al makes it clear that regardless of bleeding risk, fall risk, age, and patient compliance, older patients still receive great benefit from OAC therapy. Their review inferred that even though patients over the age of 70 require an individualized approach and individualized decisions, they still should recommend OAC to these patients. Patients who are at increased risk of bleeding should be more closely monitored, but OAC therapy should not be withheld because risk of ischemic stroke without OAC outweighs risk of bleeding with OAC (Zafraan et al, 2019). Turagam et al had a similar conclusion, however they specifically assessed the safety and efficacy of NOACs and warfarin in the context of comorbidities. NOACs have fewer limitations compared to warfarin in managing elderly patients with atrial fibrillation, regardless, for patients with comorbidities they suggest that prior to starting any OAC therapy that a comprehensive assessment needs to be done in order to determine the optimal course of therapy (Turagam et al, 2015). Cavallari and Patti have a similar assessment to the other articles, however they also dive into the safety and efficacy of warfarin vs DOACs. They conclude that DOACs are effective and are safer alternatives for elderly patients compared to warfarin due to reduced risk of bleeding.  They advise to avoid higher dose dagibatran (150 mg BID) due to risk of extracranial bleeding, and show that apixaban and edoxaban are associated with significantly lower risk of bleeding compared to warfarin (Cavallari and Patti, 2018).

Clinical Bottom Line:

Based on the evidence I would recommend continue OAC to prevent risk of stroke, however I would change to the NOAC apixiban, which RCTs have shown to reduce risk of stroke and embolism events while also reducing risk of bleeding compared to his current therapy, warfarin. Dose would be either 2.5 or 5 mg BID, dosage is based on the patient exhibiting 2 or more of the following risk factors: age >80, body weight <60 kg, or serum creatinine >1.5 mg/dL. The patient is over the age of 80 and only needs to exhibit one of the others in order for me to recommend reduced dose (2.5 mg BID)

References:

1. Jaap Seelig, Ron Pisters, Martin E Hemels, Menno V Huisman, Hugo ten Cate, and Marco Alings. When to withhold oral anticoagulation in atrial fibrillation – an overview of frequent clinical discussion topics. Vasc Health Risk Manag. 2019; 15: 399–408. Published online 2019 Sep 17. doi: 10.2147/VHRM.S187656 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755244/
2. Zafraan Zathar, Anne Karunatilleke, Ameenathul M. Fawzy, and Gregory Y. H. Lip, Atrial Fibrillation in Older People: Concepts and Controversies. Front Med (Lausanne). 2019; 6: 175. Published online 2019 Aug 8. doi: 10.3389/fmed.2019.00175 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694766/
3. Mohit K Turagam, Poonam Velagapudi, and Greg C Flaker. Stroke prevention in the elderly atrial fibrillation patient with comorbid conditions: focus on non-vitamin K antagonist oral anticoagulants. Clin Interv Aging. 2015; 10: 1431–1444. Published online 2015 Sep 3. doi: 10.2147/CIA.S80641 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562740/
4. Ilaria Cavallari and Giuseppe Patti. Efficacy and safety of oral anticoagulation in elderly patients with atrial fibrillation. Anatol J Cardiol. 2018 Jan; 19(1): 67–71. doi: 10.14744/AnatolJCardiol.2017.8256 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864792/