Best Options for Stroke Prevention Therapy for Older Adults with Difficulty Using Warfarin

Atrial fibrillation (AF) is a common condition among older adults residing in long-term care (LTC) facilities. AF is a major risk factor for stroke, resulting in an overall 5-fold increase in the incidence of stroke in the absence of anticoagulation therapy.¹ Therefore, it is common practice to prescribe oral anticoagulants for the prevention of stroke or systemic embolism in patients with AF.

The risk for stroke in AF is not homogenous but rather a continuum that includes a multitude of factors. Thus, the decision to initiate oral anticoagulant therapy, and the choice of treatment, should be driven by the patient’s individual risk assessment and the net clinical benefit, balancing stroke risk reduction against the risk of serious bleeding (Figure 1).^2-5

Assessment of Stroke Risk in Patients with AF 

Decision-making regarding anticoagulation therapy can be assisted by use of the CHADS₂ (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke) assessment or CHA₂DS₂-VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke, vascular disease, age 65-74 years, sex) assessment for stroke risk. The CHADS₂ is commonly used and well-validated.⁶ Major clinical guidelines consistently agree that oral anticoagulants should be prescribed to patients at high risk of stroke, defined by a CHADS₂ score of ≥ 2 (Table 1).^2-5 Recommendations for those with low-risk CHADS₂ scores vary amongst guidelines. The most recent American clinical guidelines for AF stroke prevention recommend the use of the CHA₂DS₂-VASc assessment, an expansion of the CHADS₂ scheme.⁵ The CHA₂DS₂-VASc is more inclusive, incorporating minor stroke risk factors, and has better discriminative ability for patients with an intermediate CHADS₂ score of 1 (Table 2).^6,7 Thus, CHA₂DS₂-VASc provides more clear guidance for anticoagulation recommendations for individual patients. The AHA/ACC/HRS guidelines allow a choice between oral anticoagulation, aspirin or no antithrombotic therapy in patients with a CHA₂DS₂-VASc of 1.⁵ Nevertheless, recent guidelines from North America and Europe differ in their recommendations for which risk assessment strategy to use and when to provide anticoagulation therapy (Table 1).^2-5

Options for Stroke Prevention Therapy

Oral anticoagulants are highly effective for preventing ischemic stroke in patients with AF. However, the use of oral anticoagulants can pose a significant bleeding risk, especially in older patients.⁸ Oral anticoagulant-related bleeding risk can also be estimated for patients with AF using the validated HAS-BLED (hypertension, renal or liver dysfunction, stroke, bleeding history, labile INR, elderly age [> 65 years], substance abuse and concomitant drugs or alcohol) assessment for bleeding risk.⁹ HAS-BLED has demonstrated a significant predictive performance for independently identifying intracranial hemorrhage risk as well as predicting other clinically relevant bleeding.⁹ High risk of bleeding is considered to be a score of 3 or greater, with a maximum score of 9.⁹ The European and ACC/AHA/HRS guidelines recommend the use of the HAS-BLED tool to assess an individual patient’s bleeding risk.^3,5 These guidelines caution clinicians against using it to exclude a patient from oral anticoagulation due to a high HAS-BLED score. Rather, the HAS-BLED score should be considered in order to identify a patient’s bleeding risk and develop a plan for risk factor reduction.³

Warfarin

Warfarin, an oral vitamin K antagonist, has been the mainstay of oral anticoagulation therapy for more than 50 years. Historically, choices for the selection of therapy for AF have been influenced by clinical trials comparing warfarin with aspirin and placebo. Several studies have demonstrated the superior effectiveness of warfarin over aspirin for stroke prevention, with a minimal relative increase in bleeding risk.

The Atrial Fibrillation Investigators (AFI) pooled data from five large controlled trials and concluded that warfarin was highly effective for reducing ischemic stroke and systemic embolism with a relative risk reduction (RRR) of 68% in patients aged 65 years and older. AFI also found a minimal increase in major bleeding risk compared with placebo (1.3% per year with warfarin vs 1.0% per year with placebo or control).¹⁰ In the same study, the bleeding risk with aspirin was comparable to that with placebo (1.0% per year for both).¹⁰ In a similar meta-analysis evaluating aspirin monotherapy for stroke prevention in AF, the same authors found a 21% RRR compared with placebo.¹¹ Another meta-analysis found that the RRR in stroke was 52% for warfarin versus aspirin.¹² Thus, the net clinical benefit of warfarin over aspirin has been widely demonstrated.¹⁰

In one large study, the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study, compared the frequency of fatal and non-fatal disabling ischemic or hemorrhagic stroke, intracranial hemorrhage, and other clinically significant arterial embolisms in 973 patients with AF older than 75 years of age (mean age, 81.5 years). Patients were randomly assigned to receive warfarin (with a target international normalized ratio [INR] range of 2-3) or aspirin 75 mg once daily. Warfarin was superior to aspirin for reducing the risks of the cardiovascular events evaluated. Additionally, the risks of major bleeding and intracranial hemorrhage with warfarin and with aspirin were similar.¹³

Because challenges related to individualized therapy, drug and dietary interactions, and monitoring requirements complicate the use of warfarin,² some clinicians prefer to avoid prescribing warfarin to patients with older age, presence of dementia, risk for falls, or an unreliable ability to adhere to the medication or the frequent laboratory monitoring required.¹⁴ 

Direct Oral Anticoagulants

There have been substantial changes to the therapeutic options for stroke prevention in AF with the introduction of direct oral anticoagulants (DOACs) in 2010. Four DOACs are currently available in the United States: dabigatran, rivaroxaban, apixaban, and edoxaban.^15-18 DOACs are highly effective and offer some advantages over warfarin: they require less frequent laboratory monitoring, are associated with lower rates of intracranial bleeding, have a more consistent pharmacokinetic profile, and require fewer dietary limitations. 

A meta-analysis of 30,866 patients on DOAC agents (dabigatran, ximelagatran, rivaroxaban, apixaban, or daraxaban) found that DOAC plus aspirin was associated with an increased risk of bleeding (composite of major and non-major) of 79% (hazard ratio [HR], 1.79; 95% CI, 1.54–2.09) compared with dual antiplatelet therapy.¹⁹ In the pivotal trials analyzing efficacy, all DOACs appeared to be non-inferior compared with warfarin in risk reduction with respect to the primary endpoint of stroke or systemic embolism. However, apixaban and dabigatran 150 mg twice daily were found to have superior efficacy in prevention of stroke and systemic embolism compared with warfarin.^15,17 The rates of major bleeding were found to be no different with DOACs or with warfarin and were even significantly less with dabigatran 110 mg twice daily (dose not approved by FDA), apixaban, and edoxaban compared with warfarin.^15-17 However, dabigatran 150 mg twice daily was found to cause an increased rate of major bleeding compared with warfarin in patients 75 years of age and older, and subsequently was included on the Beer’s list of potentially inappropriate medications to be used with caution in older adults.^20,21 Of note, a reduced risk of intracranial hemorrhage was apparent for all DOACs.^15-18

Each of the DOACs has a rapid onset of action and short half-life. Additionally, each requires dose adjustment or is contraindicated in renal failure, a common condition in an elderly population. Unlike warfarin, all of the new agents have fixed dosing and lack requirements for frequent laboratory monitoring, leading to convenience with administration and use.²² Due to these advantages, many of the clinical guidelines give preference to DOACs over warfarin.^2-4 DOACs are effective alternatives for patients who are unable to follow up for consistent monitoring. However, some patients may not be ideal candidates for DOAC use because of the high costs of these drugs, preferences not lending to DOAC therapy, or the presence of factors that prohibit their use, such as renal or liver dysfunction.⁵ Warfarin remains advantageous over DOACs when patients demonstrate proven stability on warfarin with a time in therapeutic range greater than 66%.^22,23

Antiplatelet Therapy

There are practical challenges and preferences for some patients and clinicians in using oral anticoagulants for stroke prevention. For these patients, antiplatelet therapies such as aspirin as well as dual antiplatelet therapy with aspirin plus clopidogrel have been recommended as alternatives to oral anticoagulants for stroke prevention in AF. Several studies did not find aspirin to be of benefit over placebo.^24-26 Thus, the role of aspirin in the prevention of stroke in AF has become quite minimal in light of more effective therapies.

Although antiplatelet therapy is less effective than DOACs,^3,4,22 several clinical guidelines recommend the use of aspirin plus clopidogrel for those patients who are unable to use oral anticoagulation with warfarin or DOACs and who are not at significant risk of bleeding (Table 1).^2-4 Support for these recommendations comes from the ACTIVE trial program.^27,28 One of these trials, ACTIVE A, included patients with AF who had an increased risk of stroke (CHADS₂ score ≥ 2) and for whom warfarin therapy was deemed unsuitable by a physician or because of patient refusal.²⁷ Patients were randomly assigned to receive clopidogrel 75 mg in addition to aspirin or aspirin plus placebo. The primary outcome was the composite of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes. Patients taking aspirin plus clopidogrel had a lower primary event rate, translating to an 11% reduction in vascular events, largely due to a 28% reduction in stroke. At the same time, the aspirin plus clopidogrel arm had a 57% higher incidence of major bleeding compared with aspirin plus placebo (2.0% per year vs 1.3% per year; P < .001), possibly outweighing any benefit from reduction in vascular events.²⁷

The other trial conducted was the ACTIVE W trial, which included patients with AF (CHADS₂ score ≥ 2) who were randomized to warfarin monotherapy or aspirin plus clopidogrel.²⁸ This trial was terminated early due to clear evidence of superiority of warfarin: the warfarin arm had a 56% reduction in vascular events compared with the aspirin plus clopidogrel combination. One clinically important finding of the ACTIVE W trial was that bleeding rates were similar between the two groups.²⁸ Thus, aspirin plus clopidogrel offered only a modest benefit in reducing thromboembolism over aspirin monotherapy, while offering lesser efficacy and no bleeding advantage compared with warfarin.^27,28 Nevertheless, selection of aspirin plus clopidogrel for stroke prevention in AF would be rational in specific circumstances.

Newer antiplatelet agents, prasugrel and ticagrelor, may appear to be attractive alternatives to clopidogrel in patients at high risk of stent thrombosis.²⁹ However, these agents have an increased bleeding risk. It is recommended that prasugrel not be used in adults aged 75 years or older due to bleeding risk, and neither agent has been studied in combination with DOACs nor for the purposes of AF stroke prophylaxis.²⁹

Data on the use of triple therapy (DOAC plus aspirin plus clopidogrel) is minimal and must be extrapolated from small numbers of patients using this combination in the large AF clinical trials with DOACs.^15-18 In one study, a DOAC-based triple therapy increased bleeding by 124% (HR, 2.34; 95% CI, 2.06–2.66) versus dual antiplatelet therapy.¹⁹ 

Stroke Prevention in Patients With AF Undergoing Percutaneous Coronary Intervention 

It is not uncommon for a patient with AF to have compelling indications for concomitant antiplatelet therapy in addition to oral anticoagulation. Patients with AF who have a documented history of coronary artery disease or who are undergoing percutaneous coronary intervention (PCI) may require treatment with dual antiplatelet agents.²⁹ Clinical guidelines recommend patients who receive PCI should continue aspirin indefinitely.²⁹ Depending on the indication for PCI and the type of stent implanted, P2Y₁₂ inhibitors such as clopidogrel, are recommended for an ideal period of 12 months in addition to aspirin to prevent stent thrombosis.²⁹ In a case where a patient has an inherent high risk of bleeding, assessed by a high HAS-BLED score, the bleeding risk associated with triple therapy (oral anticoagulant plus aspirin plus clopidogrel) as compared with an option that produces less risk of bleeding may be a concern.³⁰

Accordingly, clinicians may opt to mitigate bleeding risk while sacrificing some efficacy for elderly patients with AF undergoing coronary stenting who also have high risk of bleeding. One strategy to diminish bleeding risk is to use aspirin plus clopidogrel without an oral anticoagulant. This strategy may confer benefit as stent thrombosis prophylaxis as well as efficacy—albeit reduced—for AF stroke prevention.^2,27,28 A second approach to minimizing bleeding risk is to consider, on an individualized basis, the use of bare metal stents versus drug-eluting stents in PCI to minimize triple therapy duration. This approach may be preferred in patients with AF after an acute coronary syndrome.³¹ A third strategy in this population is supported by the first randomized trial comparing two regimens with and without aspirin in patients on oral anticoagulants therapy undergoing coronary stenting.² This study evaluated the safety and efficacy of triple therapy with clopidogrel plus aspirin plus warfarin versus clopidogrel plus warfarin for 1 year in patients requiring PCI already on long-term anticoagulation with warfarin. The primary outcome was any bleeding episode within 1 year of PCI assessed by intention to treat. The trial concluded that the use of triple therapy versus clopidogrel plus warfarin was associated with a significantly increased risk of bleeding complications (44.4% vs 19.4%) without any differences in stent thrombosis.³² Currently, clopidogrel plus warfarin has the highest quality of evidence supporting its use in patients with AF and undergoing PCI; however, this strategy may still remain suboptimal when compared with the alternatives described if a patient is unable to take warfarin therapy. 

Considerations for Treatment Selection

When considering selection for stroke prevention therapy in a patient, it is important to weigh specific individual patient factors in addition to their calculated stroke and bleeding risk assessment scores.^6,9 Strict adherence to daily medication use and follow-up monitoring is critical to the safety and effectiveness of anticoagulant therapy. Therefore, adherence often plays a significant role in therapy selection.

It is important to note the differences in pharmacokinetics between non-adherent warfarin therapy and non-adherent DOAC therapy. The half-life of DOACs ranges from 8 hours to 15 hours compared with a mean half-life for warfarin of ~40 hours.^22,33 If non-adherent to one of the DOACs, there is a reduced level of anticoagulation associated with a single missed dose that would be much more marked than that from a missed dose of warfarin. Frequent missed doses of DOACs may theoretically place an individual at greater stroke risk than the same individual missing doses with warfarin therapy. When a patient is non-adherent with warfarin therapy, the availability of periodic INR testing might serve as a stimulus to adherence.³⁴ Furthermore, dabigatran and apixaban require twice-daily administration.^15,17 Patients who prefer once-daily medication, or have poor compliance with twice-daily regimens, can be prescribed rivaroxaban or edoxaban. Alternatively, the combination of aspirin plus clopidogrel has platelet inhibition lasting up to 1 week, resulting in less fluctuation in steady-state pharmacokinetics with missed doses.

Socioeconomic considerations should be discussed with patients at the time of prescribing. Medication costs can be a burden to some patients and may also lead to non-adherence if affordability of the medication is overlooked.³⁴ A patient’s insurance coverage, co-insurance payments, contribution to the Medicare “donut hole,” and willingness to pay must all be evaluated when selecting DOAC therapy.³⁴ Out-of-pocket costs for a 30-day supply of any of the DOACs can range from $300 to $400, whereas the non-DOAC therapies generally cost less than $20 per month.³⁵ 

Several patient-specific factors need to be considered when selecting oral anticoagulation for elderly patients (Table 3). Thrombosis and bleeding risk assessment, as well as consideration of patient preferences, should be a priority in the selection of therapy. Frequent monitoring with warfarin offers the advantage of initial and ongoing education and adherence assessment. Nevertheless, some older adults may have difficulty taking and adhering to required monitoring. Aspirin offers little, if any benefit for elderly patients at high risk for stroke. A subset of patients with AF may benefit from dual antiplatelet therapy with aspirin and clopidogrel rather than using an oral anticoagulant. When a patient is unable or unwilling to assume the cost or copay of the newer, direct-acting agents, daily adherence with warfarin or DOAC is inconsistent, or when the patient is unable to adhere with warfarin INR monitoring, aspirin and clopidogrel is a reasonable choice.^30,36 Patients with AF and other comorbidities such as coronary artery disease requiring stenting may also be candidates for aspirin and clopidogrel maintenance.³⁰

Conclusion

Oral anticoagulants are highly effective for preventing ischemic stroke in patients with AF, a common condition among older adults residing in LTC facilities. However, the use of oral anticoagulants can pose a significant bleeding risk, especially in the older patient. Oral anticoagulant-related bleeding risk can be estimated for patients with AF using the validated HAS-BLED assessment. Warfarin, an oral vitamin K antagonist, has been the mainstay of oral anticoagulation therapy for more than 50 years. Several studies have demonstrated the superior effectiveness of warfarin over aspirin for stroke prevention, with a minimal relative increase in bleeding risk. DOACs are also highly effective and offer some advantages over warfarin. For patients with practical challenges or preferences that prevent the use of oral anticoagulants for stroke prevention, antiplatelet therapies such as aspirin as well as dual antiplatelet therapy with aspirin plus clopidogrel provide alternatives for stroke prevention in AF.

It is important to weigh specific individual patient factors when considering selection for stroke prevention therapy in a patient with AF. In addition to their calculated stroke and bleeding risk assessment scores, a clinician should consider: whether the patient has compelling indications for concomitant antiplatelet therapy in addition to oral anticoagulation, such as a documented history of coronary artery disease or PCI; challenges with treatment adherence; socioeconomic considerations; and consideration of patient preferences. A systematic approach to a high quality, patient-centered therapy selection can be aided by the use of decision support tools to provide individualized, optimized anticoagulation to elderly patients with AF. 

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