CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Released: June 26, 2024
Expiration: June 25, 2025
Risks and Benefits of DOACs
The most comprehensive analysis of the risks and benefits of DOACs vs warfarin for stroke prevention in patients with atrial fibrillation was a meta-analysis of 4 large trials comparing these 2 agents.2 This analysis demonstrated that there was a statistically significant 19% reduction in risk of stroke or systemic embolism with standard-dose DOACs vs warfarin. There was also a statistically significant 8% reduction in all-cause death and 11% reduction in cardiovascular death. These results are largely because of the ≥50% reduction in intracranial hemorrhage that one sees with a DOAC vs warfarin3,4; this intracranial hemorrhage may be fatal.
Relative Risk Reduction in Stroke With DOACs
Stroke is one of the complications of atrial fibrillation, and atrial fibrillation is one of the most common causes of preventable stroke. A meta-analysis of data from multiple trials has shown that warfarin reduced risk of stroke by 64% compared with control agents or placebo.5 Likewise, a meta-analysis of several trials showed that DOAC therapy significantly reduced stroke or systemic embolic events by 19% compared with warfarin. If we superimpose these data, we can see that there is close to a 70% relative risk reduction in stroke between DOAC therapy and placebo. This becomes a major public health opportunity: Ensure that all eligible patients are treated with this highly effective treatment.
Listen to this brief audio clip about DOAC prescribing practices.
Trends in Use of Anticoagulant Agents in Older Adults With Newly Diagnosed Atrial Fibrillation
How does real-world care compare with guideline recommendations? Data show that patients who have atrial fibrillation or risk factors for stroke are not always treated with anticoagulation.6 These data from a Medicare Advantage database are similar to what we see across many different registries and health systems: Although DOAC initiation within 12 months after incident atrial fibrillation increased from 20.2% in 2010 to 32.9% in 2020, patients with atrial fibrillation are treated <50% of the time. These data also show that there has been a shift in the anticoagulant used from warfarin to the DOACs, mainly apixaban and rivaroxaban. Lower odds of treatment were associated with older age and its comorbidities dementia, frailty, and anemia.
Contraindications to Anticoagulation
What do physicians see as contraindications to anticoagulant therapy? This slide shows an analysis from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent atrial fibrillation.7 A common theme is concern over bleeding and other safety risks, especially in the older population. These are barriers to anticoagulant use that must be overcome because the reduction in stroke far outweighs the risks of therapy in the vast majority of these patients.
AVERROES: Efficacy and Safety
Listen to this brief audio clip about the role of aspirin in prevention stroke.
What can we do to improve patient safety with the use of anticoagulant agents? One of the most effective things we can do is to switch patients away from aspirin to other oral anticoagulation. (The 2023 guidelines state that aspirin is neither safe nor effective for preventing stroke for patients with atrial fibrillation.1)
Data from the AVERROES trial are shown in this slide. Patients deemed inappropriate for warfarin were randomized to either aspirin or apixaban.8 The data and safety monitoring board for this trial recommended early termination of the study because of a clear benefit in favor of apixaban. Apixaban reduced the risk of stroke or systemic embolism by >50% without significantly increasing the risk of major bleeding or intracranial hemorrhage. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin >50% of the time and a history of daily/occasional nosebleeds.9 Intracranial hemorrhage was numerically less likely with apixaban than with aspirin.
Listen to this brief audio clip about concomitant use of DOACs and aspirin.
Patients receiving aspirin should discontinue it when starting an oral anticoagulant. By treating patients with oral anticoagulation alone, the risk of bleeding will be reduced by approximately one half.
AFIRE: Rivaroxaban Monotherapy or in Combination With an Antiplatelet for Atrial Fibrillation
The AFIRE trial done in Japan addressed the question of how to treat a patient who presents with ischemic stroke and also has an indication for anticoagulation.10 This multicenter, open-label trial included patients who had atrial fibrillation and risk factors for stroke and who had stable coronary disease (ie, no revascularization or acute coronary syndrome within a year). Patients were randomized to receive rivaroxaban monotherapy or combination therapy of rivaroxaban with a single antiplatelet agent. The outcome measure was a composite outcome of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause.
AFIRE Results
The trial was stopped early because of increased mortality in the combination therapy group.10 Predictably, bleeding was increased with combination therapy but it increased by a large increment (70%) with combination therapy in this population of patients with stable coronary disease.
By contrast, vascular events were not only not decreased with combination therapy; they actually increased. There was 38% increased risk of stroke, myocardial infarction, urgent revascularization, unstable angina, or death.
Death from any cause was almost doubled, increased by 80%. These data underscore that aspirin should be avoided when patients are started on anticoagulant, even for patients with stable coronary disease.
ARISTOTLE and RE-LY: Novel Biomarkers for Bleeding
What are the risk factors for bleeding? This slide demonstrates a biomarker-based risk score for major bleeding in 14,537 patients with atrial fibrillation randomized to apixaban or warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomized to dabigatran or warfarin in the RE-LY trial.11 The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and hemoglobin, age, and previous bleeding.
Listen to this brief audio clip about important risk factors for bleeding to consider.
Clinical factors include older age, lower hemoglobin, and previous bleeding, and if patients have a combination of those 3 factors, in particular previous gastrointestinal bleeding, antiplatelet therapy (ie, aspirin) should be avoided, and a proton pump inhibitor should be considered to reduce the risk of recurrent gastrointestinal bleeding.
Swiss Registry: Bleeding and Risk of Subsequent Events for Patients With Atrial Fibrillation on Anticoagulation
This slide represents the findings of Meyre and colleagues12 who used high-quality Swiss registries of patients with atrial fibrillation to address an important question: What is the risk of adverse outcomes (either cardiovascular or recurrent bleeding) following bleeding events with atrial fibrillation on oral anticoagulation?
In this analysis, researchers found that bleeding is common in these patients: Over 4 years, 20% had a bleeding event, and 9% had a major bleeding event. The composite clinical outcome of stroke, myocardial infarction, or death from any cause occurred in nearly one half of patients following major bleeding, at a median of 142 days after the bleeding event. Patients who had a major bleeding event had double the risk of a subsequent cardiovascular event, even after adjustment for other risk factors, in comparison with those without a bleeding event. Patients with a major bleeding event also had a shorter median time to a cardiovascular event than patients with clinically relevant nonmajor bleeding or without any bleeding.
Of importance, discontinuation of anticoagulation occurred in 21% of patients following major bleeding, and those who discontinued were at more than twice the risk of a cardiovascular event compared with those who continued anticoagulation, although rates of cardiovascular events were also elevated for patients with major bleeding who continued their anticoagulation. Among patients with a new bleeding event, approximately 25% subsequently developed another bleeding event. However, only 4% to 5% of patients with bleeding had a subsequent major bleeding event.
Early vs Late Anticoagulation for Stroke With Atrial Fibrillation
A practical question that may arise relates to how to treat patients who present with ischemic stroke and have an indication for anticoagulation, including atrial fibrillation. When can one initiate or resume anticoagulation?
This slide represents an investigator-initiated, open-label randomized trial of more than 2000 patients.13 The results of this study that showed that anticoagulation can be resumed earlier than we had previously thought. Investigators randomized patients to either start anticoagulants early, which was defined as within 48 hours of a minor or moderate stroke or 6-7 days after a major stroke. The group who initiated anticoagulants later did so at Day 3 or 4 after a minor stroke, Day 6 or 7 after a moderate stroke, or Day 12, 13, or 14 after a major stroke. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days.
Patients who had the early initiation had better outcomes: At 30 days, they had less intracranial bleeding, symptomatic intracranial hemorrhage, recurrent ischemic strokes, and symptomatic emboli. There was 1 more death in the early treatment group than the later treatment group. At 90 days, the results were similar with the composite primary outcome approaching statistical significance.
ELDERCARE-AF: Low-Dose Edoxaban in Older Patients
It is known that older age is a risk factor for stroke and for bleeding. This slide represents the results of the ELDERCARE-AF trial, which addressed the question of whether it is safe to use DOACs in older adults.14 ELDERCARE-AF was a randomized, double-blind, placebo-controlled phase III trial comparing edoxaban 15 mg once daily with placebo in elderly Japanese patients 80 years of age or older with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy endpoint was the composite of stroke or systemic embolism, and the primary safety endpoint was major bleeding.
The annualized rate of stroke or systemic embolism was reduced by more than one half in the edoxaban group (HR: 0.34; 95% CI: 0.19-0.61; P <.001), but the annualized rate of major bleeding was higher (but not statistically significantly) with treatment vs placebo (HR: 1.87; 95% CI: 0.90-3.89; P = .09). More events of gastrointestinal bleeding occurred in the edoxaban group than in the placebo group. There was no significant between-group difference in death from any cause.
Although there is some risk of bleeding with low-dose DOAC use, the risk of bleeding is outweighed by the benefit of stroke reduction in this population.
ARISTOTLE: Efficacy and Safety of Apixaban in Older Adults
This Forest plot represents a subgroup analysis of patients from the ARISTOTLE trial comparing patient cohorts who were 75 years of age or older, 65-74 years of age, or younger than 65 years of age. ARISTOTLE included 18,201 patients with atrial fibrillation and increased risk of stroke who were randomized to warfarin or apixaban 5 mg twice daily.15 Results were stratified by age group.
The plot demonstrates that apixaban was more effective at reducing stroke or systemic emboli across age groups compared with warfarin, that is, relative risk reduction for stroke and intracranial hemorrhage is similar and therefore the absolute risk reduction is even greater in the older population. However, the risk of bleeding was lower in older patients who were receiving apixaban than those receiving warfarin. The take-away from these data is to consider anticoagulation treatment of older patients.
ARISTOLE: Anticoagulant Use in Patients With a History of Falling
Falls are a common concern for older patients. It is estimated that approximately 30% of people aged 65 years or older fall 1 or more times per year.16,17
In the ARISTOTLE trial, 753 persons of more than 18,000 total participants reported a history of falling. When compared with patients without a history of falling, patients with a history of falling were older, more likely to be female, and more likely to have dementia, cerebrovascular disease, depression, diabetes, heart failure, osteoporosis, fractures, and risk scores for cardiovascular events. Subdural hematomas were uncommon in those who fell (n = 5/367 in warfarin arm; n = 0/368 in apixaban arm).18 DOACs were also shown to be associated with having less than one half the risk of traumatic intracranial hemorrhage compared with warfarin.19 Therefore, the benefits of DOACs seem to far outweigh the risks in people who have had falling.
Should Older Patients on Warfarin With Frailty Switch to DOACs?
We should consider whether older adult patients with frailty who are stable on warfarin be switched to DOACs. The results of the FRAIL-AF trial suggested that this might not be advisable.20 In this open-label, randomized trial, 1330 patients aged 75 years or older with atrial fibrillation living with frailty (Groningen Frailty Indicator score ≥3) were assigned to switch from warfarin to a DOAC or to continue warfarin. The primary outcome was first major or clinically relevant nonmajor bleeding complication, accounting for death as a competing risk. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified analysis, indicating that staying on warfarin was the preferred treatment.
On the other hand, the COMBINE-AF meta-analysis including all patients randomized in the 4 pivotal trials of DOACs vs warfarin in atrial fibrillation indicated that a switch to DOACs was associated with better outcomes.2
In this analysis, frailty was assessed with 5 domains: (1) Gencer high-risk features; (2) congestive heart failure, hypertension, age older than 75 years, diabetes, stroke/transient ischemia attack/thromboembolism score (CHA2DS2-VASc); (3) polypharmacy; (4) Charlson comorbidity Index; and (5) high fall risk.21
Outcomes of interest were stroke or systemic embolism, major bleeding, mortality, and the net clinical outcome. In this analysis, DOACs generally demonstrated lower risk of stroke/systemic embolism and death compared with warfarin, with similar rates of major bleeding. We can see that in this analysis, patients seem to do substantially better on DOACs.
Biomarkers and Risk of Stroke in Patients With Atrial Fibrillation
How do we effectively use biomarker scores to determine whether patients with atrial fibrillation are appropriate for anticoagulation?
Patients who score 1 on CHA2DS2-VASc have intermediate risk for stroke and might benefit from having additional information in the decision-making process for intervention.
N-terminal pro–B-type natriuretic peptide (NT-proBNP) is a good biomarker for risk of stroke,22 and the information we receive from analyzing this biomarker is complementary to the CHA2DS2-VASc score. In this situation, if the NT-proBNP were between 800-1000 pg/mL (green and purple bars in this diagram), combined with a CHA2DS2-VASc score of 1, we should consider stroke reduction therapy.
COMBINE_AF: Anticoagulation in Patients With Atrial Fibrillation and Chronic Kidney Disease
How does chronic kidney disease figure into our assessment for anticoagulation in patients with atrial fibrillation? As we might expect, a meta-analysis from COMBINE-AF demonstrated that the incidence of stroke or systemic embolism, major bleeding, intracranial hemorrhage, and death increased significantly with worsening kidney function.23
If we look at patients with low creatinine clearance (30 mL/min), patients on standard-dose DOACs had significantly lower risk of intracranial hemorrhage, stroke/systemic embolism, and death. The risk of major bleeding did not change for patients randomized to standard-dose DOACs compared with those randomized to warfarin.
Use of lower-dose, rather than standard-dose, DOACs was not associated with a significant difference in incident bleeding or intracranial hemorrhage in patients with reduced kidney function but was associated with a higher incidence of death and stroke/systemic embolism.
We can conclude that it is very appropriate to use DOACs in the population of patients with impaired kidney function.
Anticoagulation for Patients With Atrial Fibrillation and Advanced Kidney Disease
For patients with atrial fibrillation who have end-stage kidney disease, we lack data that inform us about anticoagulation.
There have been a number of small, randomized trials including patients with end-stage kidney disease from which we get the most reliable data.
Meta-analysis of DOAC Use in Patients With ESKD
The meta-analysis included on this slide showed that DOACs, when compared with warfarin, have no significant difference in terms of risk for major bleeding, ischemic stroke, and cardiovascular death.24
Given the small numbers of patients, the results need to be validated by further study.
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