Warfarin or new oral anticoagulant: How to choose a stroke prevention strategy for patients with high-risk atrial fibrillation?

Oral anticoagulant (OAC) effective prevention of stroke is the cornerstone of the management of patients with atrial fibrillation, and the use of OAC can reduce the risk of stroke and death.

For most patients with atrial fibrillation without moderate or severe mitral stenosis or artificial mechanical heart valves, treatment options include vitamin K antagonists (VKA, such as warfarin) and non-VKA oral anticoagulants (NOAC).

Although most guidelines generally recommend NOAC as a first-line oral anticoagulant, caution is still needed for certain patients with atrial fibrillation at high risk of stroke and bleeding, because such patients are underrepresented in randomized clinical trials for NOAC prevention of stroke.
Research has not yet been conducted.

High-risk groups for atrial fibrillation include patients with end-stage renal failure (ESRD, including patients on dialysis), elderly patients (such as those over 80 years of age with multiple risk factors for bleeding), patients with dementia or patients who require long-term care, and previous intracranial hemorrhage (ICH) or patients with recent acute bleeding (such as gastrointestinal bleeding), patients with acute ischemic stroke, and patients with intracardiac thrombosis.

This article describes stroke prevention strategies for patients with atrial fibrillation who are at high risk of stroke and bleeding.

Overview of Atrial Fibrillation Anticoagulation Therapy 2020 ESC/EACTS Atrial Fibrillation Diagnosis and Management Guidelines recommends the "ABC" atrial fibrillation management process, where A refers to anticoagulation or stroke prevention.

Compared with the control group or the placebo group, oral anticoagulation therapy can significantly reduce the risk of stroke (64%) and death (26%).

Most OAC treatment options for patients with atrial fibrillation without moderate or severe mitral stenosis or artificial mechanical valve replacement include VKA and NOAC.

Considering that anticoagulation therapy can increase the risk of bleeding, it is important to evaluate the net clinical benefit and individualized treatment that balances the risk of stroke and bleeding when determining stroke prevention strategies for patients with atrial fibrillation.

The 2020 ESC guidelines also propose a new systemic assessment program based on the pathophysiological characteristics of patients with atrial fibrillation, called the 4S-AF rule, which includes stroke risk, symptom severity, atrial fibrillation load, and atrial fibrillation matrix, designed to support atrial fibrillation The characteristics of tremor help follow-up clinical decision-making, including thrombosis prevention, heart rate or rhythm control, and management of comorbidities and risk factors.

The 4S-AF rule can also provide prognostic information and further improve the management of atrial fibrillation.

In addition to OAC, there are percutaneous treatments (including left atrial appendage occlusion) to prevent stroke, which can be combined with catheter ablation for the treatment of atrial fibrillation.

For patients with a high risk of long-term oral anticoagulant bleeding, alternative stroke prevention strategies, such as left atrial appendage occlusion (LAAO), should be selected.

There is a two-way relationship between chronic kidney disease (CKD) and atrial fibrillation in patients with end-stage renal disease (ESRD), especially in patients with end-stage renal disease (ESRD).

ESRD is defined as the glomerular filtration rate <15 ml/min/1.
73 m2 or the need for renal replacement therapy.

Approximately 12.
5% ​​of dialysis patients suffer from atrial fibrillation, and the annual incidence rate is 2.
7/1000.

Chronic kidney disease is associated with an increased risk of thromboembolism and bleeding events.

The available data indicate that the use of warfarin may accelerate the deterioration of renal function compared with the use of NOAC.

In a retrospective observational study of the use of VKA in patients with atrial fibrillation and ESRD, compared with not using warfarin, the use of warfarin was not associated with a reduced risk of stroke, but was significantly associated with an increased risk of major bleeding, including intracranial hemorrhage (ICH).

In addition, data from Sweden and Denmark show that the outcome of VKA-treated patients with atrial fibrillation and CKD is related to TTR, and the net clinical benefit of using VKA can be observed in some patients with atrial fibrillation and ESRD with a CHA2DS2-VASc score ≥2.

There are limited data on the use of NOAC in patients with atrial fibrillation and ESRD.

Only a few observational studies have provided data on the use of apixaban or rivaroxaban in patients with atrial fibrillation with ESRD or receiving renal replacement therapy.

One of the studies found that for patients with atrial fibrillation undergoing renal replacement therapy, compared with warfarin, apixaban has similar efficacy but higher safety.

Another study found that two groups of patients with atrial fibrillation and ESRD who used rivaroxaban and apixaban had ischemic stroke (HR 1.
12, 95% CI 0.
45-2.
76) and hemorrhage (HR 1.
00, 95% CI 0.
63).
-1.
58) the risks are similar.

The 2019 ACC/AHA/HRS Atrial Fibrillation Management Guidelines recommend that patients with atrial fibrillation who are at higher risk of stroke and undergo renal replacement therapy use VKA (IIB).
Apixaban 5 mg bid can be used as an alternative to VKA.

The 2018 CHEST guidelines point out that antithrombotic therapy should be highly individualized, and it is recommended that such patients use VKA with good quality control (TTR>65-70%).

The European, Asian and Canadian guidelines for the management of atrial fibrillation do not recommend the routine use of OAC in patients with atrial fibrillation and ESRD.

The RENAL-AF trial is the first RCT to evaluate apixaban (n=82) and VKA (n=72) in patients with atrial fibrillation treated on dialysis.

However, due to lack of funding, the study was terminated early.

The results showed that the annual incidence of major bleeding (8.
5% vs.
9.
7%) and stroke (2.
4% vs.
2.
8%) was similar in the Apixaban and VKA groups, but these findings are inconclusive.

The ELDERCARE-AF randomized controlled study in Japan included elderly patients with atrial fibrillation who had a high risk of bleeding and were considered not to meet OAC indications (including CKD) and were randomly divided into idoxaban (15mg qd) group and placebo group for comparison .

The results showed that compared with placebo, idoxaban is more effective and safer, and the annual incidence of stroke or systemic embolism is lower (2.
3% vs.
6.
7%, HR 0.
34, 95% CI 0.
19-0.
61, P< 0.
001), there was no significant increase in the risk of major bleeding (HR 1.
87, 95% CI 0.
90-3.
89, P=0.
09).

In summary, the best stroke prevention strategy for patients with atrial fibrillation and ESRD is still uncertain, and randomized controlled trials with sufficient effectiveness are still needed to evaluate the effectiveness and safety of specific treatment options in these patients.

In elderly patients (over 80 years old), the prevalence of atrial fibrillation is 10%-17%, and age is an independent risk factor for adverse outcomes in patients with atrial fibrillation.

With age, the risk of fatal stroke and OAC-related bleeding increases.

Published data confirm the beneficial effect of OAC on stroke prevention in elderly patients with atrial fibrillation.

The BAFTA trial compared the efficacy and safety of VKA and aspirin in elderly patients with atrial fibrillation (average age 81.
5 years).
The results showed that compared with aspirin during the 3-year follow-up, VKA had better efficacy and similar safety Sex.

The small WASPO trial further confirmed the effectiveness of VKA in elderly patients with atrial fibrillation.

For elderly patients with atrial fibrillation using NOAC, a meta-analysis showed that compared with VKA, NOAC had a significantly lower risk of stroke and systemic embolism (RR 0.
70, 95% CI 0.
61-0.
80), while the risk of major bleeding did not increase (RR 0.
91, 95% CI 0.
72-1.
16).

Similarly, other meta-analyses of NOAC clinical trials in patients with atrial fibrillation and venous thromboembolism have yielded roughly similar results.

A large observational cohort study of elderly patients with atrial fibrillation (age> 90 years) showed that compared with VKA, NOAC is more effective and safer, and is associated with a reduction in adverse events and a significant reduction in the risk of ICH.

Although the benefits of OAC therapy in elderly patients with atrial fibrillation have been proven, real-world data show that OAC is underused in elderly patients with atrial fibrillation.

Early studies have shown that only about 50% of elderly patients with atrial fibrillation receive OAC treatment.

Patients who are frail and sick with multiple medications and who are frail with cognitive impairment are less likely to receive OAC, but the use of OAC has a preventive effect on the development of dementia.

Studies have found that atrial fibrillation increases the risk of Alzheimer's disease and vascular dementia, and a higher CHA2DS2-VASc score is associated with an increased risk of cognitive decline.

Researchers speculate that anticoagulation therapy may prevent cognitive decline by reducing minor subclinical thrombotic events.

The use of OAC in patients with atrial fibrillation and frail or cognitive impairment may be effective, while strict stratification of bleeding risk and assessment of frailty in the elderly are required.

Randomized controlled trials are needed to study whether atrial fibrillation is an independent risk factor for dementia and confirm the preventive effect of OAC.

In the past decade, patients with atrial fibrillation have grown older and the burden of comorbidities has increased.

The AFFIRM test showed that 54.
4% of patients with atrial fibrillation have multiple diseases.

A population-based cohort study showed that the cumulative incidence of stroke, major bleeding, and death in patients with coexisting atrial fibrillation was higher than that in patients with fewer comorbidities, and was negatively correlated with OAC use (OR 0.
92, 95% CI 0.
89-0.
92).

In addition, studies have shown that the proportion of multiple medications in patients with atrial fibrillation is high (40%), which is related to poor clinical outcomes.

A meta-analysis published in 2020 showed that 42.
7% of patients with atrial fibrillation use 5-9 drugs, and 20.
7% use more than 9 drugs.

Patients with previous intracranial hemorrhage and atrial fibrillation patients with previous intracranial hemorrhage are particularly challenging to prevent stroke, and their risks of stroke and rebleeding are higher.

In the pivotal NOAC trial, all NOACs were associated with a lower risk of intracranial hemorrhage than warfarin.

Studies have shown that for patients with atrial fibrillation with a history of intracranial hemorrhage, NOAC is more effective and safer than VKA.

Related RCTs, such as PRESTIGE-AF and SoSTART, will evaluate the difference between anticoagulation and non-anticoagulation.

In view of the complexity of ICH and the uncertainty of the benefit-risk ratio of OAC, a multidisciplinary team should assist in evaluating whether to start OAC treatment, and other stroke prevention strategies (such as LAAO) can be considered.

According to the 2020 ESC and AHA/ASA guidelines, if the cause of ICH has been determined and successfully treated, including trauma-related ICH, OAC treatment should be started or restarted after 2-4 weeks.

In all other cases, the risk of bleeding may outweigh the potential benefits of OAC, and some patients may be suitable for LAAO.

Patients with recent acute gastrointestinal bleeding For patients with atrial fibrillation who have recent gastrointestinal bleeding, the available evidence supports the resumption of warfarin therapy as soon as possible after the bleeding event.

Patients who received OAC after gastrointestinal bleeding had a better prognosis than patients who did not receive OAC in terms of thromboembolism and all-cause mortality.

A meta-analysis showed that compared with VKA, patients with atrial fibrillation using NOAC had an increased risk of gastrointestinal bleeding (RR 1.
25, 95% CI 1.
01-1.
55, P=0.
04).

Nevertheless, the net clinical benefit analysis still supports the resumption of OAC treatment after anticoagulant-related gastrointestinal bleeding (net clinical benefit 0.
11, 95% CI 0.
09-0.
14, P<0.
001).

These results are consistent with the expert consensus guidelines of ESC and ACC.

In most patients with atrial fibrillation with gastrointestinal bleeding indicated for OAC, restarting OAC after bleeding can bring positive net clinical benefits, especially in patients with the highest risk of thrombosis.

When the bleeding source is under control and the clinical situation is stable, OAC should be restarted as soon as possible, usually within 7 days after the occurrence of gastrointestinal bleeding.

In addition, in clinical practice, a history of gastrointestinal bleeding may lead to consideration of OAC alternative therapies, such as LAAO.

References: Kotalczyk A, Mazurek M, Kalarus Z, et al.
Stroke prevention strategies in high-risk patients with atrial fibrillation[J].
Nat Rev Cardiol.
2021 Apr; 18(4): 276-290.