Keywords
APHRS - atrial fibrillation - stroke prevention - consensus guidelines - executive
summary
Epidemiology of AF and Risk of AF-Related Stroke
Epidemiology of AF and Risk of AF-Related Stroke
Atrial fibrillation (AF) is a global problem, with an increasing incidence and prevalence
with an aging population.[1] Similar to Western countries, the prevalence rates of AF will continuously increase
in the following decades, which are projected to be 4.0% in Taiwan and 5.4% in South
Korea in year 2050 ([Fig. 1]).[2]
[3]
Fig. 1 Projected prevalence of AF in Taiwan and South Korea. Data used in the figure were
adapted from Chao et al and Kim et al.[2]
[3] AF, atrial fibrillation.
For Asian AF patients, the annual risk of ischemic stroke is around 3.0% (1.60–4.95%)
based on the pooled analysis of eight studies.[4] Importantly, the 1-year risk of ischemic stroke after newly diagnosed AF was similar
from year 2000 (4.45%) to 2010 (3.95%),[2] and gradually decreasing in the era of non-vitamin K antagonist (non-VKA) oral anticoagulants
(NOACs).[5] The observed reduction in stroke risk may be contributed to the increasing initiation
rates of oral anticoagulants (OACs) in newly diagnosed AF patients, which significantly
increased from 13.6 to 35.6%, contemporaneous with the introduction of NOACs ([Fig. 2]).[5]
Fig. 2 Temporal trend of prescriptions of OACs and risks of clinical events in newly diagnosed
AF patients. The figure was redrawn and data were adapted from Chao et al.[5] AF, atrial fibrillation; OACs, oral anticoagulants.
This is an executive summary of the 2021 focused update of the 2017 consensus guidelines
of the Asia-Pacific Heart Rhythm Society (APHRS) on stroke prevention in AF. The full
document has been published in Journal of Arrhythmia
[6] and includes further details of the evidence/data pertaining to the recommendations
made in these guidelines.
The Importance of Integrated or Holistic Care in Managing Patients with AF: Impact
on Stroke Risk Reduction and Adverse Outcomes in AF
The Importance of Integrated or Holistic Care in Managing Patients with AF: Impact
on Stroke Risk Reduction and Adverse Outcomes in AF
Since AF patients usually had multiple comorbidities, a more holistic and integrated
approach to AF management has been proposed to improve clinical outcomes in patients
with AF.[7]
This integrated approach is directed at stroke prevention, better symptom management,
and to tackle other cardiovascular risk factors/comorbidities (e.g., hypertension)
aimed to reduce AF-related mortality, morbidity, and hospitalizations. This can streamline
decision-making for a holistic approach to AF management in an integrated manner,
proposed as the ABC (Atrial fibrillation Better Care) pathway ([Fig. 3])[7]:
-
“A”: Avoid stroke with anticoagulation, i.e., well-managed warfarin (time in therapeutic range [TTR] > 65–70%)
or NOACs. NOACs are recommended in preference to warfarin for NOAC-eligible AF patients.
-
“B”: Better symptom management with patient-centered symptom-directed decisions for rate or rhythm control.
-
“C”: Cardiovascular risk and comorbidity management (blood pressure [BP] control, heart failure, cardiac ischemia, sleep apnea, etc.)
as well as lifestyle changes (obesity reduction, regular exercise, reducing alcohol/stimulants,
psychological morbidity, etc.).
With the focus on patient-centered management, explanation using the simple ABC concept
can also lead to improved understanding and disease awareness amongst patients, better
knowledge about their condition, and the priorities of management. Different health
care professionals managing the AF patient can also discuss the management based on
the A, B, and C pillars of the ABC pathway.
Fig. 3 The ABC pathway of integrated care management. The figure was redrawn and modified
from Lip et al.[7] ABC, Atrial fibrillation Better Care; NOAC, non-vitamin K antagonist oral anticoagulant;
OAC, oral anticoagulant; TTR, time in therapeutic range; VKA, vitamin K antagonist.
A systematic review and meta-analysis showed a lower risk of all-cause death (odds
ratio [OR]: 0.42, 95% confidence interval [CI]: 0.31–0.56), cardiovascular death (OR:
0.37, 95% CI: 0.23–0.58), stroke (OR: 0.55, 95% CI: 0.37–0.82), and major bleeding
(OR: 0.69, 95% CI: 0.51–0.94), with management adherent to the ABC pathway compared
with noncompliance ([Fig. 4]).[8]
Fig. 4 Impacts of adherence to the ABC pathway on clinical outcomes in AF patients. The
figure was redrawn and modified from Romiti et al.[8] ABC, Atrial fibrillation Better Care; CI, confidence interval; OR, odds ratio.
The integrated care AF pathway approach (“simple as ABC…”) has been adopted and promoted
in the Primary Care Clinical Pathway for AF Detection and Management (https://bit.ly/2FhrwXQ). The key feedback from multidisciplinary colleagues is the reassurance felt that
a holistic approach to management can be streamlined across primary–secondary care,
not being regarded as complex but is “simple as ABC…” The ABC pathway is now included
within guidelines from American College of Chest Physicians,[9] the Korean national AF guidelines,[10] and the 2020 European AF guidelines,[11] and is therefore recommended in this guideline as part of the holistic approach
to AF management. In this APHRS consensus document, we will particularly focus on
the “A” domain and update data for stroke prevention in AF, but would highlight the
importance of full compliance with the ABC pathway to improve outcomes in AF patients.
Recommendation
Stroke Risk Assessment (and Re-assessment)
Stroke Risk Assessment (and Re-assessment)
In our 2017 consensus document, we recommended the use of the CHA2DS2-VASc score for stroke risk assessment for Asian AF patients.[12]
In this focused update, we still recommend the use of the CHA2DS2-VASc score as the stroke risk prediction scheme since it has been well validated
in the Asian AF population.[13]
[14]
[15]
[16]
[17]
[18] We should acknowledge that all clinical risk stratification scores are simplifications
to aid decision-making, and to recognize the limitations of such scores. For example,
there are many stroke risk factors[19] and only the more common and validated ones have been included into risk scores,
such as the CHA2DS2-VASc score.
The impact of individual stroke risk factors is not uniform, and for a single CHA2DS2-VASc risk factor in those aged <65, and assuming an ischemic stroke risk treatment
threshold of ≥1% per year with NOACs, the tipping point with heart failure as a single
risk was age 35 years, while for patients with hypertension, diabetes mellitus, and
vascular diseases, the age thresholds for treatment were 50 years, 50 years, and 55
years, respectively.[20]
[21] Not all CHA2DS2-VASc risk factors carry equal weight, as event rates would be dependent on the population
studied (e.g., hospitalized vs. community), study type (trial vs. real world), ethnicity,
and study methodology.[22]
Also, stroke risk is not static, given that aging and incident comorbidities would
increase risk and the dynamic nature of stroke risk in AF would result in increments
of their CHA2DS2-VASc scores.[23] For example, in a study from Taiwan which enrolled 31,039 AF patients without comorbidities
of the CHA2DS2-VASc score except for age and sex at baseline, the mean CHA2DS2-VASc scores increased from 1.29 to 2.31 during a follow-up of 171,956 person-years
([Fig. 5]).[23]
[24]
[25] Similar observations were reported in the Korean nationwide AF registry.[26]
Fig. 5 Cumulative incidences of increment of CHA2DS2-VASc score to ≥1 (males) or ≥2 (females). The figure was redrawn and data were adapted
from Chang et al and Chao et al.[23]
[25] AF, atrial fibrillation.
Both the follow-up CHA2DS2-VASc score and change in stroke risk (“delta-CHA2DS2-VASc” score, i.e., the difference between the baseline and follow-up scores) had
better predictive value for ischemic stroke compared with the baseline CHA2DS2-VASc score.[24]
[27] For initially low-risk (CHA2DS2-VASc score 0 for males or 1 for females) nonanticoagulated AF patients, the use of
OACs once their CHA2DS2-VASc scores increased was associated with a lower risk of clinical events.[28]
In summary, regular reassessment of stroke risk of AF patients and the timely prescriptions
of OACs once the stroke risk of patients increased is important, given the increase
in stroke risks with age and new comorbidities.
Frequency of Stroke Risk Reassessment
Frequency of Stroke Risk Reassessment
Data regarding the reasonable timing interval at which the stroke risk of AF patients
should be reassessed are limited. In the study by Chao et al, which studied 14,606
AF patients with a baseline CHA2DS2-VASc score of 0 (males) or 1 (females), 6,188 patients acquired new risk factors
with the acquisition of one or more new comorbidities approximately 4 to 5 months
after their initial AF diagnosis; the most common incident comorbidity was hypertension,
followed by heart failure, diabetes mellitus, and vascular disease; indeed, the onset
of new comorbidities would depend on the type of comorbidity. Importantly, 596 of
these original patients experienced ischemic stroke and the duration from the acquirement
of incident comorbidities to the occurrence of ischemic stroke was an average of 4.4
months for 90% of the patients.[28] Based on these data, 4 months may be a reasonable timing interval at which the stroke
risk of AF patients should be reassessed.
Recommendations
-
The CHA2DS2-VASc score is recommended for stroke risk assessment for Asian AF patients.
-
The stroke risk of AF patients is not static and should be reassessed regularly (at
least annually and every 4 months if possible).
-
In patients with AF initially at low risk of stroke (CHA2DS2-VASc = 0 in men, or 1 in women), a reassessment of stroke risk should ideally be
made at 4 months after the index evaluation and OACs should be prescribed in a timely
manner once their CHA2DS2-VASc scores increase.
Bleeding Risk Assessment and Reassessment
Bleeding Risk Assessment and Reassessment
As with the 2017 consensus document, the HAS-BLED score is recommended for bleeding
risk assessment for Asian AF patients in this focused update. In a PCORI systematic
review and evidence appraisal, the HAS-BLED score was found to be the best score for
bleeding risk prediction.[29] In a recent analysis of ESC-EHRA EORP-AF General Long-Term Registry, the HAS-BLED
score still performed better than the ORBIT score in the contemporary cohort of AF
patients treated with NOACs.[30]
The HAS-BLED score has been well validated in Asian cohorts, outperforming other bleeding
risk scores (e.g., ATRIA, ORBIT, HEMORRH2AGES) and an approach simply focused only
on modifiable bleeding risks.[31] The HAS-BLED score performs well even in contemporary AF patients taking NOACs.[30] Bleeding risk is also not static and may change among AF patients initially having
a low HAS-BLED score (≤2).[32] In a previous study from Taiwan, the accuracy of the follow-up or delta HAS-BLED
score in the prediction of major bleeding was significantly higher than that of the
baseline HAS-BLED score; importantly, the bleeding risk is higher within several months
after the increment of the HAS-BLED score.[32] The HAS-BLED score has also been validated in AF patients who are taking no antithrombotic
therapy (e.g., when first diagnosed), antiplatelet therapy (e.g., when AF develops
in patients on aspirin for vascular disease), and on anticoagulation (whether warfarin
or NOACs). Thus, the HAS-BLED score would be applicable at all steps of the patient-management
pathway.
Appropriate use of the HAS-BLED score has been tested in the mAFA-II trial,[33] which was a prospective cluster-randomized trial that compared an mHealth integrated
care approach against usual care. The intervention arm used the HAS-BLED to identify
and mitigate modifiable bleeding risks, and schedule high bleeding risk patients for
regular review and follow-up; this led to lower major bleeding rates at 1 year and
an increase in OAC use.[34] In contrast, the usual care arm has higher major bleeding and a decline in OAC use
([Fig. 6]). A recent study from Taiwan further demonstrated that for anticoagulated AF patients
with a baseline HAS-BLED score of 0 to 2 which increased to ≥3, the continuation of
OACs was associated with better clinical outcomes.[35] A high HAS-BLED score is not a reason to withhold OACs even among AF patients with
one non-sex risk factor (CHA2DS2-VASc score 1 for males and 2 for females) but a high bleeding risk (HAS-BLED score
≥ 3) as the use of OACs was still associated with a lower risk of composite adverse
events of ischemic stroke, intracranial hemorrhage (ICH), or mortality (adjusted hazard
ratio [aHR]: 0.781) in this population.[36]
Fig. 6 Use of OACs and risk of bleeding among patients who received integrated care approach
and usual care. The figure was redrawn and modified from Guo et al.[34] AF, atrial fibrillation; BP, blood pressure; INR, international normalized ratio;
NOAC, non-vitamin K antagonist oral anticoagulant; OACs, oral anticoagulants.
In summary, bleeding risk reassessment is important for anticoagulated AF patients,
and the appropriate and responsible use of bleeding risk scores such as the HAS-BLED
score is to identify and mitigate modifiable bleeding risk factors, and to identify
high bleeding risk patients for early review and follow-up.
Recommendations
-
For bleeding risk assessment, a formal structured risk-score-based bleeding risk assessment
with the HAS-BLED score is recommended to help identify nonmodifiable and address
modifiable bleeding risk factors, and to identify patients potentially at high bleeding
risk for early and more frequent clinical review and follow-up.
-
The bleeding risk of AF patients is not static, which should be reassessed regularly,
and the identified modifiable bleeding risk factors should be corrected.
-
An increased HAS-BLED score in anticoagulated AF patients should not be the only reason
to withhold OACs, but reminds physicians to correct modifiable bleeding risk factors
and follow up patients more closely.
In this focused update, we emphasize the dynamic natures of CHA2DS2-VASc and HAS-BLED scores and highly emphasize the clinical importance of risk reassessment.
The recommended clinical practice about stroke and bleeding risk assessments is summarized
in [Fig. 7].
Fig. 7 Stroke and bleeding risk assessment in AF. The figure was redrawn and modified from
Chang et al.[23] AF, atrial fibrillation; NOAC, non-vitamin K antagonist oral anticoagulant; NSAIDs,
nonsteroidal anti-inflammatory drugs; OACs, oral anticoagulants; TTR, time in therapeutic
range.
Approach to Stroke Prevention in Asian AF Patients
Approach to Stroke Prevention in Asian AF Patients
Given the limitations of all stroke risk scores in predicting high stroke risk in
AF patients and the dynamic nature of stroke risk, the artificial categorization into
low, moderate, and high risk strata is discouraged. Thus, stroke prevention (which
is oral anticoagulation) should be the default strategy, unless patients are at low
risk (defined as CHA2DS2VASc score 0 in males or 1 in females). [Fig. 8] shows our recommendations, which were consistent to other guidelines.[9]
Fig. 8 Three-step approach for the use of OACs for stroke prevention in AF. The flowchart
was redrawn and modified from Lip et al.[9] AF, atrial fibrillation; INR, international normalized ratio; NOAC, non-vitamin
K antagonist oral anticoagulant; OACs, oral anticoagulants; VKA, vitamin K antagonist.
Patients with AF and significant valvular heart disease (previously referred to as
“valvular AF”), defined as prosthetic mechanical heart valves or moderate–severe mitral
stenosis, should be offered warfarin, when oral anticoagulation is recommended.[37] Indeed, NOACs are contraindicated in such patients.
In other patients without significant valvular heart disease (so-called “nonvalvular
AF” [NVAF]), the first step (Step 1) is to identify low-risk patients (CHA2DS2VASc score 0 in males or 1 in females) where no antithrombotic therapy is recommended.
The next step (Step 2) is to offer stroke prevention (i.e., oral anticoagulation) to patients with ≥1 non-sex
stroke risk factors (i.e., CHA2DS2VASc score ≥1 in males or ≥2 in females). Most of the randomized trials included patients
with ≥2 non-sex stroke risk factors, but some clinical trials with warfarin (ACTIVE-W),
dabigatran, and apixaban (RE-LY, ARISTOTLE, AVERROES) included patients with a single
non-sex stroke risk factor.[38]
[39]
[40]
[41]
Since the risk of stroke of each CHA2DS2-VASc risk component was not the same and age is an important driver, patients' ages
and the comorbidities which contribute to the score 1 for males or 2 for females could
be considered when making management decisions about the use of OACs or not[20]
[42]
[43]
[44]
[45]
[46] as summarized in [Fig. 9]. As OAC is being started, bleeding risk assessment is recommended, using the HAS-BLED
score to identify and mitigate modifiable bleeding risks, and to identify high bleeding
risk patients for early review and follow-up.
Fig. 9 Considerations about the use of NOACs for Asian AF patients with a CHA2DS2-VASc score of 1 (males) or 2 (females). AF, atrial fibrillation; NOAC, non-vitamin
K antagonist oral anticoagulant.
Step 3 is to make the choice of OAC. We recommend the use of NOACs in preference to warfarin
for stroke prevention. If NOACs are used, the recommended label dosing is important,
given that the best outcomes are with label-adherent prescribing.[47]
[48]
[49]
[50]
[51]
[52] Apart from guideline-directed anticoagulation prescribing, adherence and persistence
with therapy are important.[53]
[54]
[55]
If warfarin is considered, we recommend a target international normalized ratio (INR)
of 2.0 to 3.0 with an average TTR ≥65% (ideally ≥70%). We do not recommend low-intensity
anticoagulation or lower target INRs, given the higher risk of thromboembolism although
bleeding risk is lower.[56] Of note, a “one off” INR reading gives no indication of the quality of anticoagulation
control, and many serious bleeds occur when the INR is between 2.0 and 3.0.[57] A high TTR is associated with low rates of stroke and bleeding,[58] but many factors influence the quality of anticoagulation control. The more common
and validated factors associated with poor labile INRs have been used to formulate
clinical risk scores such as the SAMe-TT2R2 scores. A high SAMe-TT2R2 score (>2) is associated with a likelihood of poor TTR, and such patients should
be flagged up for more attention to ensure good-quality anticoagulation (e.g., education
and counseling, more frequent INR checks) or to reconsider the decision to prescribe
NOACs (if suitable).[59]
[60]
[61]
[62]
[63] One ongoing prospective randomized trial, TREAT-AF, is examining the impact of an
educational intervention versus usual care on anticoagulation therapy control based
on a SAMe-TT2R2 score-guided management strategy amongst anticoagulant-naïve Thai patients with AF.[64]
Recommendations
-
In AF patients with mechanical heart valves or moderate-to-severe mitral stenosis,
warfarin is recommended.
-
For stroke prevention in AF patients without significant valvular heart disease (i.e.,
mechanical heart valves or moderate-to-severe mitral stenosis; so-called “valvular
AF”) who are eligible for OAC, NOACs are recommended in preference to VKAs.
-
Clinical pattern of AF (i.e., whether first detected, paroxysmal, persistent, long-standing
persistent, permanent) should not condition the indication to thromboprophylaxis,
if stroke risk factors are present.
-
For stroke risk assessment, a risk-factor-based approach is recommended, using the
CHA2DS2-VASc stroke risk score to initially identify patients at “low stroke risk” (CHA2DS2-VASc = 0 in men, or 1 in women) who should not be offered antithrombotic therapy.
-
In AF patients with CHA2DS2-VASc score ≥2 in men or ≥3 in women, OAC is recommended for stroke prevention.
-
In AF patients with a CHA2DS2-VASc score of 1 in men or 2 in women, OAC should be considered for stroke prevention.
Different age thresholds for different comorbidities may help guide NOAC use (e.g.,
age 35 years for heart failure, 50 years for hypertension or diabetes mellitus, and
55 for vascular diseases).
-
If a VKA is used, a target INR of 2.0 to 3.0 is recommended, with individual TTR ≥65%
(ideally ≥70%).
-
- A high SAMe-TT2R2 score (>2) is associated with a likelihood of poor TTR, and such patients have more
attention to ensure good-quality anticoagulation (e.g., education and counseling,
more frequent INR checks) or to reconsider the decision to prescribe NOACs (if suitable).
-
In patients on VKAs with low time in INR therapeutic range (e.g., TTR < 70%), recommended
options are:
-
- Switching to a NOAC but ensuring good adherence and persistence with therapy.
-
- Efforts to improve TTR (e.g., education/counseling and more frequent INR checks).
-
Antiplatelet therapy alone (monotherapy or aspirin in combination with clopidogrel)
is not recommended for stroke prevention in AF patients.
-
Estimated bleeding risk, in the absence of absolute contraindications to OAC, or patients
at high risk of falls, should not in itself guide treatment decisions to use OAC for
stroke prevention.
Review Update Data Regarding Warfarin (Including INR Range) in Asia
Review Update Data Regarding Warfarin (Including INR Range) in Asia
When OAC is being considered, NOACs are the preferred option for stroke prevention
in AF, because the benefits of NOAC on efficacy and safety compared with the VKAs
are more profound in Asian than non-Asian population.[65] In some settings, the use of VKA is still needed because of the high cost of NOACs
or in patients with specific indications including moderate to severe mitral stenosis
and mechanical heart valves. Maintenance of a high TTR has been shown to reduce the
risk of ischemic and bleeding events and should be the primary goal in the treatment
of these patients independent of the type of management approach. Conversely, a change
in the approach to these patients needs to be considered if a low TTR is consistently
observed.
Several observational studies suggested that low-intensity warfarin therapy can reduce
hemorrhage without increasing thromboembolism for East-Asian patients with NVAF receiving
warfarin therapy, but the evidence is weak and no focus on quality of anticoagulation
control, as reflected by TTR.[66]
[67] In a systematic review and evidence appraisal, low-intensity anticoagulation or
lower target INRs are associated with a higher risk of thromboembolism although bleeding
risk may be lower.[56] Of note, a “one off” INR reading does not reflect the quality of anticoagulation
control, especially since many serious bleeds actually occur when the INR is between
2.0 and 3.0.[57] Hence, we strongly recommend evidence-based management, with the strongest data
currently for INR 2.0 to 3.0 and TTR ideally ≥65% (or even 70%) in Asian patients.[68] We should ensure TTR is ≥65% (optimal ≥70%), with appropriate education and counseling,
or more frequent INR checks. Efforts to improve OAC uptake, adherence, and persistence
with therapy are also crucial, as are efforts to improve service provisions.[69]
[70]
[71]
Recommendations
-
The use of VKA is recommended in patients with moderate to severe mitral stenosis
and mechanical heart valve.
-
For the optimal management of VKA therapy, INR of 2.0 to 3.0 is recommended in Asian
AF patients, with attention to ensure TTR is ≥65%.
The results of the four pivotal phase III NOAC trials showed that all NOACs were at
least noninferior to warfarin in prevention of stroke/thromboembolism, and NOACs were
associated with lower rates of intracranial bleeding than was warfarin. In the meta-analysis
of four NOACs,[72] NOACs significantly reduced stroke or systemic embolic events by 19% compared with
warfarin (relative risk [RR]: 0.81, 95% CI: 0.73–0.91; p < 0.0001), mainly driven by a reduction in hemorrhagic stroke (RR: 0.49, 95% CI:
0.38–0.64; p < 0.0001). NOACs also significantly reduced all-cause mortality (RR: 0.90, 95% CI:
0.85–0.95; p = 0.0003) and ICH (RR: 0.48, 95% CI: 0.39–0.59; p < 0.0001), but increased gastrointestinal (GI) bleeding (RR: 1.25, 95% CI: 1.01–1.55;
p = 0.04). There was a greater RR reduction in major bleeding with NOACs when the TTR
was less than 66% than when it was 66% or more (RR: 0.69, 95% CI: 0.59–0.81 vs. RR:
0.93, 95% CI: 0.76–1.13; p for interaction = 0.022).
The efficacy and safety of NOACs was more profound in the Asian population than in
non-Asian population.[65] Comparing with VKAs, standard-dose NOACs reduced stroke or systemic embolism (SE;
OR = 0.65 vs. 0.85, p interaction = 0.045) more in Asians than in non-Asians and were safer in Asians than
in non-Asians for major bleeding (OR = 0.57 vs. 0.89, p interaction = 0.004) and hemorrhagic stroke (OR = 0.32 vs. 0.56, p interaction = 0.046). There was no excess of GI bleeds in Asians, whereas GI bleeding
was significantly increased in non-Asians (OR = 0.79 vs. 1.44, p interaction = 0.041). Generally, reduced-dose NOACs were safer than VKAs without
heterogeneity in efficacy and safety between Asians and non-Asians, except for ischemic
stroke, major bleeding, and GI bleeding.[65] In the recent subanalysis of ENGAGE AF-TIMI 48 trial comparing patients of Asian
and non-Asian races, Asians treated with warfarin had a higher adjusted risk of ICH
(aHR: 1.71, p = 0.03) compared with non-Asians.[73] Compared with warfarin, higher dose edoxaban significantly reduced ICH while preserving
the efficacy of stroke prevention in both Asians and non-Asians. Two of three net
clinical outcomes appeared to be more favorably reduced with edoxaban in Asians compared
with non-Asians (p
int = 0.063 for primary, 0.037 for secondary, and 0.032 for third net clinical outcomes,
respectively).
Real-World Data about NOACs in Asia
Real-World Data about NOACs in Asia
In a systematic review and meta-analysis of real-world comparisons of NOACs for stroke
prevention in Asian patients with AF,[74] the NOACs were associated with lower risks of thromboembolism (HR: 0.70; [95% CI:
0.63–0.78]), acute myocardial infarction (0.67; [0.57–0.79]), all-cause mortality
(0.62; [0.56–0.69]), major bleeding (0.59; [0.50–0.69]), ICH (0.50; [0.40–0.62]),
GI bleeding (0.66; [0.46–0.95]), and any bleeding (0.82; [0.73–0.92]) than warfarin.
While real-world data are no substitute for randomized trials, this meta-analysis
shows that the NOACs had greater effectiveness and safety compared with warfarin in
real-world practice for stroke prevention, among Asian patients with NVAF.[74]
NOACs also showed better effectiveness and safety than warfarin in “high risk” real-world
Asian AF populations including the very elderly, those with low body weight or liver
disease.[45]
[75]
[76]
[77]
[78]
[79]
[80]
The Importance of On-Label Dosing of NOACs in Asians
The Importance of On-Label Dosing of NOACs in Asians
Varying degrees of renal function require recommendations for reduced dosing regimens
of NOACs; however, different cut-off values for age, body weight, or interacting drugs
also require consideration for appropriate dose selection. In routine clinical practice
in Asia, prescribed NOAC doses are often inconsistent with drug labeling.[47]
[48]
[49]
[50]
[52] These prescribing patterns may be associated with worse safety profiles with no
benefit in effectiveness in patients with severe kidney disease and worse effectiveness
with no benefit in safety in apixaban-treated patients with normal or mildly impaired
renal function.[81]
[82]
In meta-analysis of four NOAC trials, low-dose NOAC regimens showed similar overall
reductions in stroke or systemic embolic events to warfarin (RR: 1.03, 95% CI: 0.84–1.27;
p = 0.74), and a more favorable bleeding profile (RR: 0.65, 95% CI: 0.43–1.00; p = 0.05), but significantly more ischemic strokes (RR: 1.28, 95% CI: 1.02–1.60; p = 0.045).[72]
In patients eligible for reduced-dose NOACs, effects of reduced-dose NOACs compared
with warfarin on stroke or SE (RR 0.84, 95% CI 0.69–1.03) and on major bleeding (RR:
0.70, 95% CI: 0.50–0.97) were consistent with those of full-dose NOACs relative to
warfarin (RR: 0.86, 95% CI: 0.77–0.96 for stroke or SE and RR: 0.87, 95% CI: 0.70–1.08
for major bleeding; interaction p-values of 0.89 and 0.26, respectively). In addition, NOACs were associated with reduced
risks of hemorrhagic stroke, ICH, fatal bleeding, and death regardless of patients'
eligibilities for NOAC dose reduction (interaction p > 0.05 for each).[83]
When checking the eligibility and determining the dosages of NOACs, it should be emphasized
that the creatinine clearance (CCr) of AF patients should be calculated using the
Cockcroft–Gault (CG) equation which was adopted in four pivotal randomized clinical
trials.[84] Compared with the CG formula, modified diet in renal disease (MDRD) or Chronic Kidney
Disease Epidemiology Collaboration (CKD-EPI) equations would overestimate the renal
functions of AF patients, especially for the elderly (≥75 years) and those with a
low body weight (<50 kg).[85] The overestimations of the estimated glomerular filtration rates (eGFRs) would potentially
result in inappropriate dosing of NOACs (mainly overdoing), and may therefore, attenuate
the advantages of NOACs compared with warfarin.[85]
A dose reduction of rivaroxaban in Asian patients might be necessary, but lacks the
confirmation in large adequately powered prospective randomized clinical trials. Pharmacokinetic
modeling data indicated that, at steady state, the distribution of both the maximum
concentration and area under the curve (AUC) of rivaroxaban in Japanese patients with
AF who received a 15 mg o.d. (once daily) dose of rivaroxaban would be comparable
to the C
max and AUC 0 to 24, in Caucasian patients with AF who received a 20 mg o.d. dose. Accordingly,
instead of the 20 and 15 mg o.d. dose, the 15 and 10 mg o.d. doses of rivaroxaban
were selected in Japan. The Korean AF guidelines recommend the use of 15 mg o.d. dose
of rivaroxaban in very elderly (≥80 years) AF patients.[10] Another recent study from Taiwan which compared the clinical outcomes of AF patients
receiving rivaroxaban following ROCKET-AF and J-ROCKET AF dosing regimens demonstrated
that the risks of stroke/systemic and major bleeding did not differ significantly
between the two groups.[86] However, a lower risk of major bleeding was observed for J-ROCKET AF dosing among
patients with an eGFR <50 mL/min with a borderline p-value of 0.0445.[86] Of note, off-label underdosing rivaroxaban (10 mg/d for patients with an eGFR >50 mL/min)
should be avoided since it was associated with a 2.75-fold higher risk of ischemic
stroke.[49]
Recommendations
-
Because NOACs are more effective and safer than warfarin in Asian AF patients, NOACs
are the recommended choice of oral anticoagulation in Asian AF patients.
-
The CG equation should be adopted to calculate CCr to determine the dosing of NOACs.
-
On-label or guideline-adherent dosing of NOACs is recommended in Asian patients.
AF Complicating Acute Coronary Syndrome/Percutaneous Coronary Intervention
AF Complicating Acute Coronary Syndrome/Percutaneous Coronary Intervention
AF often occurs in patients with coronary artery disease (CAD). It has been reported
that 5 to 8% of patients who undergo percutaneous coronary intervention (PCI) have
AF.[87]
[88] Importantly, patients with CAD and AF are at high risk of stroke.
In the warfarin era, a major concern in Asian patients with AF was the risk of serious
bleeding by combining OAC with antiplatelets; however, temporal trends of patients
with AF undergoing PCI after introduction of NOAC show increasing use of OAC and combination
therapy with antiplatelets, especially in the NOAC era ([Fig. 10]).[89]
Fig. 10 Increasing use of OACs (especially NOACs) and combination therapy with antiplatelet
agents among AF patients undergoing percutaneous coronary intervention. The figure
was redrawn and data were adapted from Kwon et al.[89] AF, atrial fibrillation; DAPT, dual antiplatelet therapy; NOAC, non-vitamin K antagonist
oral anticoagulant.
Patients with CAD and AF are not only at risk of stroke, but also at risk of bleeding
due to associated comorbidities, and decision making should balance ischemic and bleeding
risks when considering the duration, type, and treatment regime especially given the
potential sensitivity of Asians to bleeding risks on OAC ([Fig. 11]).[90]
[91]
Fig. 11 Factors tipping the balance between ischemic and bleeding risk in AF patients presenting
with ACS and/or undergoing PCI. The figure was redrawn and modified from Vitolo et
al.[90] ACS, acute coronary syndrome; AF, atrial fibrillation; BMI, body mass index; BRS,
bioresorbable scaffold; CKD, chronic kidney disease; CTO, chronic total occlusion;
DAT, dual antithrombotic therapy; DES, drug-eluting stent; ESRD, end-stage renal disease;
LAD, left anterior descending artery; MI, myocardial infarction; NSAID, nonsteroidal
anti-inflammatory drug; PCI, percutaneous coronary intervention; TAT, triple antithrombotic
therapy.
In the warfarin era, the WOEST study demonstrated a higher bleeding risk of triple
therapy compared with double therapy of OACs and clopidogrel.[92] More recently, the safety and efficacy of NOACs in combination with antiplatelet
drugs in patients with CAD and AF have been reported in the PIONEER AF-PCI,[93] RE-DUAL PCI,[94] AUGUSTUS,[95] and ENTRUST-AF PCI trials.[96] The summary of those trials is presented in [Table 1].
Table 1
Summary of four randomized clinical trials in patients with coronary artery disease
and atrial fibrillation[93]
[94]
[95]
[96]
|
PIONEER-PCI
|
RE-DUAL PCI
|
AUGUSTUS
|
ENTRUST-AF PCI
|
|
No. of participating patients (Asian patients, %)
|
2,124
(4.0%)
|
2,725
(NA)
|
4,614
(3.1%)
|
1,506
(11.2%)
|
|
Randomization
|
• Rivaroxaban 15 mg + a P2Y12 inhibitor (group 1)
• Rivaroxaban 2.5 mg + DAPT (group 2)
• VKA + DAPT (group 3)
|
• Dabigatran 110 mg + a P2Y12 inhibitor
• Dabigatran 150 mg + a P2Y12 inhibitor
• VKA + DAPT
(except United States, dabigatran 110 mg + a P2Y12 inhibitor or VKA + DAPT for elderly
patients)
|
A 2 × 2 factorial design
• Apixaban 5 mg vs. VKA
• Aspirin vs. placebo
|
• Edoxaban 60 mg + a P2Y12 inhibitor vs. VKA + DAPT
|
|
Duration from the PCI to randomization
|
Within 72 hours
|
Within 120 hours
|
Within 14 days
|
4 hours to 5 days
|
|
Primary endpoint
|
Major or minor bleeding
|
Major or minor bleeding
|
Major or minor bleeding
|
Major or minor bleeding
|
|
Hazard ratio for the primary endpoint
|
Group 1 vs. group 3: 0.59 (0.47–0.76)
Group 2 vs. group 3: 0.63 (0.50–0.80)
|
Dabigatran 110 mg vs. VKA + DAPT: 0.52 (0.42–0.63)
Dabigatran 150 mg vs. VKA + DAPT: 0.72 (0.58–0.88)
|
Apixaban 5 mg vs. VKA: 0.69 (0.58–0.81)
Aspirin vs. placebo: 1.89 (1.59–2.24)
|
Edoxaban + a P2Y12 inhibitor vs. VKA + DAPT: 0.83 (0.65–1.05)
|
Abbreviations: DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention;
VKA, vitamin K antagonist.
In the PIONEER AF-PCI, RE-DUAL PCI, and ENTRUST-AF PCI trials, dual therapy with a
NOAC and a P2Y12 inhibitor was compared with a triple therapy with warfarin plus a
dual antiplatelet therapy (DAPT). In the RE-DUAL PCI trial, elderly patients (≥80
years; age ≥ 70 years in Japan) were given 110 mg of dabigatran when assigned to the
dual therapy group. The PIONEER AF-PCI and RE-DUAL PCI trials demonstrated that dual
therapy decreased bleeding and did not increase thrombotic events, as compared with
triple therapy. In the ENTRUST-AF PCI trial, dual therapy was noninferior to triple
therapy for bleeding. The RE-DUAL PCI trial was also adequately powered to investigate
a comparison of the combined dabigatran arms against warfarin for the composite thrombotic
outcomes, and no significant difference was seen. The highest ticagrelor use was in
RE-DUAL PCI, where 12% of the trial cohort used ticagrelor instead of clopidogrel;
no significant interaction was evident.[97] Based on these trials, a NOAC-based anticoagulation strategy was safer than a warfarin-based
strategy in terms of bleeding.
The role of aspirin was tested in the AUGUSTUS trial using a two-by-two factorial
design.[95] In the AUGUSTUS trial, the use of apixaban reduced bleeding by 31% as compared with
VKAs, and the use of aspirin resulted in an increase in bleeding by 47%, i.e., dual
therapy with apixaban and a P2Y12 inhibitor was associated with a lower rate of bleeding
than triple therapy or dual therapy with warfarin. Furthermore, patients taking apixaban
had a lower incidence of death or hospitalization than those taking VKAs, mainly driven
by a reduction in the incidence of hospitalizations. The incidence of death or ischemic
events did not differ significantly between aspirin and a placebo or between apixaban
and VKAs, but was numerically greater in the placebo-treated patients compared with
aspirin. The incidence of stroke decreased by 50% in patients with apixaban as compared
those with VKAs.
In all four trials, randomization was performed after the PCI, and all patients were
treated by triple therapy during the periprocedural period, in which stent thromboses
were most likely to occur. Thus, this consensus recommends an initial period of triple
therapy with OAC plus a DAPT during the PCI and the following 7 to 28 days, depending
on the balance between thrombotic and bleeding risks ([Fig. 12]), as recommended by 2021 European Heart Rhythm Association (EHRA) Practical Guide
on the Use of NOACs in Patients with AF.[98] Indeed, in patients at very high bleeding risks and acceptable thrombotic risk,
aspirin may be dropped much earlier. In contrast, where patients have a high thrombotic
risk (e.g., post-acute coronary syndrome [post-ACS]) but acceptable bleeding risks,
the period of triple therapy should be continued for at least 4 weeks.
Fig. 12 Anticoagulation therapy after elective PCI or ACS in AF patients. A, aspirin 75–100 mg
QD; C, clopidogrel 75 mg QD; Tica, ticagrelor 90 mg BID. The figure was redrawn and
modified from the 2021 European Heart Rhythm Association Practical Guide on the use
of NOACs in patients with AF by Steffel et al.[98] ACS, acute coronary syndrome; AF, atrial fibrillation; BID, twice daily; BMS, bare
metal stent; DES, drug-eluting stent; LAD, left anterior descending artery; MI, myocardial
infarction; NOAC, non-vitamin K antagonist oral anticoagulant; PCI, percutaneous coronary
intervention; PPI, proton pump inhibitor; QD, once daily.
Following the period of triple therapy, patients should be managed with an OAC plus
a P2Y12 inhibitor, usually clopidogrel. After 1 year, the patient should be managed
with OAC alone. The OAC strategy should be a NOAC (ideally with the potential for
less bleeding) or if on warfarin, with good-quality anticoagulation control (TTR ≥
70%)
Beyond 1 year, the evidence suggests that OAC monotherapy is the preferred option,
given similar or worse major adverse cardiac events and more bleeding with combining
NOAC and antiplatelets.[99] The AFIRE trial included AF patients who underwent PCI or coronary artery bypass
grafting (CABG) more than 1 year earlier or did not require revascularization.[100] The patients were assigned to receive monotherapy with rivaroxaban (10 mg o.d. for
patients with an eGFR of 15 to 49 mL/min or 15 mg o.d. for patients with an eGFR ≥50 mL/min)
or a combination of rivaroxaban plus a single antiplatelet drug. The incidence of
both cardiovascular and noncardiovascular death was lower in the rivaroxaban monotherapy
group. For the primary efficacy endpoint (a composite of stroke, SE, myocardial infarction,
unstable angina requiring revascularization, or death from any cause), monotherapy
was noninferior to dual therapy (HR: 0.72, 95% CI: 0.55–0.95). Additionally, monotherapy
decreased major bleeding by 41%. Therefore, monotherapy with rivaroxaban is recommended
rather than a combination of rivaroxaban with an antiplatelet drug in AF patients
with stable CAD at more than 1 year after a PCI or CABG. Although the AFIRE trial
only investigated rivaroxaban at the J-ROCKET AF dosing, it suggests that monotherapy
with a NOAC at the stroke prevention dosing without a combination of an antiplatelet
drug is favored for AF patients with stable CAD.
Recommendations
-
In AF patients eligible for NOACs, it is recommended to use a NOAC in preference to
a VKA in combination with antiplatelet therapy.
-
In patients at high bleeding risk (HAS-BLED ≥ 3), rivaroxaban 15 mg o.d. should be
considered in preference to rivaroxaban 20 mg o.d. for the duration of concomitant
single or DAPT, to mitigate bleeding risk.
-
In patients at high bleeding risk (HAS-BLED ≥ 3), dabigatran 110 mg b.i.d. (twice
daily) should be considered in preference to dabigatran 150 mg b.i.d. for the duration
of concomitant single or DAPT, to mitigate bleeding risk.
-
In AF patients with an indication for a VKA in combination with antiplatelet therapy,
the VKA dosing should be carefully regulated with a target INR of 2.0 to 2.5 and TTR
>70%.
Patients with ACS
-
In AF patients with ACS undergoing an uncomplicated PCI, early cessation (≤1 week)
of aspirin and continuation of dual therapy with an OAC and a P2Y12 inhibitor (preferably
clopidogrel) for up to 12 months is recommended if the risk of stent thrombosis is
low or if concerns about bleeding risk prevail over concerns about risk of stent thrombosis.
-
Triple therapy with aspirin, clopidogrel, and an OAC for longer than 1 week after
an ACS should be considered when risk of stent thrombosis outweighs the bleeding risk,
with the total duration (≤1 month) decided according to assessment of these risks.
Elective PCI
-
After uncomplicated PCI for stable CAD, early cessation (≤1 week) of aspirin and continuation
of dual therapy with OAC for up to 6 months and clopidogrel is recommended if the
risk of stent thrombosis is low or if concerns about bleeding risk prevail over concerns
about risk of stent thrombosis, irrespective of the type of stent used.
-
After uncomplicated PCI for stable CAD, triple therapy with aspirin, clopidogrel,
and an OAC for longer than 1 week should be considered when risk of stent thrombosis
outweighs the bleeding risk, with the total duration (≤1 month) decided according
to assessment of these risks.
Stable CAD: In patients with stable CAD, such as more than 1 year after the PCI or CABG, a standard
dose of NOAC monotherapy is recommended.
Footnotes
Risk of stent thrombosis encompasses: (1) risk of thrombosis occurring, and (2) risk
of death should stent thrombosis occur, both of which relate to anatomical, procedural,
and clinical characteristics. Risk factors for stable CAD (chronic coronary syndrome)
patients include: stenting of left main stem or last remaining patent artery; suboptimal
stent deployment; stent length >60 mm; diabetes mellitus; chronic kidney disease;
bifurcation with two stents implanted; treatment of chronic total occlusion; and previous
stent thrombosis on adequate antithrombotic therapy.
Management of OACs before, during, and after AF Ablation
Management of OACs before, during, and after AF Ablation
Catheter ablation procedures for AF are associated with both prothromboembolic and
bleeding risks, and appropriate anticoagulation managements before, during, and after
the procedure are quite important. Since the COMPARE randomized study demonstrated
lower risks of both thromboembolism and bleeding complications under uninterrupted
VKA compared with interrupted VKA with heparin bridging,[101] it is generally accepted that the procedure should be performed without interrupting
VKA, when anticoagulation control is appropriate.[102]
NOACs are currently used in many patients even in those undergoing AF ablation. The
Japanese Catheter Ablation Registry of AF (J-CARAF) during 2011 to 2016 showed that
of the 9,048 patients with periprocedural oral anticoagulation, 3,231 (35.7%) were
treated with VKA, whereas the other 5,817 (64.3%) were managed with NOACs.[103] A meta-analysis of nonrandomized studies showed that interrupted dabigatran for
a minimum period (12–24 hours) before the procedure was associated with similar thromboembolism
and bleeding complication rates to uninterrupted VKA.[104]
Several randomized, prospective clinical trials on uninterrupted NOACs versus uninterrupted
VKA have been conducted ([Table 2]). These trials include VENTURE-AF study for rivaroxaban versus VKA[105]; RE-CIRCUIT study for dabigatran versus VKA[106]; AXAFA-AFNET 5 study for apixaban versus VKA[107]; and ELIMINATE-AF study for edoxaban versus VKA.[108] In these studies, therapeutic doses of NOACs and VKA with target prothrombin time-INR
between 2.0 and 3.0 were generally administered for >3 weeks before ablation, with
exception of short-period administration in some cases in which transesophageal or
intracardiac echocardiography confirmed the absence of intra-atrial thrombus. After
the ablation procedure, the drugs were continued for >30 days. During the procedure,
heparin was given to maintain activated clotting time >300 seconds in all studies.
The RE-CIRCUIT,[106] AXAFA-AFNET 5,[107] and ELIMINATE-AF[108] studies included patients enrolled from the Asian countries. The incidences of major
complications in uninterrupted NOACs versus uninterrupted VKA groups in each study
are shown in [Table 2].
Table 2
Outlines and major outcomes of four randomized trials on NOACs versus VKA for AF ablations[105]
[106]
[107]
[108]
|
VENTURE-AF
|
RE-CIRCUIT
|
AXAFA-AFNET
|
ELIMINATE-AF
|
|
NOAC
|
Rivaroxaban
20 mg QD (evening)
|
Dabigatran
150 mg BID
|
Apixaban
5 mg BID[a]
|
Edoxaban
60 mg QD[a] (evening)
|
|
Comparator
|
VKA
(INR, 2.0–3.0)
|
VKA
(INR, 2.0–3.0)
|
VKA
(INR, 2.0–3.0)
|
VKA
(INR, 2.0–3.0)
|
|
Study design
|
Open-label, randomized
|
Open-label, randomized
|
Open-label, randomized
|
Open-label, randomized
|
|
No. of patients (NOAC vs. VKA)
|
124 vs. 124
|
317 vs. 318
|
318 vs. 315
|
375 vs. 178
|
|
Enrollment from Asian countries
|
No
|
Yes
|
Yes
|
Yes
|
|
Duration of administration before ablation
|
>3 wk
|
4–8 wk
|
>30 days
|
3–4 wk
|
|
Follow-up period after ablation
|
>30 days
|
8 weeks
|
>30 days
|
90 days
|
|
Patient characteristics
|
|
|
|
|
|
Mean or median age (y)
|
59.6 ± 10.2
|
59.1 ± 10.4
|
64 (58, 70)
|
60.5 (53–67)
|
|
Percentage of male patients
|
71.0%
|
74.8%
|
67.0%
|
71.5%
|
|
Percentage of paroxysmal AF
|
73.4%
|
67.6%
|
58.0%
|
67.6%
|
|
Mean CHA2DS2-VASc score
|
1.6
|
2.1
|
2.4
|
0/1 in 49.8%
|
|
Primary endpoints
|
ISTH/GUSTO/TIMI major bleeding
|
ISTH major bleeding
|
All-cause death, stroke, or major bleeding
|
All-cause death, stroke (ischemic, hemorrhagic, or undetermined), or ISTH major bleeding
|
|
Major complication rates
|
Rivaroxaban
|
VKA
|
Dabigatran
|
VKA
|
Apixaban
|
VKA
|
Edoxaban
|
VKA
|
|
ISTH major bleeding
|
0%
|
0.8%
|
1.6%
|
6.9%
|
3.1%
|
4.4%
|
2.4%
|
1.7%
|
|
Ischemic stroke
|
0%
|
0.8%
|
0%
|
0.3%
|
0.6%
|
0%
|
0.3%
|
0%
|
|
Death
|
0%
|
0.8%
|
0%
|
0%
|
0.3%
|
0.3%
|
0%
|
0%
|
|
Composite
|
0%
|
2.4%
|
1.6%
|
7.2%
|
4.0%
|
4.7%
|
2.7%
|
1.7%
|
Abbreviations: AF, atrial fibrillation; BID, twice daily; INR, international normalized
ratio; NOACs, non-vitamin K antagonist oral anticoagulants; QD, once daily; VKA, vitamin
K antagonist.
a Dose reduced when dose reduction criteria were met.
In a meta-analysis of these four trials comparing NOACs versus VKA,[108] the rate of death was 0.1 versus 0.2%; ischemic stroke, 0.2 versus 0.2%; major bleeding,
2.1 versus 4.2%; and the composite outcome, 2.4 versus 4.6%, respectively. Another
meta-analysis of six randomized studies[109] on uninterrupted NOACs (dabigatran, rivaroxaban, and apixaban) versus uninterrupted
VKA revealed that the incidence of major bleeding was significantly lower in the NOAC
group (1.68%) than in the VKA group (3.80%) (OR = 0.45, 95% CI: 0.26–0.81, p = 0.007); while the incidence of ischemic stroke or transient ischemic attack (TIA)
was low and similar between the NOAC (0.21%) and VKA groups (0.21%). Further, the
incidence of silent cerebral thromboembolic events (in three studies) was similar
between NOAC (14.0%) and VKA groups (13.3%). Similar results were reported by another
meta-analysis.[110]
Interrupted NOAC protocols versus uninterrupted regimes have been tested by prospective,
randomized studies done in Asian countries.[111]
[112]
[113]
[114] Notwithstanding the small-size study cohorts which may be underpowered for the thromboembolic
outcomes, an ablation strategy with minimally interrupted periprocedural NOACs may
be an option.
Recommendations
-
We recommend a preferential use of NOACs over VKA because of their safety profile
relative to VKA in addition to their ease of management before and after ablation.
-
NOAC dosing protocols, uninterrupted or minimally interrupted, should be determined
in each institution, depending on the volume of AF ablation done, experience of the
operator, back-up system in case of life-threatening complications, baseline renal
function and thromboembolism and bleeding risks of each patient, time of administration
of once-daily NOACs (morning or evening), preparation of specific antidotes to NOACs,
etc. ([Fig. 13]).
-
When VKA is used, it should be controlled within a therapeutic range and uninterrupted
throughout the periprocedural period unless bleeding events preclude its continuous
use.
-
In general, OAC therapy is continued for 2 months following ablation in all patients.
Beyond this time, a decision to continue OAC long term is determined primarily by
the presence of CHA2DS2-VASc stroke risk factors rather than the rhythm status.
Fig. 13 A flow chart about the general recommendation for NOACs in the periprocedural period
of catheter ablation. NOACs, non-vitamin K antagonist oral anticoagulants; TEE, transesophageal
echocardiography.
Reversal Agents
The general principles of managements of bleeding are summarized in [Fig. 14]. For severe bleeding or life-threatening bleeding, reversal agents could be considered
to reverse the anticoagulant effects of NOACs.
Fig. 14 General principles of managements of bleeding for anticoagulated AF patients. AF,
atrial fibrillation; FFP, fresh frozen plasma; NOACs, non-vitamin K antagonist oral
anticoagulants; OACs, oral anticoagulants.
Idarucizumab is a monoclonal antibody fragment and binds dabigatran with an affinity
that is 350 times as high as that observed with thrombin.[115] In the RE-VERSE AD study, the efficacy and safety of idarucizumab was tested in
patients who had serious bleeding or required urgent procedures. In an interim analysis
of the first 90 patients, idarucizumab reversed the anticoagulant effect of dabigatran
within minutes in 88 to 98% of patients.[116] In the whole cohort of 503 patients, the median time to cessation of bleeding was
2.5 hours in those with uncontrolled bleeding who could be assessed.[117] For the periprocedural group, the median time to the initiation of the intended
procedure was 1.6 hours. Periprocedural hemostasis was assessed as normal in 93.4%
of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days,
thrombotic events had occurred in 6.3% of the patients in the uncontrolled bleeding
group and in 7.4% in the periprocedural group, while the mortality rate was 18.8 and
18.9%, respectively. No serious adverse safety signals were noted. More recently,
it was found that although both dabigatran and idarucizumab were renally cleared,
impaired renal function did not affect the reversal of anticoagulation.[118] The REVERSE-AD study results were consistent and supported by observations from
a post-approval global registry (RE-VECTO), which also showed that off-label use was
minimal.[119] Idarucizumab is approved in many countries for patients treated with dabigatran
when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent
procedures and in life-threatening or uncontrolled bleeding.
Andexanet alfa is a recombinant modified human factor Xa decoy protein that is catalytically
inactive but which retains the ability to bind factor Xa inhibitors in the active
site with high affinity.[120] In a clinical study of older healthy volunteers, andexanet reversed the anticoagulant
activity of apixaban and rivaroxaban within minutes after administration and for the
duration of infusion, without clinical evidence of toxic effects.[121] In the multicenter, open label, single-arm ANNEXA-4 trial, 352 patients with acute
major bleeding associated with factor Xa inhibitors (mostly on rivaroxaban and apixaban)
were given an initial bolus and subsequent 2-hour infusion of andexanet alfa. This
substantially reduced anti-factor Xa activity after the bolus (75–92%) and this effect
persisted till the end of the infusion. Good or excellent hemostatic efficacy was
achieved in 82%, 12 hours after the infusion.[122] During 30 days of follow-up, 49 patients (14%) died and 34 (10%) experienced a thrombotic
event. Similar data are based on an earlier interim analysis of this study,[121] and andexanet alfa was granted accelerated approval by the Food and Drug Administration
for the reversal of anticoagulation if needed due to life-threatening or uncontrolled
bleeding in patients treated with apixaban or rivaroxaban.
When managing OAC-related bleeding, it is important to survey for occult malignancies
that are the cause/origin of the bleeding, e.g., GI tract cancer in patients with
GI bleeding.[84] In a nationwide study from Taiwan, incident GI cancers were diagnosed in 1 of 37
AF patients at 1 year after OAC-related GI bleeding, and were more common among patients
treated with NOACs (1/26) compared with warfarin (1/41).[123] Interestingly, the risk of mortality after GI tract cancers were diagnosed was lower
in patients treated with NOACs than in those treated with warfarin (23.5 vs. 51.8%;
aHR: 0.441; p < .001), and more patients treated with NOACs (33.8%) underwent surgery than those
treated with warfarin (18.9%), suggesting that NOACs may serve as a stronger “screening
test” than warfarin and may be able to disclose GI cancers at an earlier stage when
operation is possible, therefore leading to a better prognosis.[123] Similar findings have been reported for anticoagulated patients presenting with
hematuria among whom the possibility of underlying bladder cancers should be kept
in mind.[124]
Recommendations
-
Idarucizumab is indicated for the reversal of dabigatran in patients with serious
bleeding or requiring urgent procedures.
-
Andexanet alfa can be useful for reversing anticoagulation in patients treated with
factor Xa inhibitors with life-threatening or uncontrolled bleeding.
-
The possibility of occult malignancies that are the cause/origin of the bleeding should
be kept in mind when managing OAC-related bleeding.
Stroke Prevention in Special Patient Groups
Stroke Prevention in Special Patient Groups
Issues about stroke prevention in special patient groups are discussed in the [Supplementary Material] (available in the online version).
Left Atrial Appendage Occlusion
Left Atrial Appendage Occlusion
The efficacy, safety, and procedural aspects, as well as the limitations of current
data on left atrial appendage (LAA) occlusion have recently been the subject of a
detailed expert consensus statement: EHRA/EAPCI (European Association of Percutaneous
Cardiovascular Interventions) on catheter-based LAA occlusion.[125] More recently, the role of surgical occlusion of the LAA in AF patients undergoing
cardiac surgery has gained prominence with publication of the LAAOS III trial.[126] The latter showed that stroke/SE occurred in 4.8% in the LAA occlusion group and
in 7.0% in the no-occlusion group (HR: 0.67; 95% CI: 0.53–0.85; p = 0.001). The incidence of perioperative bleeding, heart failure, or death did not
differ significantly between the trial groups. Thus, among participants with AF who
had undergone cardiac surgery, the risk of ischemic stroke or SE was lower with concomitant
LAA occlusion performed during the surgery than without it.
Catheter-Based LAA Occlusion
Catheter-Based LAA Occlusion
Efficacy
There are two randomized controlled trials (RCTs) comparing percutaneous LAA occlusion
with the Watchman device to warfarin in patients with NVAF and high risk of stroke.[127]
[128] Data from these and their associated registries[129]
[130] demonstrate noninferiority to warfarin for prevention of ischemic stroke or SE >7
days postprocedure. There were more ischemic strokes in the device group (1.6 vs.
0.9 events/100 patient-years, p = 0.05), largely driven by procedure-related strokes, and a significant reduction
in hemorrhagic stroke (0.15 vs. 0.96/100 patient-years, p = 0.004).[130] To date, there are limited data comparing LAA occlusion devices with NOACs. Noninferiority
to NOACs has been examined in the PRAGUE-17 trial, ClinicalTrials.gov identifier NCT02426944,[131] which showed that in AF patients at high risk for stroke (CHA2DS2-VASc: 4.7 ± 1.5) and increased risk of bleeding, LAAO was noninferior to NOACs in
preventing major AF-related cardiovascular, neurological, and bleeding events. There
were no differences between groups for the components of the composite endpoint: all-stroke/TIA
(subdistribution HR [sHR]: 1.00; 95% CI: 0.40–2.51), clinically significant bleeding
(sHR: 0.81; 95% CI: 0.44–1.52), and cardiovascular death (sHR: 0.75; 95% CI: 0.34–1.62).
Major LAAC-related complications occurred in 9 (4.5%) patients.[132]
Safety
Safety data are available from the RCTs[127]
[128] and several registries,[129]
[133]
[134]
[135] including two conducted in the Asia-Pacific region.[136]
[137] In modern practice, there is high implantation success of 95 to 98.5%.[128]
[133]
[137]
Procedure- and device-related complications in the first 7 days were high in the earlier
PROTECT AF trial[127] at 8.7% but lower at 4.2% in the subsequent PREVAIL trial.[128] Similar reduction in complication rate has been seen over time in registries, with
early data showing a high complication rate of 8.6%,[138] reducing to 2.2 to 3% for more contemporaneous registries.[128]
[133]
[137] However, trials and registries have selection bias and real-world data suggest that
the complication rate may be significantly higher.[139]
The rates of early device thrombosis in meta-analysis and registry data are 3.7 to
3.9%,[135]
[140] and there are no RCTs to guide the duration of anticoagulation and number, and type
and duration of antiplatelet agents, although registry data suggest safety of a single
antiplatelet agent. Other “real-world” reports of device-related thrombus (DRT) suggest
incidence rates as high as 7.2% per year,[141] as well as high annual rates of mortality (7.4%), ischemic strokes (4.3%), and major
hemorrhages (4.5%).[142] The EUROC-DRT registry reported that substantial proportion of DRT (18%) was detected
>6 months after LAA closure, highlighting the need for imaging follow-up, especially
since such patients were at high risk for stroke and mortality (13.8 and 20.0%, respectively).[143]
Although there are registry data on safety of LAA occlusion in patients with a contraindication
to anticoagulation,[135] there are no published RCT data on efficacy and safety of LAA occlusion devices
in this cohort, although ongoing studies may address this.[125]
[144]
Issues Specific to the Asia-Pacific Region
Issues Specific to the Asia-Pacific Region
Asians are significantly underrepresented in clinical trials and registries of LAA
occlusion devices with <1% of patients in the PROTECT-AF and PREVAIL trials and associated
registries being of Asian ethnicity.[130] However, evidence for safety and efficacy in Asian patients come from two small
registries from the Asia-Pacific region—the WASP registry[137] performed in South-East Asia and Australia with 106/203 patients being of Asian
ethnicity and the SALUTE registry of 54 patients in Japan.[136] The WASP registry suggested important differences in anatomy and need for larger
device sizes in Asian patients.[136]
The lack of comparative data to NOACs may be especially pertinent in the Asia-Pacific
region given the more profound benefits of NOACs in Asian populations, especially
with respect to reduced incidence of intracranial hemorrhage.[65]
Finally, cost-effectiveness analysis has been performed utilizing health care costs
from the United States,[145]
[146] which may not be applicable in the Asia-Pacific region, especially when one considers
the diverse health care systems, costs, and funding models across the region.
Recommendations
-
LAA occlusion may be considered for stroke prevention in patients with AF and clear
contraindications for long-term anticoagulant treatment (e.g., intracranial bleeding
without a reversible cause).
-
Surgical occlusion or exclusion of the LAA is recommended for stroke prevention in
patients with AF undergoing cardiac surgery.
Role of Environmental and Lifestyle Factors in AF
Role of Environmental and Lifestyle Factors in AF
Cardiovascular risk factors, including lifestyle factors and comorbidities, affect
the risk and prognosis of AF. Management of these risk factors, unhealthy lifestyle
behaviors and practices, and comorbidities is important for stroke prevention and
to control the burden of AF and symptoms associated with AF. This strategy constitutes
the “C” component of the ABC pathway.[11] Lifestyle modifications, including weight loss, physical activity, alcohol abstinence,
and risk factor modifications including BP control, have been shown to reduce AF burden.[147]
[148]
[149]
[150]
[151]
[152]
[153]
[154]
Unhealthy lifestyle factors tend to cluster together, and increased numbers of unhealthy
lifestyle factors (current smoking, heavy drinking [>30 g/day], and lack of regular
exercise) have been associated with a higher risk of incident AF.[155]
[156] Overall, the promotion of a healthy lifestyle to lower the risk of new-onset AF
and AF-related complications is recommended.
Body Weight: Role of Obesity and Low Body Weight
Body Weight: Role of Obesity and Low Body Weight
Obesity is an important and potentially modifiable risk factor for AF and can affect
the incidence and persistence of AF.[157]
[158] Obesity is also associated with other cardiovascular disease risks, including hypertension,
sleep apnea, impaired glucose tolerance, and diabetes, which are all associated with
incident AF and AF-related complications.
Aggressive weight reduction and risk factor modification have been shown to reduce
AF recurrences and arrhythmia burden, as well as AF symptom burden; thus, there is
improved maintenance of sinus rhythm and beneficial effects on cardiac remodeling
compared with conventional therapy in patients with obesity.[148]
[149]
[159]
[160] For example, in patients diagnosed with overweight or obesity concomitant with AF,
>10% weight reduction was associated with reduction in the AF burden and reversal
of AF type and natural progression.[149]
[161] Underweight patients are not uncommon in the Asian population, and these patients
show an increased risk of AF.[162] Moreover, fluctuations in body weight were associated with an increased risk of
AF, particularly amongst those with low body weight.[163]
With regard to clinical outcomes, the risk of the composite outcome of ischemic stroke,
thromboembolism, or death is higher in those with overweight and obesity, even after
adjustment for CHA2DS2-VASc scores.[164] However, in a systematic review and meta-analysis, an obesity paradox was observed
in patients with AF taking anticoagulation therapy, particularly with regard to all-cause
and cardiovascular death in subgroup analyses of randomized trial cohorts.[165] Another study showed that the risk of ischemic stroke, major bleeding, and mortality
was lower in Asian patients with AF, who showed a high body mass index and received
OACs compared with those with normal weight, whereas underweight patients had an increased
risk of mortality and composite outcome compared with those with normal weight.[166] For stroke prevention, NOACs are generally associated with better outcomes than
those with warfarin administration in Asians across patients of different body weights,
particularly in underweight patients.[76] Given the observed obesity paradox in AF patients, keeping a normal body weight
is recommended.
Alcohol
Excessive alcohol consumption is a well-known risk factor and trigger for AF.[167] Excessive alcohol consumption acts synergistically with other lifestyle risk factors
for AF, including hypertension, obesity, obstructive sleep apnea, and cardiomyopathy
to magnify their effects. Excessive alcohol consumption is a known clinical risk factor
for bleeding during anticoagulation therapy, and is included in the HAS-BLED score.[168] High alcohol consumption is also associated with an increased risk of thromboembolism
and death in patients with incident AF.[169] Asian data have shown that high alcohol consumption was associated with a high ischemic
stroke risk.[170]
One recent randomized trial has reported that alcohol abstinence reduced the risk
of recurrent AF in those with heavy alcohol consumption patterns.[171] Alcohol abstinence was also associated with a low risk of incident AF in patients
with newly diagnosed type 2 diabetes,[172] and alcohol abstinence after a diagnosis of AF was associated with a low risk of
ischemic stroke.[170]
Smoking
Smoking is associated with an increased risk of incident AF,[173]
[174] and smoking cessation seems to lower the risk of AF compared with current smokers.[173]
[174] In Asian AF patients with a low CHA2DS2-VASc score, smoking was identified as a risk factor for ischemic stroke.[175] Furthermore, quitting smoke after incident AF was associated with a low risk of
ischemic stroke, lower stroke severity, and death from cerebrovascular events.[176]
Air pollution
Epidemiological studies have suggested that elevated ambient particulate matter (PM)
<2.5μμm (PM2.5) or <10μμm (PM10) in aerodynamic diameter is consistently associated with adverse cardiac events.
In the Asian general population, long-term exposure of PM2.5 is associated with the
increased incidence of new-onset AF.[177]
[178]
Physical Activity
Moderate-intensity exercise (150 min/week) or vigorous-intensity exercise (75 min/week)
recommended by the 2018 Physical Activity Guidelines Advisory Committee is known to
improve cardiovascular health. Physical inactivity is associated with an increased
risk of incident AF,[179] and regular exercise could reduce AF burden and improve AF-related symptoms and
patients' quality of life.[180]
[181]
[182]
[183] However, the risk of AF increased in those who participate in extreme endurance
exercise that far exceeds the levels recommended by the Physical Activity Guidelines
Advisory Committee report.[184] Cardiorespiratory fitness generally reduces the AF burden and symptom severity in
patients with obesity and concomitant AF, which may be attributable to the beneficial
effects of weight loss.[147]
One recent observational study in Asian patient with incident AF reported that regular
exercise was associated with low risks of heart failure, mortality, and dementia in
addition to a marginal benefit on ischemic stroke.[185]
[186] Regular moderate exercise (170–240 min/week) showed maximal cardiovascular benefits
in patients who initiated exercise after diagnosis of AF. Patients who initiated or
continued regular exercise after diagnosis of AF were associated with a lower risk
of dementia than persistent non-exercisers, with no risk reduction associated with
exercise cessation.[186]
Recommendations
-
The promotion of a healthy lifestyle (smoking cessation, reduced alcohol consumption,
regular exercise) is recommended to lower the risk of new-onset AF and AF-related
complications.
-
Appropriate weight control is an important strategy to improve outcomes in patients
with AF.
-
Reduced consumption or alcohol abstinence is recommended in AF patients with moderate-to-high
levels of alcohol use to minimize AF burden and stroke risk.
-
Smoking cessation is recommended in patients with AF to reduce the stroke risk, even
in those categorized as low-risk patients based on the CHA2DS2-VASc score.
-
Regular exercise based on the recommendations of the 2018 Physical Activity Guidelines
Advisory Committee (150 min/week of moderate-intensity exercise or 75 min/week of
vigorous-intensity exercise) can improve cardiovascular outcomes in patients with
AF ([Fig. 15]).
Fig. 15 The integration of lifestyle management in patients with AF. AF, atrial fibrillation.
OAC Use in AF Patients during the COVID-19 Pandemic
OAC Use in AF Patients during the COVID-19 Pandemic
AF is a common clinical manifestation in hospitalized patients with coronavirus disease
2019 (COVID-19) infection and is associated with a higher risk of mortality and/or
requirement for intensive care.[187]
[188]
[189]
[190] The latter is perhaps unsurprising given the higher risk of adverse outcomes in
COVID-19 with associated cardiovascular comorbidities.[190]
During the COVID-19 pandemic, TTR values associated with VKA (e.g., warfarin) treatment
may be suboptimal with the lack of INR monitoring, and in appropriate patients, a
switch to NOACs may be appropriate.[191] Furthermore, the anticoagulated AF patients may not seek medical help even in the
case of bleeding.[192] Thus, for the outpatients during the COVID-19 pandemic (during the lockdown phase
or discharge after recovery from COVID-19 infection), NOAC therapy in replacement
of VKA (except for the absolute contraindications of NOACs like prosthetic mechanical
valve or moderate-to-severe mitral stenosis) is recommended to minimize the necessity
for frequent clinic/office visits for INR monitoring and contact with health care
workers.[193] Remote anticoagulation management/monitoring for elderly patients with NVAF receiving
NOACs during the COVID-19 pandemic was associated with a reduction in bleeding complications
and delays in the first outpatient revisit after discharge.[194]
COVID-19 is associated with a prothrombotic state, perhaps due to cytokines and immunothrombosis.[195] For patients already treated with NOACs or VKA and infected with COVID-19 and particularly
in the case of severe infection requiring hospitalization, patients should ideally
continue their anticoagulation rather than discontinue, although outcome data are
conflicting.[196]
[197]
[198]
[199]
Conversion from NOAC or VKA into low-molecular-weight heparin (LMWH) during the hospitalization
course (especially if severely affected, requiring intensive care unit admission)
may be preferable due to less drug interaction with antiviral drugs (e.g., remdesivir)
or immunomodulating drugs (e.g., dexamethasone, baricitinib, or tocilizumab), and
a higher risk of clinical deterioration due to severe COVID-19 infection (particularly
of coagulation and renal function).[193]
[195] It would therefore be reasonable to shift NOACs into alternative LMWH for patients
with severe COVID-19 infection as long as antiviral agents are deemed necessary and
until discharge. LMWH regimes have been tested in recent clinical trials of hospitalized
COVID-19 patients but showed conflicting results.[200]
[201]
[202]
[203]
[204] For example, in noncritically ill patients with COVID-19, the ATTACC, ACTIV-4a,
and REMAP-CAP investigators found that an initial strategy of therapeutic-dose anticoagulation
with heparin increased the probability of survival to hospital discharge with reduced
use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis.[201] However, in patients hospitalized with COVID-19 and elevated D-dimer concentration,
in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by
rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared
with prophylactic anticoagulation in the ACTION trial.[204] Besides, these studies did not specifically enroll AF patients, and therefore, data
about the optimal dosage of LMWH for hospitalized AF COVID-19 patients were very limited.
COVID-19 vaccines are usually administered by intramuscular injection, and are an
important part of our pandemic response.[205] An opportunity to screen for AF amongst attendees for vaccination has been promoted.[206] In AF patients treated with NOACs, it is advisable to follow the scheme for “minor
risk” interventions, and therefore, it is not necessary to withhold any NOAC dosage
before and after the injection procedure.[207] However, it is recommended to use a fine-gauge needle for injection, and apply firm
pressure for 5 to 10 minutes after the injection. If the scheduled NOAC dosage is
close to the injection time before, the scheduled NOAC dosage may be postponed until
after the injection if no progression of local hematoma noted.
Recommendations
-
For outpatients with AF during the COVID-19 pandemic, NOAC therapy as a replacement
of VKA (unless contraindicated) may be considered.
-
For AF patients already treated with NOACs or VKA and infected with COVID-19 and particularly
in case of severe infection requiring hospitalization or critical care, conversion
from NOAC or VKA into LMWH during the hospitalization course of COVID-19 infection
may be considered.
-
In AF patients taking NOACs and planned to receive COVID-19 vaccine injection, it
is advisable to follow the scheme for “minor risk” interventions, and therefore, it
is not necessary to withhold any NOAC dosage before and after the injection procedure.
