Download Update on Management of Non-Valvular Atrial Fibrillation

National Medicines
Information Centre
VOLUME 19
NUMBER 1
2013
ST. JAMES’S HOSPITAL • DUBLIN 8
TEL 01-4730589 or 1850-727-727 • FAX 01-4730596 • www.nmic.ie
UPDATE ON MANAGEMENT OF NON-VALVULAR ATRIAL FIBRILLATION
Atrial fibrillation (AF) is a major risk factor for embolic strokes which are usually more severe than
strokes due to other causes
The goals of therapy are to reduce the thromboembolic risk, control the heart rate and rhythm and
relieve symptoms
Choice of anti-thrombotic therapy involves assessment of the risks of stroke and bleeding at an
individual level
The risk of AF-related stroke changes over time, therefore patients should be re-evaluated regularly
INTRODUCTION
Atrial fibrillation (AF) is the commonest cardiac arrhythmia worldwide, occurring in 1-2% of the general population.1 It is a disease of increasing age: the estimated prevalence is 4-7% in those aged 65-74 years of age, increasing to 14-19% in those aged >85
years.1 AF is associated with increased mortality and morbidity, including stroke and other thromboembolic events, cardiovascular
disease (CVD) and reduced quality of life.1 Moreover, studies have shown that stroke due to AF is more severe, leading to greater
mortality and disability, increased lengths of hospital stay and greater requirements for long-term institutional care, compared with
strokes due to other causes.2
A recent Irish study using data from TILDA (the Irish longitudinal study on ageing) reported a prevalence of 3.2% of ECGdocumented AF in the cohort (ranging from 0.8% in the 50-59 years age group to 10.8% of those aged >80 years) of whom approximately 40% were unaware that they had an arrhythmia.3 In the 65-70 year age group this lack of awareness of diagnosis rose
to over 60%. Estimated demographic changes are expected to increase future costs of stroke in Ireland by >50% from 2007-2021,
therefore active management of AF is an important public health measure that may help offset some of these projected costs.4 This,
the second of two bulletins, will outline the management of non-valvular AF in current practice.
RISK FACTORS FOR ATRIAL FIBRILLATION
The mechanisms underlying AF are multifactorial and challenging to pinpoint on an individual case basis.5 Age is the strongest
determinant of AF with a life-time risk estimated at 25% for a 40-year old person.5,6 A familial component of AF is also well
established, especially in the case of young-onset AF; having an affected parent doubles an individual’s risk.6 The presence of
cardiovascular disease such as hypertension or heart failure may also induce AF probably due to remodelling. In addition, there are
many known extrinsic factors involved in the development of AF including cigarette smoking, chronic alcohol consumption
(dose-related effect), use of illicit drugs such as marijuana and cocaine, and obesity (associated with sleep apnoea, hypertension
and atrial dilation).5
CLASSIFICATION AND DIAGNOSIS OF ATRIAL FIBRILLATION
AF is characterised by chaotic contraction of the atrium. Table 1 outlines the internationally-agreed classification system for types
of AF that may be identified in an individual patient.7
Table 1: Classification of Atrial Fibrillation7
Paroxysmal AF
Persistent AF
Longstanding persistent AF
Permanent AF
>2 episodes of AF that each terminate spontaneously within 7 days
Continuous AF that is sustained beyond 7 days
Continuous AF of > 12 months’ duration
Sustained AF where a decision not to restore sinus rhythm has been made
The method of presentation depends on the type of AF. Patients may present with palpitations or with signs of acute disease such as
acute heart failure or stroke in association with previously undiagnosed AF.8 However, many patients with AF are asymptomatic,
although a thorough medical history may uncover symptoms potentially related to arrhythmia, especially in the case of paroxysmal AF.8 The most cost-effective method for the detection of AF in primary care is by opportunistic screening of people
aged >65 years by pulse palpation.9 If an irregular pulse is found, a 12-lead ECG will clarify the diagnosis in the majority of
patients and may also identify structural heart disease.8 Where paroxysmal AF is suspected, longer ECG monitoring periods (at
least 24 hours) should be used.9 The National Cardiovascular Strategy has recommended the establishment of an AF screening
programme in Ireland for people aged 65 years and over.1
MANAGEMENT OF ATRIAL FIBRILLATION
AF is associated with increased rates of death, stroke and other thromboembolic events, heart failure and hospitalisations, reduced
quality of life, reduced exercise capacity and left ventricular dysfunction.2 Management includes prevention of AF-related thromboembolic events, rhythm and/or rate control, adequate therapy of concomitant cardiac disease and relief of concomitant symptoms.8
PREVENTION OF AF-RELATED THROMBOEMBOLIC EVENTS
There are 2 main types of anti-thrombotic therapies (ATT) that have been used in the prevention of AF-related thromboembolic
events - oral anticoagulants and anti-platelet therapies.
Oral Anticoagulants (OACs). The Vitamin K antagonist, warfarin, has been the principal OAC for many years. A meta-analysis
of ATT trials reported a relative risk reduction of 64% with warfarin therapy compared with placebo in the primary prevention of
non-valvular AF-related thromboembolism.10 It was shown to be significantly more effective than aspirin, the most frequently used
anti-platelet therapy which had a relative risk reduction of 22% versus placebo.10 Studies have shown that the beneficial effect of
warfarin on reducing ischaemic stroke increases with increasing age, while benefit decreases for aspirin as patients get older.11
An important aspect of treatment with warfarin is the need to ensure that the patient achieves and maintains an optimal INR
(international normalised ratio).8 The optimal INR range for stroke prevention in AF with warfarin is 2.0 – 3.0 with the
recommendation that patients should achieve a TTR of >70% (time in the therapeutic range).12 However problems with warfarin
therapy include the high inter- and intra-individual variation in INRs and significant drug, food and alcohol interactions;12,13 in
order to achieve optimal control, regular monitoring is required which has time and cost implications.14 Therefore, real-life studies
suggest that some patients may achieve optimal TTR for less than 50% of the time, which offsets the potential benefits of warfarin
in the prevention of stroke.8
Anticoagulation management has been improved in recent years by use of self-monitoring and point-of-care testing which results
in improved TTR targets.12 A recent Irish study showed a median TTR of 74% in patients who were self-testing compared with a
median TTR of 58.6% for those attending an anticoagulation management service.15 Pharmacogenetics of warfarin are also better
understood and may aid in optimising warfarin dosing in the future; however such testing is not readily available.12
In recent years, OACs with new modes of action have been developed. Dabigatran is a direct thrombin inhibitor, while rivaroxaban
and apixaban are direct Factor Xa inhibitors.16-18 The pharmacology of these individual agents is described in detail in the
NMIC companion bulletin (NMIC 2012; Vol 18: 6).19
The clinical studies relating to use of the new OACs (NOACs) in non-valvular AF are outlined in Table 2.20-23 Each NOAC was
compared with warfarin in individual large randomised controlled, non-inferiority “pivotal” trials in patients with non-valvular AF
at increased risk of stroke.20-22 A further trial compared apixaban with aspirin in patients who were unsuitable for warfarin therapy.23
Table 2: Pivotal trials for NOACs in patients with atrial fibrillation at increased risk of stroke20-23
Drug / study
RE-LY study:
n=18,213 (mean age
71 years) at moderate
risk* of stroke. Followup was median 2.0
years.
Dosage Regimen
Dabigatran 150mg or
110mg twice daily (randomly assigned to either
dose) vs. dose-adjusted
warfarin.
Efficacy Results
Dabigatran 110mg was
non-inferior [and 150mg
dose was superior] to
warfarin in prevention
of stroke or systemic
embolism.
Safety Results
Comment
Compared with warfarin, rates of ICH + Patients with severe
haemorrhagic stroke significantly ↓ with renal dysfunction
dabigatran while rate of major GI bleed- (CrCl<30ml/min) and
ing was significantly ↑with dabigatran active liver disease
150mg dosage. Non-significant ↑ in rate were excluded from
of MI with dabigatran compared with
trial.
warfarin.
Rivaroxaban was nonCompared with warfarin, rates of ICH Patients with severe
ROCKET AF study: Rivaroxaban 20 mg daily
+ haemorrhagic stroke significantly ↓
renal dysfunction
n=14,264, (median age vs. dose-adjusted warfarin. inferior to warfarin in
73 years) at high risk** [Dosage ↓ to 15mg daily for prevention of stroke or
with rivaroxaban while rate of major GI (CrCl<30ml/min)
patients with CrCl of
systemic embolism.
bleeding was significantly ↑with rivar- were excluded from
of stroke.
oxaban compared with warfarin. Rate of trial.
Follow-up was median 30-49ml /min]
MI was similar in both groups.
1.9 years.
ARISTOTLE study: Apixaban 5 mg twice daily Apixaban was superior
Compared with warfarin, the rates of
Patients with severe
n=18,201 (median age vs. dose-adjusted
to warfarin in prevention major bleeding, haemorrhagic stroke
renal dysfunction
70 years) at moderate warfarin. [Dosage ↓ to 2.5 of composite endpoint
and death were significantly less with
(serum creatinine
risk* of stroke. Follow mg twice daily for patients of stroke or systemic
apixaban. The rates of GI haemorrhage >221 µmol/l; calcuup was median 1.8
with serum creatinine >133 embolism.
and MI were similar in both groups.
lated CrCl <25ml/
years.
µmol/l, age >80 years or
min) were excluded
low body weight (<60kg)]
from trial.
No significant difference in rates of ma- Exclusion criteria for
Apixaban 5 mg twice
Apixaban was superior
AVERROES study:
n=5,599, (median age daily vs. aspirin (81-324mg to aspirin in prevention jor bleeding, haemorrhagic stroke, ICH renal dysfunction were
70 years) at moderdaily). [Dosage ↓ to 2.5 mg of stroke or systemic em- or death between the treatment groups. similar to the ARISTOTLE study.
ate risk*** of stroke. twice daily as in ARISTO- bolism. [Study stopped
early because of favourFollow-up was mean TLE study]
able results]
1.1 years.
RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy)
ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial
in Atrial Fibrillation)
ARISTOTLE (Apixaban for Reduction in Stroke and other Thromboembolic Events in Atrial Fibrillation)
AVERROES (Apixaban Versus Aspirin to Reduce the Risk of Stroke)
* CHADS2 score 2.1 (mean); ** CHADS2 score 3.5 (mean); ***CHADS2 score 2.0 (mean) – see below for details of CHADS2 scoring system
ICH=intracranial haemorrhage; CrCl=creatinine clearance; GI=gastrointestinal; MI=myocardial infarction
It is not possible to undertake a direct comparison of the efficacy and safety of the NOACs, due to the methodological differences
between the currently available trials, in particular the different patient populations enrolled in terms of thromboembolic risk (see
Table 2).14,24 Furthermore, no head-to-head comparison studies between the NOACs are available. Data from post-marketing
cohort studies are needed to enable extrapolation of the trial results (outlined in Table 2) to the general population.12
Anti-platelet therapies. Aspirin at doses of 75-300mg has been reported to reduce the risk of stroke versus placebo (22% relative risk reduction versus placebo).10 However, as noted previously, aspirin is significantly less effective than warfarin and the
anti-thrombotic effect appears to lessen with age, while the risk of major bleeding with aspirin is at least equivalent to warfarin
in elderly populations.12 More recently, the AVERROES study (Table 2) showed that apixaban significantly reduced the rate of
stroke or systemic embolism compared with aspirin; no statistically significant differences in the rates of death, major bleeding or
haemorrhagic stroke between the treatment groups were noted.23 Therefore aspirin monotherapy is no longer recommended
for prevention of AF-related thromboembolic events.2,12
The addition of clopidogrel 75mg to aspirin further reduces the risk of stroke compared with aspirin alone but is associated with
increased risk of bleeding; therefore the combination is not recommended as first-line ATT for this patient group.25 However, it
may be useful in patients for whom OAC therapy is not suitable.12,14,25
EVALUATING THE NEED FOR THROMBOPROPHYLAXIS IN CLINICAL PRACTICE
Not all patients with AF have a similar risk of thromboembolism.26 Several scales have been developed to estimate the risk and
assess the need for ATT on an individual basis. The simplest scoring system is the CHADS2 (0-6 score) which calculates stroke
risk on the basis of existing CVS disease, diabetes mellitus, age and prior stroke / TIA into high (>2), moderate (1-2) and low
risk (0).8 However, it is now recognised that the risks associated with AF change over time with age and medical status, which
may not be captured in the CHADS2 score. Therefore an updated scoring system (CHA2DS2-VASc) was developed which takes
into account additional risk factors including female gender, vascular disease, and age 65-74 years (Table 3).27
Table 3: CHA2DS2-VASc score for estimating stroke risk in non-valvular AF27
Table 4: Risk of stroke according to
CHA2DS2-VASc score28,29
Parameter Score
Score
Adjusted Stroke rate
(% per year)
Cardiac Failure / LVD
10 0
Hypertension111.3
Age > 75 years222.2
Diabetes Mellitus133.2
Prior Stroke / TIA244.0
Vascular disease156.7
Age 65-74 years169.8
Female Sex179.6
(max score 9)
86.7
9 15.2
The CHA2DS2-VASc scoring system is more inclusive of common stroke risk factors and has been validated in numerous studies,
which have confirmed its ability to identify truly low risk patients who could be managed with no ATT as well as to predict
stroke and thromboembolism in higher risk patients (Table 4).28,29 In addition, this scale provides clearer guidance for those
patients with a previous CHADS2 score of 0-1; in a recent study it was possible to reclassify 26% of patients with a CHADS2 score
of 1 to a low annual risk of stroke / systemic embolus of 1% i.e. truly “low risk” not requiring ATT.30
However, many of the risk factors associated with AF-related thromboembolic events are also associated with an increased risk of
bleeding with ATT.31 Therefore an evaluation of the risk of bleeding consequences should also be undertaken in the individual
patient prior to ATT. Several bleeding risk scores are available; the HAS-BLED (see Table 5)8,12 and HEMORR2HAGES (see
Table 6)32 scoring systems.
Table 6: HEMORR2HAGES scoring
system* for risk of bleeding32
Table 5: HAS-BLED scoring system* for risk of bleeding8,12
Parameter
Score
Parameter
Score
Hypertension
Abnormal renal / liver function
Stroke
Bleeding history or predisposition
Labile INR
Elderly
Drugs / alcohol
1
1/1
1
1
1
1
1/1
* low risk <3; high risk >3
Hepatic or renal disease
Ethanol (alcohol) abuse
Malignancy
Older age
Reduced platelet count or function
Re-bleeding
Hypertension
Anaemia
Genetic factors
Excessive risk of falls
Stroke
1
1
1
1
1
1
1
1
1
1
1
Each scoring system has been evaluated in several independent cohorts.32
The HEMORR2HAGES score has the advantage of including the risk
of falls. The HAS-BLED score has shown a significant predictive performance for ICH8 and, in addition, highlights risk factors that can be
*low risk <1; intermediate 2-3; high risk>3
actively managed to reduce the bleeding risk (such as use of NSAIDs or
2
uncontrolled hypertension).
A high bleeding risk score (see Tables 5 and 6) does not necessarily constitute a contraindication to the use of OACs but
rather will indicate the need for careful monitoring and education of the patient.12
RHYTHM / RATE CONTROL IN ATRIAL FIBRILLATION
There has been much debate over which is the best strategy for managing AF in terms of rhythm versus rate management. Studies
comparing outcomes of rhythm vs. rate control strategies in AF patients found no difference in the incidence of mortality or stroke
between the groups.9 Therefore the choice depends on individual patient factors. Figure 1 outlines guidance for choosing rhythm
versus rate management first in AF.
Figure 1: Rhythm versus Rate Control in patients with non-valvular AF 2,8
Rhythm control first for patients: Rate control first for patients:
•
•
•
•
•
•
Symptomatic
Younger (< 65 years old)
Presenting for first time with lone AF
Secondary to treated or corrected precipitant
(e.g. thyroid disease)
With congestive heart failure
Patients who may be considered for catheter ablation
•
•
•
•
> 65 years old
With coronary artery disease
With contraindications to anti-arrhythmic drugs
Unsuitable for cardioversion
Rhythm control by way of cardioversion is usually undertaken in a hospital setting and may consist of pharmacological
cardioversion (PCV) and/or electrical cardioversion (ECV); a recent international survey showed that the preference for PCV or
ECV varies between countries.33 Pharmacological agents include the anti-arrhythmic agents flecainide, vernakalant or amiodarone,
depending on whether there is no, moderate or severe structural heart disease present respectively.2,8,34-36 Patients must undergo
adequate anticoagulation before cardioversion is undertaken: anticoagulation (for 3 weeks) is mandatory for AF of > 48 hours
/ unknown duration. In emergency situations, patients should be heparinised.8 Follow-up consists of appropriate thromboprophylaxis (even if in sinus rhythm) for at least 4 weeks and ß-blocker therapy (unless in bradycardia). Patients should be evaluated
at 1 and 6 months to see if sinus rhythm is maintained. If AF has recurred, patients should be re-evaluated to see if further rhythm
control is warranted; otherwise they should be considered for rate control and need for ATT.8
Patients with paroxysmal or persistent AF who have achieved sinus rhythm may be treated with dronedarone to maintain sinus
rhythm.2 Because of its safety profile, including multiple drug interactions, it should only be initiated and monitored in the
specialist setting, after alternative treatments have been considered.37 It is contraindicated in heart failure, and in combination
with dabigatran.37 It must not be used in patients with permanent AF because of an increased risk of mortality and morbidity.37,38
Great care is needed when switching from PCV medications to dronedarone.
If AF recurs while on dronedarone, or any rhythm-controlling agent, consideration should be given to its discontinuation and the
patient re-evaluated.8,34-37
Rate control. As well as being evaluated for ATT, patients undergoing rate control therapy should be treated with a ß-blocker or
rate-limiting calcium antagonist (e.g. verapamil or diltiazem) in order to achieve a target resting heart rate of < 100bpm and an
exercise heart rate of <110bpm.8,9 Some patients achieve these targets without the need for any pharmacological treatment.
Amiodarone is also effective in this setting but because of its extra cardiac toxicity profile it should only be used if the above ratecontrol measures are ineffective.36 If amiodarone was used in the acute setting for rhythm control, it should be discontinued if the
patient develops permanent AF.8 Current guidelines recommend that digoxin should only be added if inadequate rate control is
achieved with the above drugs. Digoxin should only be considered as monotherapy in predominantly sedentary patients as
it does not control the increased heart rate that may occur with exercise.8
SPECIALIST INTERVENTION THERAPIES IN ATRIAL FIBRILLATION
Ablation therapy (most commonly catheter ablation therapy) is used in specialist settings for selected patients in order to
restore sinus rhythm and/or improve quality of life.7 It is particularly suitable for patients with symptomatic AF refractory to,
or intolerant of, prior PCV.7 To date, there is limited evidence that ablation improves prognosis but trials are ongoing.9 Patients
must have adequate ATT cover and patients may require long-term OAC post-procedure depending on the outcome and existing
risk factors for stroke.2
Left atrial appendage (LAA) closure: The LAA is considered the main (but not the only) site of thrombus formation inducing
AF-related stroke. Procedures such as occlusion / closure of the LAA orifice or excision of the LAA may be undertaken in specialist
settings for selected AF patients with a high stroke risk.2 ATT cover is also required with these procedures.
MANAGEMENT OF ATRIAL FIBRILLATION IN PRACTICE
Figure 2 summarises the current guidance for the management of non-valvular AF in clinical practice.2,8,12,39-41 In addition to rhythm
and/or rate management, concomitant cardiovascular disease should be actively managed; many of these conditions are known
to be independent risk factors for stroke and, in addition, optimal control reduces the risk of cardiac remodelling which may worsen
AF.8,42 OAC therapy is the mainstay of thromboprophylaxis for patients who are judged to be at risk of AF-related stroke. A patient
with a CHA2DS2-VASc score of >1 should be considered for OAC (Figure 2); the exception is a patient with lone AF <65 years
(including females) who is judged to be truly low risk, who does not require thromboprophylaxis.12 Individual circumstances,
including renal function and risk of bleeding (using a scoring system appropriate to the patient’s risk factors) should be taken into
account when deciding on the type of OAC.2,12 Education is important: patients should be informed that all OACs are associated with a risk of bleeding.13,16-19 For patients who are taking warfarin, the potential risks and benefits of switching to a NOAC
should be considered in light of their level of INR and TTR.39-41 For patients currently well-controlled on warfarin, automatic
switching to a NOAC is not routinely recommended.24,43 Similarly, warfarin may be preferable for patients with poor renal function.12 However a patient who has difficulty maintaining a therapeutic INR, but is otherwise adherent, may benefit from
changing treatment to a NOAC.24,43
Prescribers should be aware that clinical experience with the NOACs is still limited, therefore care, vigilance and further
information on their effectiveness in clinical practice are needed.2 Renal function must be reviewed regularly and creatinine
clearance should be estimated at least annually (see companion bulletin: NMIC 2012; Vol 18: 6).19 In addition, the risk of AFrelated stroke (and therapy-related bleeding) changes over time, therefore patients should be re-evaluated regularly regarding their
need for OAC therapy.12
Figure 2: Treatment Algorithm for Non-Valvular Atrial Fibrillation9,10,12
Confirm diagnosis of non-valvular atrial fibrillation (AF)
Rhythm and/or rate therapy as appropriate
↓
↓
Management of concomitant CVD
← YES ← Is patient <65 years and lone AF (including females)?
↓↓ NO
Assess risk of stroke using the CHA2DS2-VASc scoring system
↓↓
↓
↓
← ← ← ← 0
1
>2
↓
↓
↓
Consider chronic OAC Chronic OAC recommended
↓
↓
↓
Assess bleeding risk (HAS-BLED\HEMORR2HAGES scoring system)
↓
(Consider patient circumstances, including renal function,
abbility to comply with therapy and preferences)
↓↓
↓
No ATT OAC (warfarin therapy / NOAC)
OAC = anticoagulant therapy; ATT= anti-thrombotic therapy
In Ireland, approval for individual patient reimbursement for a NOAC must be obtained from the HSE through the Primary Care Reimbursement
Service. Applications forms are available online at:
http://www.sspcrs.ie/libr/html/OralAnticoagulantIndividualReimbursemenApplication.pdf
FOR PERSONAL USE ONLY. NOT TO BE REPRODUCED WITHOUT PERMISSION OF THE EDITOR
List of references available on request. Date of preparation: February 2013
Every effort has been made to ensure that this information is correct and is prepared from the best available resources at our disposal at the time of issue.
Prescribers are recommended to refer to the individual Summary of Product Characteristics (SmPC) for specific information on a drug.
Volume 19
Number 1
2013
Update On Management Of Non-Valvular Atrial Fibrillation: References
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