Download Management of New Onset Atrial Fibrillation

Management of New Onset Atrial
Fibrillation
William E Lawson, MD
Professor of Medicine
SUNY, Stony Brook
Magnitude of the Problem
• AF is the most common tachyarrhythmia
requiring therapy and the most common
arrhythmia leading to hospitalization.
• AF patients have increased mortality and
impaired quality of life.
– Associated with the AF
– Associated with its therapy
• Economic costs are in the billion of $/yr
range
Question #1
An 82 year old man is in your office for an
annual Medicare physical. What is the chance
he has atrial fibrillation?
1. 1%
2. 5%
3. 10%
4. 25%
Prevalence of Diagnosed AF
Stratified by Age and Sex
12.0
10.0
Women
Men
11.1
10.3
9.1
8.0
7.3
6.0
5.0
4.0
3.0
1.7
2.0
0.0
0.1 0.2 0.4
<55
0.9
7.2
5.0
x-axis = %
y-axis = # of
men/women
3.4
1.7
1.0
55-59
60-64
65-69
70-74
75-79
80-84
> 85
# Women
530
310
566
896
1498
1572
1291
1132
# Men
1529
634
934
1426
1907
1886
1374
759
Go AS, JAMA. 2001 May 9;285(18):2370-5. Pub Med PMID: 11343485
Question #2
A 46 year old male patient is in for an annual
physical exam. What is his lifetime risk of
developing AF?
1. 1%
2. 5%
3. 10%
4. 25%
Incidence of AF
Lifetime Risk for AF at Selected Index Ages by Sex
Index Age, yrs
Men
Women
40
26.0% (24.0 – 27.0)
23.0% (21.0 – 24.0)
50
25.9% (23.9 – 27.0)
23.2% (21.3 – 24.3)
60
25.8% (23.7 – 26.9)
23.4% (21.4 – 24.4)
70
24.3% (22.1 – 25.5)
23.0% (20.9 – 24.1)
80
22.7% (20.1 – 24.1)
21.6% (19.3 – 22.7)
1 in 4
Men & women
>40 Years
will develop AF
Lifetime risk if
currently free
of AF
Lloyd-Jones DM, et al. Circulation. 2004 Aug 31;110(9):1042-6. Pub Med PMID: 15313941.
Atrial Fibrillation Definitions
Term
Definition
Paroxysmal A Fib
Terminates spontaneously or with Rx within 7 days
Persistent A Fib
Continuous A Fib sustained ≥ 7 days
Long-standing
persistent A Fib
Continuous A Fib ≥ 12 months duration
Permanent A Fib
Joint decision of Pt and Physician to stop attempts to
restore or maintain sinus rhythm
Nonvalvular A Fib A Fib in absence of rheumatic mitral stenosis, valve
replacement or mitral repair
Magnitude of the Problem
• Inadequate recognition and treatment
• Controversy regarding optimal approach,
therapy is evolving
– Rate versus rhythm control
– Antiarrhythmic drug (AAD) vs
nonpharmacologic therapy
– Hybrid therapies
– Anticoagulation/ bleeding risk
AF Comorbidities/ Risk Factors
(Top Offenders)
•
•
•
•
Hypertension
Diabetes mellitus
Hyperthyroidism
Hypertrophic
cardiomyopathy
• Congestive heart
failure
• Valvular heart disease
• Pericardial disease
• Obstructive sleep
apnea
• Pulmonary disorders
• Obesity
• Alcohol
• Stimulants
• Occasionally ischemic
heart disease
• Post CT surgery
Comorbidity Resulting from AF
• Congestive heart failure
– Tachycardia [>120 bpm] mediated cardiomyopathy
– Loss of atrial kick
• Stroke
– Thromboembolic (usually LAA)
– Risk increases with advancing age and other risk
factors [CHA2DS2-VASc score]
Overview of AF Management
AF Detected
Management of
Arrhythmia
Assessment of
Thromboembolic
Risk (CHADS2)
ASA
OAC
Rate
Control
No antithrombotic therapy may be appropriate in selected
young patients with no stroke risk factors
Rhythm
Control
Dr. YD, Age 42, Family Practitioner
• Last evening he was out celebrating the marriage of his receptionist and consumed
about 12 ounces of Johnny Walker Black label.
• He went home by taxi, slept poorly and realized this morning about 6:00 am that
his heart rate was rapid and pulse irregular.
• He has a mild bitemporal headache and is driven to the ED by his wife.
• He has been well, no known hypertension, DM, heart disease, TIA/stroke and no
known arrhythmias although he does have mild palpitations from time to time. No
COPD or asthma.
• In ED: no chest pain, mild SOB, slightly sweaty. HR 140, irregularly irregular, BP
140/90, JVD 4 cm, Chest clear. ECG shows AF, rate 140.
Dr. YD, Age 42, Family Practitioner
How will you manage his rhythm?
1.
Electrical cardioversion (150-200 j) in ED as soon as it can be done.
2.
IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110.
Home on po metoprolol 50-100 mg bid if AF persists.
3.
IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110.
Add propofenone 450 mg po about 10-15 minutes after first dose of metoprolol
if AF persists.
4.
IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110.
Electrical cardioversion if AF persists.
5.
Digoxin 0.25 mg IV, repeat at 1 hour intervals up to 4 doses if AF persists.
How will you manage his rhythm?
1.Electrical cardioversion (150-200 j) in ED as soon as it can be done.
2.IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Home on po
metoprolol 50-100 mg bid if AF persists.
3.IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Add
propofenone 450 mg po about 10-15 minutes after first dose of metoprolol if AF persists.
4.IV metoprolol 5 mg, repeated Q 5 min up to 3 times if rate remains above 110. Electrical
cardioversion if AF persists. Best answer! *
5.Digoxin 0.25 mg IV, repeat at 1 hour intervals up to 4 doses if AF persists.
*This is a young man with no stroke risk factors. His AF has been present for only a few hours. It is likely the AF was precipitated by his
alcohol indiscretion and he is likely to return to NSR with cardioversion and likely to remain in sinus rhythm. Accordingly, electrical
cardioversion is a good option. It makes sense to give IV metoprolol to slow his rate before cardioversion. The cardioversion may be done
without prior anticoagulation. He requires no ongoing OAC or ASA.
Hence, the best answer is #4. #3 would be acceptable if there is some reason not to do electrical cardioversion, or if there is any expectation
that he may have recurrent episodes of AF and might be suitable for a pill in the pocket regimen, but this does not appear indicted in this first
presentation of AF. #2 is OK, but in a young person with acute onset, electrical (or pharmacological) cardioversion has a high likelihood of
resolving the AF. #1 is not advised since there is no rush to cardiovert him and giving metoprolol will be likely to decrease symptoms prior to
cardioversion. #5 would not be a good choice.
Atrial Fibrillation in the ED
Is Patient Stable?
Immediate Risk for
Stroke?
Low Risk
1. Clear onset <48 hours, or
2. Therapeutic OAC ≥ 3 wks
Pharmacological or
electrical CV at 150-200
J
(Immediate anticoagulation in ED
before CV not required) *
Antithrombotic therapy
-Initiate OAC upon discharge from ED (or
continue current OAC) if age ≥ 65 or
CHADS2 ≥ 1
-Otherwise, initiate ASA if CAD or vascular
disease
-Early follow-up to review long-term OAC
YES
NO
High Risk**
No therapeutic OAC ≥ 3 weeks and one of:
1. Onset >48 hours or unknown, or
2. Stroke/TIA <6 months or
3. Mechanical or rheumatic valve disease.
Rate-control
Therapeutic OAC for 3
Trans-esophageal
weeks before
echocardiography (TEE)
outpatient CV
guided CV
Antithrombotic therapy
- Continue OAC for ≥4
weeks after CV
- Early follow-up to review
long-term OAC
Antithrombotic therapy
- Initiate immediate OAC* in ED
and continue for ≥4 weeks
- Early follow-up to review
long-term OAC
Unstable – AF causing:
1. Hypotension, or
2. Cardiac ischemia, or
3. Pulmonary edema
Consider urgent
electrical CV if rate
control not effective
Antithrombotic therapy
- Initiate immediate OAC* in ED and
continue for ≥4 weeks if any ‘high
risk’ ** features present
- Early follow-up to review
long-term OAC
Emergency Management of AF
* Immediate OAC = a dose of OAC should be given just prior to cardioversion - either a novel direct oral anticoagulant (NOAC) or a dose of heparin or low molecular weight heparin
with bridging to warfarin if a NOAC is contraindicated.
Dr. YD, Age 42, Family Practitioner
How will you reduce his risk of stroke if you decide to
cardiovert him?
1. IV LMWH or a NOAC po about 1 hour prior to any cardioversion
attempt.
2. IV LMWH or a NOAC po about 1 hour prior to electrical
cardioversion, but not required for pharmacologic cardioversion.
3. No anticoagulant required pre cardioversion attempt.
4. Start dabigatran 150 mg bid and have him return for cardioversion
after 3 weeks of dabigatran.
How will you reduce his risk of stroke if you decide
to cardiovert him?
1. IV LMWH or a NOAC po about 1 hour prior to any cardioversion
attempt.
2. IV LMWH or a NOAC po about 1 hour prior to electrical
cardioversion, but not required for pharmacologic cardioversion.
3. No anticoagulant required pre cardioversion attempt. Best answer!
He is young, has no risk factors for stroke, and the duration of AF
has been short. The risk of a stroke with cardioversion and no
anticoagulation is very low. He requires no anticoagulation pre
cardioversion.
4. Start dabigatran 150 mg bid and have him return for cardioversion
after 3 weeks of dabigatran.
How will you reduce his risk of stroke post
discharge from ED?
1. If AF persists, he requires maintenance ASA 81 mg daily at least
until follow-up at 1 month.
2. Whether AF persists or resolves, he requires maintenance ASA 81
mg at least until follow-up at 1 month.
3. If AF persists, he requires maintenance OAC at least until followup at 1 month.
4. Whether AF persists or resolves, he requires maintenance OAC at
least until follow-up at 1 month.
5. Whether AF persists or resolves, he requires no maintenance
antithrombotic therapy.
How will you reduce his risk of stroke post
discharge from ED?
1. If AF persists, he requires maintenance ASA 81 mg daily at least until
follow-up at 1 month.
2. Whether AF persists or resolves, he requires maintenance ASA 81 mg at
least until follow-up at 1 month.
3. If AF persists, he requires maintenance OAC at least until follow-up at 1
month.
4. Whether AF persists or resolves, he requires maintenance OAC at least
until follow-up at 1 month.
5. Best Answer! Whether AF persists or resolves, he requires no
maintenance antithrombotic therapy. - He is young, has no risk factors
for stroke. He fits the CCS algorithm of no antithrombotic therapy for AF.
New CCS Algorithm
80 year old female with hypertension
• She lives alone with her dog. She is without other significant medical
problems other than obesity [5 feet 5 inches, 190 lbs].
• Medications: Ramipril 10 mg/d, bisoprolol 5mg/d.
• Comes to the office for routine BP follow-up. Her BP is 145/85 on repeat
readings, pulse is 85 bpm and irregularly irregular. No heart murmurs or
clinical evidence of heart failure.
• With further discussion she admits to a decrease in exercise tolerance and
increase in fatigue and dyspnea on exertion.
• ECG demonstrates atrial fibrillation with a ventricular response of 88.
What next?
Why does she have AF?
1.
Thyroid
2.
Hypertension
3.
Sleep apnea
4.
Ethanol
5.
Obesity
History
Establish Severity (including impact on QOL)
Identify Etiology
Identify reversible causes (hyperthyroidism, ventricular pacing, SVT,
exercise)
Identify factors whose treatment could reduce recurrent AF or improve
overall prognosis (i.e. hypertension, sleep apnea, left ventricular
dysfunction)
Identify potential triggers (i.e. alcohol, intensive aerobic training)
Identify potentially heritable causes of AF (particularly in lone AF)
Determine thromboembolic risk (e.g. CHA2DS2 - VASc Score)
Determine bleeding risk to guide antithrombotic therapy (HASBLED)
Review prior pharmacologic therapy for AF, for efficacy and adverse
effects
Rate vs Rhythm; Effect on Mortality
? Rate or Rhythm control
• Quality of Life significantly affected by atrial fibrillation
• Choices:
– More tightly control heart rate (increase BB)
– Attempt to restore sinus rhythm
• CHA2DS2- VASc score = 4 [4.0% annual risk of CVA]
• TT Echocardiogram to assess valves, LA and LV size and function.
• OAC for 3 weeks of therapeutic anticoagulation prior to attempted
Electrical Cardioversion. Continue anticoagulation regardless of result.
Rate vs Rhythm Control for with Symptomatic AF
SYMPTOMATIC AF
ATTEMPT RATE CONTROL
Beta-blocker
Calcium channel blocker
Special circumstances in
which to consider early
rhythm control:
Highly symptomatic
Multiple recurrences
Extreme impairment in QOL
Arrhythmia-induced
cardiomyopathy
YES
SYMPTOMS RESOLVE
NO
CONTINUE RATE
CONTROL
MODIFY RATE CONTROL - CONSIDER RHYTHM CONTROL
Paroxysmal AF
Low burden
recurrence
Pill in pocket
antiarrhythmic therapy
High burden recurrence
Maintenance
antiarrhythmic therapy
Catheter ablation
Persistent AF
Consider cardioversion
Symptoms
Symptoms
improve,
improve,
and patient
but AF recurs maintains sinus
rhythm
Symptoms
don’t change
in sinus
rhythm and
AF recurs
Observe. If AF
recurs, determine if symptomatic
Overview of AF Management
AF Detected
Assessment of
Thromboembolic
Risk (CHADS2)
Appropriate
Antithrombotic
Therapy
Detection and
Treatment of
Precipitating Causes
Management of
Arrhythmia
Rate
Control
Rhythm
Control
Rhythm Control in A Fib
Rhythm Control Choices
Normal Systolic Function
No Hx of CHF
Dronedarone+
Flecainide*
Propafenone*
Sotalol#
Rhythm Control Choices
Hx of CHF or Left Ventricular
Systolic Dysfunction
EF > 35%
EF ≤ 35%
Amiodarone
Sotalol**
Amiodarone
Catheter
Ablation
Amiodarone
Catheter Ablation
Drugs are listed in alphabetical order
+ Dronedarone should be used with caution in combination with digoxin
• Class I agents should be AVOIDED in CAD and should be COMBINED
with AV-nodal blocking agents
# Sotalol should be used with caution in those at risk for torsades de
pointes VT (e.g. female, age > 65 yr, taking diuretics)
** Sotalol should be used with caution with EF 35-40% and those at risk
for torsades de pointes VT (e.g. female, age > 65 yr, taking diuretics)
Rate Control in A Fib
Rate Control Drug Choices
Heart Failure
CAD
No Heart Failure
or CAD
β-blocker
± Digoxin
β-blocker*
Calcium Channel
Blocker#
Combination Rx
β-blocker*
Calcium Channel
Blocker#
Digoxin†
Combination Rx
Drugs are listed in alphabetical order
*β-blockers preferred in CAD
# Non-dihydropyridine calcium channel blockers (diltiazem, verapamil)
†Digoxin may be considered as monotherapy only in particularly sedentary
individuals
Rate Control Drugs
ß-Blockers
Drug
Dose
Adverse Effects
Atenolol
50 - 150 mg p.o. daily
bradycardia, hypotension, fatigue,
depression
Bisoprolol
2.5 - 10 mg p.o. daily
as per atenolol
Metoprolol
25 mg - 200 mg p.o. bid
as per atenolol
20 - 160 mg p.o daily - bid
as per atenolol
80 - 240 mg p.o. tid
as per atenolol
Nadolol
Propranolol
Calcium Channel Blockers and Digoxin
Drug
Dose
Adverse Effects
Verapamil
120 - 480 mg p.o. daily
120 - 240 mg p.o. bid
bradycardia, hypotension, constipation
Diltiazem
120 - 480 mg p.o. daily
120 - 240 mg p.o. bid
bradycardia, hypotension, ankle swelling
Digoxin
0.0625 mg - 0.25 mg p.o. daily
bradycardia, nausea, vomiting,visual
disturbance
Rhythm Control - Drugs
Drug/Dose
Flecainide
50-150 mg
BID
Propafenone
150-300 mg
TID
Amiodarone
100-200 mg
OD (after 10g
loading)
Dronedarone
400 mg BID
Sotalol
80-160 mg
BID
Efficacy
Toxicity
Comments
30-50%
Ventricular tachycardia
Bradycardia
Rapid ventricular response to AF
or atrial flutter (1:1 conduction)
Contraindicated in patients with CAD or LV dysfunction
Should be combined with an AV nodal blocking agent
30-50%
Ventricular tachycardia
Bradycardia
Rapid ventricular response to AF
or atrial flutter (1:1 conduction)
Abnormal taste
Contraindicated in patients with CAD or LV dysfunction
Should be combined with an AV nodal blocking agent
60-70%
Photosensitivity, Bradycardia,
GI upset, Thyroid dysfunction,
Hepatic toxicity, Neuropathy,
Tremor, Pulmonary toxicity,
Torsades de pointes (rare)
Low risk of proarrhythmia
Limited by systemic side effects
Most side effects are dose & duration related
GI upset
Bradycardia
Hepatic toxicity
Should not be used for rate control or for rhythm control in
patients with a history of CHF or LV EF < 40%.
Should be used with caution when added to digoxin.
Liver enzyme monitoring required.
New agent – limited experience outside clinical trials.
Torsades de pointes
Bradycardia
Beta-blocker side effects
Should be avoided in patients at high risk of torsades de pointes
VT – especially women >65 years taking diuretics or those with
renal insufficiency
QT interval should be monitored 1 week after starting
Use cautiously when EF<40%
40%
30-50%
New Rate/Rhythm Algorithm
Changes in A Fib Management
1.
2.
3.
4.
5.
6.
Removal of Class 1A antiarrhthymic agents.
Potential use of “pill-in-pocket” approach.
Increasing role for catheter ablation.
Novel oral anticoagulants.
Assessment of bleeding risk.
Joint decision making patient and physician
“Pill-in-Pocket” Approach
• Paroxysmal and sporadic AF may be treated
with intermittent rather than daily AAD
therapy.
• Self administration of AAD:
– Improves QOL, decreases hospitalizations, reduces
treatment costs
• Class 1C drugs are recommended
(propafenone & felecainide) for their efficacy,
rapid action, and safety.
– Low organ toxicity, low proarrhythmia risk
Role of Catheter Ablation
• Catheter ablation is reasonable in patients
with symptomatic atrial fibrillation.
• Radiofrequency ablation may be preferred
in symptomatic young patients.
• May be an effective adjunct procedure in
pts undergoing cardiac surgery (e.g. cardiac
bypass, mitral valve repair).
Limitations of Catheter Ablation
• Limited data on long term efficacy.
• Recurrence rates of 10- 44% have been
reported.
• Major complication rate is 1-6%.
• Embolic stroke has an incidence of 0-5%.
• Results dependent on operator expertise.
AF Ablation
• First line therapy for patients in whom
anticoagulation is contraindicated?
• First line therapy for patients who will be
noncompliant with chronic anticoagulation?
• First line therapy for patients who do not
wish to be chronically anticoagulated?
Who is a Candidate for AF
Ablation?
• Symptomatic AF (paroxysmal or persistent).
• At least 1 antiarrhythmic drug failure.
• Younger pts with “lone” paroxysmal AF are
the best candidates, but pts with persistent AF,
older pts, and those with comorbidities
(structural heart disease, CHF) may also be
appropriate candidates.
Consensus Indications for Catheter
Ablation of Atrial Fibrillation
Indications for Catheter Ablation of AF
Class
LOE
Symptomatic AF refractory or intolerant to at least 1 class 1 or class 3 antiarrhythmic
medication
Paroxysmal AF: Catheter ablation is
recommended*
I
A
Persistent AF: Catheter ablation is reasonable
IIa
B
Longstanding persistent AF: Catheter ablation
may be considered
IIb
B
Symptomatic AF before initiation of antiarrhythmic drug therapy with a class 1 or
class 3 antiarrhythmic agent
Paroxysmal AF: Catheter ablation is reasonable
IIa
B
Persistent AF: Catheter ablation may be
considered
IIb
C
Longstanding persistent AF: Catheter ablation
may be considered
IIb
C
Electroanatomic map of the left atrium (left), with dots marking areas of radiofrequency
energy delivered during ablation.
Chinitz J S et al. Circulation 2013;127:408-416
Copyright © American Heart Association
Bleeding Risk Scores in AF
ATRIA
HAS-BLED
HEMORR2HAGES
Anemia1
3
Hypertension4
1
Hepatic10 or
disease2
1
1
Severe renal disease2
3
Abnormal Renal5 or
1
1
Ethanol abuse
1
Age ≥75 yrs
2
Stroke
1
Malignancy
1
Any prior hemorrhage
1
Bleeding
1
Older Age (>75 yrs)
1
Hypertension3
1
Labile INR8
1
Reduced platelet number
1
Elderly (>65 yrs)
1
Rebleeding12
2
Drugs9 or
1
1
Hypertension4
1
Anemia13
1
Genetic factors14
1
Excessive fall risk15
1
Stroke
1
1.
2.
3.
4.
5.
6.
8.
9.
10.
11.
12.
13.
14.
15.
Liver
function6
Alcohol
Hemoglobin <13 g/dl men; <12 g/dl women
Estimated glomerular filtration rate <30 ml/min or dialysis-dependent
Diagnosed hypertension
Systolic blood pressure >160 mmHg
Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 mmol/L
Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in association
with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)
Unstable/high INRs or poor time in therapeutic range (eg <60%)
Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc.
Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl
Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia
Prior hospitalization for bleeding
Most recent hematocrit <30 or hemoglobin <10 g/dl
CYP2C9*2 and/or CYP2C9*3
Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls
Renal
or function11
Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] Online Appendix.
PMID: 22858389.
AMADEUS Cohort
Stratified by the HEMORR2HAGES, HAS-BLED, and ATRIA Schemes
All Patients
Clinically Relevant
Bleeding
Major
Bleeding
1,738 (76.6)
182 (10.5)
25 (1.4)
517 (22.8)
63 (12.2)
13 (2.5)
13 (0.5)
3 (23.1)
1 (7.7)
2,268
248 (10.9)
39 (1.7)
Low Risk (<3)
1,739 (75.9)
159 (9.1)
22 (1.3)
High Risk (≥3)
553 (24.1)
92 (16.6)
17 (3.1)
2,292
251 (11.0)
39 (1.7)
Scheme
HEMORR2HAGES
Low (≤1) Risk
Intermediate Risk (2–3)
High Risk (>3)
TOTAL
HAS-BLED
TOTAL
ATRIA
Low Risk (<4)
2,038 (90)
220 (10.8)
31 (1.5)
Intermediate Risk (4)
102 (4.4)
13 (12.7)
3 (2.9)
High Risk (>4)
128 (5.6)
18 (14.1)
5 (3.9)
2,268
248 (10.9)
39 (1.7)
TOTAL
Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print] Online Appendix.
PMID: 22858389.
44
CVA & Bleeding Rates
CHA2DS2VASc
Score
Adjusted
Thromboem
bolism Rate,
%/y†
HAS-BLED
Score
Major
Bleeding
Rate, %/y‡
1.9
0
0
0
0
1
2.9
1
1.3
1
1.2
2
4.0
2
2.2
2
2.2
3
5.9
3
3.2
3
5.9
4
8.5
4
4.0
4
7.0
5
12.5
5
6.7
5–6
19.4
6
18.2
6
9.8
7
9.6
8
6.7
9
15.2
Adjusted
Stroke Rate,
%/y*
0
CHADS2
Score
Advantages of new oral anticoagulants
(NOACs) over vitamin K antagonists (VKAs)
for thromboembolic prevention in patients
with non-valvular AF
• predictable effect without need for monitoring
• fewer food and drug interactions
• more predictable half-life/elimination
• improved efficacy/safety ratio
www.escardio.org/EHRA
1
Checklist during follow-up of AF patients
on NOACs
Interval
Comments
Compliance
Each visit
Inspect remaining medication
Stress importance of compliance
Inform about compliance aids
Thrombo-embolism
Each visit
Cerebral, systemic and pulmonary circulation
Bleeding
Each visit
Side effects
Each visit
Co-medications
Each visit
“Nuisance” bleeding – prevention possible?
Bleeding with risk or impact on QoL – prevention possible? Need
to revise dose?
Continuation? Temporary cessation with bridging? Change of
anticoagulant drug?
Prescription or over-the counter drugs?
Even temporary use can be risky
Yearly
6-monthly
Haemoglobin, renal, liver function
Renal function if CrCl 30-60 ml/min or if on dabigatran and aged >75
years or fragile
3-monthly
on indication
If CrCl 15-30 ml/min
If intercurring condition may impact renal or hepatic function.
Blood sampling
www.escardio.org/EHRA
8
Drug-drug interactions and pharmacokinetics of NOACs
Absorption and metabolism of NOACs
www.escardio.org/EHRA
15
Absorption and metabolism of NOAC
Dabigatran
Apixaban
Edoxaban
3-7%
50%
62%
yes
no
no
66% (w/o food)
~100% with food
no
20%/80%
73%/27%
50%/50%
65%/35%
no
yes (elimination;
minor CYP3A4)
minimal (<4%
of elimination)
yes (elimination)
no effect
no effect
6-22% more
+39%
no
no
no official
recommendation yet
mandatory
Absorption with
H2B/PPI
plasma level -12 to
-30%
no effect
no effect
no effect
Asian ethnicity
plasma level +25%
no effect
no effect
no effect
dyspepsia 5-10%
no problem
no problem
no problem
12-17h
12h
9-11h
5-9h (young)/11-13h (elderly)
Bioavailability
Prodrug
Clearance:
non-renal/renal of
adsorbed dose if
normal renal function
Liver metabolism:
CYP3A4
Absorption with food
Intake with food?
GI tolerability
Elimination half-life
www.escardio.org/EHRA
16
Rivaroxaban
Drug-drug interactions – NOAC plasma levels
Pradaxa
Atorvastatin
P-gp/ CYP3A4
Digoxin
P-gp
Verapamil
P-gp/ wk CYP3A4
Diltiazem
P-gp/ wk CYP3A4
Quinidine
Eliquis Savaysa
Xarelto
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
+18%
no data yet
no effect
no effect
no effect
no data yet
no effect
no effect
+12–180%
no data yet
+ 53% (slow release)
minor effect
no effect
+40%
No data
minor effect
P-gp
+50%
no data yet
+80%
+50%
Amiodarone
P-gp
+12–60%
no data yet
no effect
minor effect
Dronedarone
P-gp/CYP3A4
+70–100%
no data yet
+85%
no data yet
Ketoconazole;
itraconazole;
voriconazole;
posaconazole;
P-gp and BCRP/
CYP3A4
+140–150%
+100%
no data yet
up to +160%
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations
www.escardio.org/EHRA
19
Drug-drug interactions – NOAC plasma levels
Interaction
Fluconazole
Cyclosporin;
tacrolimus
Clarithromycin;
erythromycin
Pradaxa
Eliquis
Savaysa
Xarelto
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
CYP3A4
no data
no data
no data
+42%
P-gp
no data
no data
no data
+50%
+15–20%
no data
no data
+30–54%
P-gp/ CYP3A4
HIV protease
inhibitors
P-gp and BCRP/
CYP3A4
no data
strong increase
no data
up to +153%
Rifampicin;
St John’s wort;
carbamezepine;
phenytoin;
phenobarbital
P-gp and BCRP/
CYP3A4/CYP2J2
-66%
-54%
-35%
up to -50%
Antacids
GI absorption
-12-30%
no data
no effect
no effect
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations
www.escardio.org/EHRA
20
Factors associated with raised plasma levels of
NOACs part 3
Pradaxa
Eliquis
Savaysa
Xarelto
Dabigatran
Apixaban
Edoxaban
Aged ≥ 80 years
Increased plasma level
no data
Aged ≥ 75 years
Increased plasma level
no data
Weight ≤ 60 kg
Increased plasma level
Renal function
Increased plasma level
Rivaroxaban
Pharmacodynamic interactions – antiplatelet drugs, NSAIDs
Other increased
bleeding risk
Systemic steroid therapy
Other anticoagulants
Recent surgery on critical organ (brain, eye)
Thrombocytopenia (e.g. chemotherapy)
HAS-BLED ≥ 3
Orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations
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21
Switching between anticoagulant regimens
VKA to NOAC
Parenteral anticoagulant to NOAC:
Intravenous unfractioned heparin
(UFH)
Low molecular weight heparin (LMWH)
INR <2.0: immediate
INR 2.0–2.5: immediate or next day
INR >2.5: use INR and VKA half-life to estimate time to INR <2.5
Start once UFH discontinued (t½=2h). May be longer in patients with renal
impairment
Start when next dose would have been given
NOAC to VKA
Administer concomitantly until INR in appropriate range
Measure INR just before next intake of NOAC
Re-test 24h after last dose of NOAC
Monitor INR in first month until stable values (2.0–3.0) achieved
NOAC to parenteral anticoagulant
Initiate when next dose of NOAC is due
NOAC to NOAC
Initiate when next dose is due except where higher plasma concentrations
expected (e.g. renal impairment)
Aspirin or clodiprogel to NOAC
Switch immediately, unless combination therapy needed
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22
How to deal with dosing errors
Missed dose:
BID: take missed dose up to 6 h after scheduled intake. If not possible
skip dose and take next scheduled dose.
QD: take missed dose up to 12 h after scheduled intake. If not
possible skip dose and take next scheduled dose.
Double dose:
BID: skip next planned dose and restart BID after 24 h.
QD: continue normal regimen.
Uncertainty about intake:
BID: continue normal regimen.
QD: take another dose then continue normal regimen.
Overdose:
Hospitalization advised.
www.escardio.org/EHRA
25
NOACs in renal dysfunction – dosing in chronic
kidney disease
Pradaxa
Eliquis
Savaysa
Xarelto
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
When CrCl 30-49 ml/min, 150
CrCl 15-29 ml/min: 2.5 mg
not available
15 mg OD when CrCl
mg BID is possible (SmPC) but
BID is possible
110 mg BID if ‘high risk of
Serum creatinine ≥ 1.5 mg/dl
bleeding’ (SmPC) or
in combination with age ≥80
‘recommended’ (GL update)1
years or weight ≤60 kg
15-49 ml/min
(SmPC) or with other yellow’
Note: 75 mg BID approved in US
factor: 2.5 mg BID
only **
-if CrCl 15-30 ml/min
- if CrCl 30-49 ml/min
-and other orange factor (e.g.
verapamil)
**FDA recommendation based on pharmacokinetics. Carefully consider benefits and risks of this approach Note that 75 mg capsules are not
available in Europe for AF indication.
1. Camm et al, Eur Heart J 2012;33:2719-47
www.escardio.org/EHRA
28
When to stop NOACs before a planned surgical
intervention Last intake of drug before elective surgical intervention
Pradaxa
Dabigatran
Eliquis
Savaysa
Apixaban
Xarelto
Edoxaban
Rivaroxaban
No important bleeding risk and/or local haemostasis possible: perform at trough level
(i.e. ≥12h or 24h after last intake)
Low risk
High risk
Low risk
High risk
CrCl ≥80 ml/min
≥24h
≥48h
≥24h
≥48h
CrCl 50–80 ml/min
≥36h
≥72h
≥24h
≥48h
CrCl 30–50 ml/min
§
≥48h
≥96h
≥24h
≥48h
CrCl 15–30 ml/min
§
not
indicated
not
indicated
≥36h
≥48h
CrCl <15 ml/min
Low
risk
no data
yet
no data
yet
no data
yet
no data
yet
High risk
Low risk
High risk
no data
yet
no data
yet
no data
yet
≥24h
≥48h
≥24h
≥48h
≥24h
≥48h
no data
yet
≥36h
≥48h
no official indication for use
Low risk: surgery with low risk of bleeding. High risk: surgery with high risk of bleeding § many of these patients may be on the lower dose of
dabigatran (i.e. 2x110 mg/d) or apixaban (i.e. 2x2.5 mg/d), or have to be on the lower dose of rivaroxaban (15 mg/d).
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A
40
When to restart NOACs after a planned surgical
intervention
Procedures with immediate and complete
Resume 6–8 h after surgery
haemostasis:
Atraumatic spinal/epidural anethesia
Clean lumbar puncture
Procedures associated with immobilization:
Initiate reduced venous or intermediate dose of
LMWH 6–8 h after surgery if haemostasis achieved.
Procedures with post-operative risk of
Restart NOACs 48–72h after surgery upon
bleeding:
complete haemostasis
Thromboprophylaxis (e.g. with LMWH) can be
initiated 6-8 h after surgery
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A
41
Lariat Device
WATCHMAN LAA Closure
3000838-20
Atrial Fibrillation- One heart beat away
from a Stroke