Anticoagulation in atrial fibrillation

ANTICOAGULATION IN ATRIAL FIBRILLATION

DR. MD. MASHIUL ALAMResidentUniversity Cardiac CenterChairperson: Prof. F. Rahman

Atrial fibrillation

• Irregular, ineffective atrial contraction• Worsens over time, leads to atrial remodeling1

• Slow but steady progression to chronic AF after initial paroxysmal AF2

1. Allessie M et al. Cardiovascular Research 2002;54(2):230-246. 2. Kerr CR et al. Am Heart J 2005;149(3):489-496.

Atrial fibrillation: Epidemiology

• Affects about 1% of population - about 350,000 Canadians1,2

• Most common cardiac arrhythmia requiring medical care1

• Lifetime risk 1 in 4 for age ≥ 40 years3

• Prevalence increases with age; hence increasing due to increasingly elderly population2

1. Go As. et al. JAMA 2001;285(18):2370-2375. 2. Brembilla-Perrot B et al.. Pacing and Clinical Electrophysiology 2004;27(3):287-292. 3. Lloyd-Jones DM et al. Circulation 2004;110(9):1042-1046.

Stroke risk in AF

• 4-5 fold increase in stroke risk in AF; 1 in 6 strokes occurs in AF patients1,2

• Stroke risk in AF increases from 1.5% at age 50-59 to 23.5% at age 80-891

• About 40% of AF patients in primary care may be at high risk of stroke3

1. Kannel WB et al. Am J Cardiol 1998;82(7):2N-9N. 2. Mattle HP. Cerebrovascular Diseases 2003;16(Suppl. 1):3-8. 3. Carroll K, Majeed A. Br J Gen Pract 2001;51(472):884-6, 889-91.

CHADS2 score and stroke riskRisk factor Points

C - Congestive heart failure 1

H - Hypertension 1

A - Age >75 years 1

D - Diabetes 1

S - Prior Stroke or TIA 2

CHADS2 score Stroke rate per 100 patient-years

0 1.9

1 2.8

2 4.0

3 5.9

4 8.5

5 12.5

6 18.2

Gage BF et al. JAMA 2001;285(22):2864-2870.

CHA2DS2-VASc scoreRisk Factor Score

C - Congestive heart failure 1

H - Hypertension 1

A - Age ≥ 75 yrs 2

D - Diabetes mellitus 1

S2 - Prior stroke or TIA 2

V - Vascular disease 1

A - Age 65-74 years old 1

Sc - Sex category (female) 1

Lip GYH, Halperin JL. Am J Med 2010;123(6):484-488.

CHADS2 CHA2DS2VASc Antithrombotic therapy

0 0 ASA 75-325 mg/d or preferably nothing

1 1 OAC or ASA (Preferably OAC)

2 2 OAC (INR 2-3)

Initial Evaluation: CHADS2If CHADS2 ≥ 2 -----OACIf CHADS2 < 2------CHA2DS2VASc

HAS-BLED scoreCondition Points

H - Hypertension 1A - Abnormal renal or liver function (1 point each) 1 or 2

S - Stroke 1

B - Bleeding 1

L - Labile INRs 1

E - Elderly (> 65 years) 1

D - Drugs or alcohol (1 point each) 1 or 2

HAS-BLED score

Bleeds per 100 patient-years

0 1.13

1 1.02

2 1.88

3 3.74

4 8.70

5 12.5

Pisters R et al. Chest 2010;138(5):1093-1100.

Note: HAS-BLED has been validated for warfarin, but not for the new anticoagulants.

Underutilization of anticoagulation in high risk AF patients

Gladstone DJ, et al. Stroke. 2009;40:235-40.

Warfarin subtherapeutic

Warfarin therapeutic

Single antiplatelet agent

No antithrombotics

Dual antiplatelet therapy

In addition, only 18% of AF patients who had a previous stroke had a therapeutic INR of warfarin at the time of stroke

29%

29%

30%

10%

2%

Antithrombotic drugs in AF

Antiplatelet:• ASA• P2Y12 antagonist (e.g. Clopidogrel)Anticoagulant:• Warfarin• NOAC (Debigatran, Rivaroxaban, Apixaban)• Heparin

Newer anticoagulants (apixaban, dabigatran, rivaroxaban)

• Quickly achieve maximal blood levels and anticoagulant effects following oral administration

• Absorption and elimination largely unaffected by food or other medications.

• Administered in fixed daily doses• Anticoagulation monitoring not required• Relatively short serum and receptor inhibition

half-lives; anticoagulant effects diminish quickly after discontinuation

Skanes AC et al. Can J Cardiol 2012;28(2):125-136.

Novel Oral Anticoagulants – Pharmacological Properties

Characteristic Apixaban Dabigatran Rivaroxaban

Target Factor Xa Factor IIa Factor Xa

Prodrug No Yes No

Dosing BID BID OD

Bioavailability, % 50% 6.5% 80-100%*

Half-life 8-15 h 12-14 h 5-13h

Renal clearance (unchanged drug)

27% 85% ~33%

Cmax 3-4 h 1-2 h 2-4 h

Drug interactions Potent inhibitorsof both CYP3A4 and P-gp

P-gp inhibitors Potent inhibitorsof both CYP3A4 and P-

gp

* When the 15mg and 20mg dose is taken with food

Trials Comparing New Anticoagulants vs. Warfarin

ARISTOTLE1,2 RE-LY3 ROCKET AF4

No. of patients 18,201 18,113 14,264

CHADS2 score 2.1 2.1 3.5

Statistical objective

Non-inferiority Non-inferiority Non-inferiority

Study drugs Double-blind apixaban Two doses of double-blind dabigatran

Double-blind rivaroxaban

Control Double-blind warfarin (INR 2–3)

Open-label warfarin (INR 2–3)

Double-blind warfarin (INR 2–3)

Primary Dose(s) Studied

5 mg BID 110 mg BID and150 mg BID

20 mg OD

Adjusted Dose Studied

2.5 mg BIDFor patient with any two of the following: - Age ≥80 years- Body weight ≤60 kg- Serum creatinine ≥1.5 mg/dl (133 µmol/l)(27% renal excretion)

None(~85% renal excretion)

15 mg ODFor patients with CrCl = 30-

49 mL/min(~33% renal excretion)

1. Lopes RD et al, 2010; 2.Granger CB et al, 2011; 3. Connolly SJ et al, 2009; 4. Patel MR et al, 2011.

Comparison of new anticoagulants

• No head-to-head comparative studies comparing new anticoagulants with each other

• Different study designs and patient populations; hence indirect comparisons are difficult

New anticoagulants in AF

CHADS2 score

HAS-BLED score

CHADS2

≥2

CHADS2

≥1

Consider anticoagulation for all patients

New AF patient

Balance stroke risk against bleeding risk. HAS-BLED score of ≥ 3 indicates increased risk of major bleeding

Consider anticoagulation for most patients

Starting a new oral anticoagulant in a new patient

Apixaban Dabigatran Rivaroxaban

Usual dosage 5 mg BID 150 mg BID 20 mg OD

Take with food? - - Yes

Renal impairment

CrCl ≥ 30 mL/min: No dose adjustment

CrCl 15-30 ml/min: Use with caution

CrCl <15 ml/min: not recommended

CrCl 30-50 ml/min: No dose adjustment (consider 110 mg dosage); use with caution; assess renal function at least twice a year and with changes in clinical status

CrCl <30 ml/min: contraindicated

CrCl 30-49 mL/min: 15 mg OD

CrCl <30 ml/min: not recommended

Other Age ≥75 with other risk factor(s) for bleeding: 110 mg BID; also assess renal function

AF with specific conditions

AF with CHA2DS2VASc = 0

A. No therapyB. AspirinC. ASA + ClopidogrelD. WarfarinE. NOAC

Patient with Nonrheumatic AF

For patients with AF, including with Paroxysmal AF, with low risk of stroke

• No therapy preferred (Grade 2B)• Aspirin once daily or ASA with clopidogrel

(Grade 2B)

AF with CHA2DS2VASc = 1

A. No therapyB. ASAC. ASA + ClopidogrelD. WarfarinE. NOAC

Patient with Nonrheumatic AF

AF, including with paroxysmal AF, with score = 1• OAC (Grade 1B)• Aspirin (Grade 2B)• ASA + Clopidogrel (Grade 2B)

AF + CHA2DS2VASc ≥ 2


Norheumatic AF

AF including paroxysmal AF at high risk of stroke• OAC (Grade 1A)• ASA or ASA + Clopidogrel (Grade 1B)

ACC guidelines- Warfarin: IA, NOAC: IB

AF with high risk of stroke, ESRD or hemodialysis


NOAC not recommanded because of lack of evidence

AF + MS


AF and MS

• Warfarin ( INR 2-3) (Grade 1 B)• Unsuitable for warfarin (for reasons other

than concerns about major bleeding)----- ASA and Clopidogrel combination therapy (Grade 1B)

AF + Stable IHD

A. No therapyB. ASAC. ASA + ClopidogrelD. WarfarinE. NOACF. ASA + Warfarin

AF + Stable IHD

• Adjusted dose VKA (Warfarin) alone rather than VKA and aspirin (Grade 2C)

Recommendation is same irrespective of risk of stroke

AF and Intracoronary stent with high risk of stroke

A. AspirinB. ASA + ClopidogrelC. Warfarin + clopidogrelD. NOAC + ASAE. ASA + warfarinF. ASA + warfarin + clopidogrel

AF and Intracoronary stent with high risk of stroke

• During the first month after BMS or the first 3 to 6 months after DES, triple therapy recommended. (Grade 2C)

• After this initial period VKA plus a single antiplatelet drug (Grade 2C)

• After 12 months after stent placement antithrombotic therapy as for patients with AF and stable IHD.

AF + Intracoronary stent (low or intermediate risk)

A. ASAB. ASA + ClopidogrelC. Warfarin + ClopidogrelD. NOAC + ASAE. ASA + warfarinF. ASA + warfarin + clopidogrel

AF + Intracoronary stent (low or intermediate risk)

• During the first 12 months after stent placement (BMS or DES), DAPT rather than triple therapy recommended. (Grade 2C)

• After 12 months antithrombotic therapy as for patiens with AF and stable IHD.

AF and ACS (Intermediate to high risk)

A. ASAB. ASA + ClopidogrelC. Warfarin + ClopidogrelD. NOAC + ASAE. ASA + warfarinF. ASA + warfarin + clopidogrel

AF and ACS (Intermediate to high risk)

• During the first 12 months VKA plus single antiplatelet therapy rather than DAPT or triple therapy. (Grade 2C)

• After 12 months, antithrombotic therapy as for patients for AF and stable IHD

AF and ACS (low risk)

A. ASAB. ASA + ClopidogrelC. Warfarin + ClopidogrelD. NOAC + ASAE. ASA + WarfarinF. ASA + Warfarin + Clopidogrel

AF and ACS (low risk)

• DAPT rather than VKA plus single antiplatelet therapy or triple therapy. (Grade 2C)

• After 12 months, antithrombotic therapy as for patients with AF and stable IHD.

AF managed with a rhythm control strategy

• For patients with AF being managed with a rhythm control strategy (Pharmacological or catheter ablation), antithrombotic therapy decisions follow the general risk based recommendations for patients with AF, regardless of the apparent persistence of normal sinus rhythm. (Grade 2C)

Patients undergoing elective cardioversion of AF

Presentation greater than 48 hours or unknown Therapeutic anticoagulation regardless of score ( VKA,

LMWH, debigatran) for at least 3 weeks before cardioversion or

TEE guided approach with no anticoagulation. (Grade 1B)

Continue anticoagulation for at least 4 weeks after successful cardioversion (Grade 1B). After 4 weeks decisions in accordance with risk based recommendation for long term antithrombotic therapy.

Presentation with in 48 hours or less• Start anticoagulation (LMWH or UFH or NOAC) and proceed

cardioversion. (Grade 2C)• After successful cardioversion, therapeutic anticoagulation

for at least 4 weeks (Grade 2C)• Long term anticoagulation in accordance with risk based

recommendations for long term antithrombotic therapy• In patient with low thromboembolic risk no anticoagulation

therapy may be considered and also without the need for postcardioversion oral anticoagulaiton. ( Grade IIb, LOE: C) ACC –HRS 2014

Unstable AF requiring urgent cardioversion

• Parenteral anticoagulation started before cardioversion, if possible but should not delay emergency intervation. (Grade 2C)

• After successful cardioversion anticoagulation for at least 4 weeks than in accordance with risk based recommendations for long term antithrombotic therapy. (Grade 2C)

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Anticoagulation in atrial fibrillation