prepared by: dr ronnie jardine fcp(sa)

SA Heart Lecture Series – Atrial Fibrillation

Prepared by: Dr Ronnie Jardine FCP(SA)


AF increases the risk of stroke AF is associated with a ~5 fold increase in stroke risk

i.e. to ~5% per year1

Risk of stroke is the same in AF regardless of whether it is paroxysmal / persistent / permanent 2,3

AF is associated with 15-20% of all strokes

Up to 3 million people suffer AF related stroke each year worldwide4

1. Wolf PA et al. Stroke 1991; 22: 983-8. 2. Rosamond W et al. Circulation 2008; 117: e25–

146. 3.Hart RG et al. J Am Coll Cardiol 2000; 35: 183-187. 4. Atlas of Heart disease and

Stroke, World Health Organisation, September 2004.

http://www.who.int/cardiovascular_diseases/en/cvd_atlas_15_burden_stroke.pdf


Stroke severity in AF

AF-related strokes tend to be especially severe and disabling

30-day mortality = 25%1

1-year mortality = 50%2

1. Lin HJ et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27: 1760-4.

2. Marini C et al. Stroke 2005; 36: 1115-9.


Stroke severity in patients with AF

% o

f p

ati

en

ts

Disabling Fatal

60%

40%

0%

50%

30%

20%

10%

Effect of first ischaemic stroke in patients with AF (n=597)1

Gladstone DJ et al. Stroke 2009; 40: 235-240.


Economic burden of AF

The American Heart Association estimates that

the direct and indirect cost of stroke in the US is $65.5 billion1

A German Registry has shown that the overall

first-year cost of AF is €18,5172

A 15% reduction in stroke-related hospital admissions

in the UK would save an estimated

£30 million/year3

1. Rosamond W et al. Circulation 2008; 117: e25–146. 2. Kolominsky-Rabas PL et al. Stroke2006; 37: 1179–83. 3. Stewart S et al. Heart 2004; 90: 286–292.


Thrombo-embolism in AF

Thrombus from LA / LAA


Thrombus from LA/LAA

Virchow’s triad

Stasis

Endothelial dysfunction

Hyper-coagulable state

Watson T et al. Lancet 2009; 373: 155-66.


Thrombo-embolism in AF

Thrombus from LA / LAA (only 75%)

Other cardio-embolic, e.g. prosthetic valve, LV aneurysm

Aortic atheroma

Cerebro-vascular disease


CHADSVASc scoreRisk factor Score

CHF / LV dysfunction 1

Hypertension 1

Age > 75 2

Diabetes mellitus 1

Stroke/TIA/other embolism 2

Vascular disease 1

Age 65-74 1

Sex category (female) 1

Max score 9


Stroke rate according to CHADSVASc

Score % per annum

0 0

1 1.3

2 2.2

3 3.2

4 4.0

5 6.7

6 9.8

7 9.6

8 6.7

9 15.2


ESC recommendations CHADSVASc score = 0

Aspirin or nothing

Preferably nothing

CHADSVASc score = 1

Consider Oral Anticoagulant (OAC)

Preferably Novel OAC (NOAC)

CHADSVASc score = 2 or more

Oral Anticoagulant mandatory

Preferably Novel OAC


HAS-BLED score

Risk factor Score

Hypertension 1

Abn renal/liver function 1-2

Stroke 1

Bleeding 1

Labile INR 1

Elderly (>65) 1

Drugs / alcohol 1-2

Max score 9


ESC Guideline 2012.


Coagulation cascade

Vit K Antagonists

IIVIIIXX


Anti-thrombotic therapy in AF

Hart RG et al. Ann Intern Med 2007; 146: 857-67.


Brush up on Warfarin - 1 Anti-coagulate all those who require it

Educate patients starting warfarin

◦ Understand the reason for treatment

◦ Understand what warfarin does

◦ The meaning of the INR

◦ Appropriate response to bleeding

◦ Vitamin K and other antidotes

◦ Drug-drug and food-drug interactions esp. non-

prescription

◦ MedicAlert bracelet

◦ Frequency of INR monitoring and a log book

Dalby AJ, Wessels P and Opie LH. S Afr Med J 2013; 103: 901-4.


Brush up on Warfarin - 2 Take steps to ensure patient compliance

System to ensure regular monitoring of INR

-Lab

-Patient self-monitoring?

◦ Use an algorithm to guide dose adjustment. Algorithm

consistent dosing relates to better TTR, which in turn

relates strongly to thromboembolic and bleeding outcomes

Follow an accepted protocol for bridging the peri-operative

period


RE-LY algorithm

Calculate the dose on a weekly, rather than daily basis because the recommended dose changes are small and will be difficult to achieve with daily dosing.

Do weekly INR monitoring for out-of-range INR values.

(INR 5.00-8.99 + high bleeding risk or when INR >9.00, give Vitamin K 2.5 mg p.o.)

van Spall HGC, Wallentin L, Yusuf S et al. Circulation 2012; 126: 2309-16.


Bridging therapy: Cleveland Clinic

Jaffer AK. Cleveland Clinic J Med 2009; 76 (supp 4): S37-S44.


When is it not necessary to stop Warfarin?

Jaffer AK. Cleveland Clinic J Med 2009; 76 (supp 4): S37-S44.


Limitations of VKA therapy

VKA

therapy has

several

limitations

that make it

difficult to

use in

practice

Unpredictable

response

Narrow therapeutic

window

(INR range 2-3)

Routine coagulation

monitoring

Slow onset/offset

of action

Frequent dose

adjustments

Numerous food-drug

interactions

Numerous drug-drug

interactions

Warfarin resistance

1. Ansell J et al. Chest 2008; 133: 160S-198S. 2. Umer Ushman MH et al. J Interv Card

Electrophysiol 2008; 22: 129-37. 3. Nutescu EA et al. Cardiol Clin 2008; 26: 169-87.


Narrow therapeutic range with VKA

Hylek EM et al. N Eng J Med 2003; 349: 1019-26.


ACTIVE-W trial: mean TTR by country

Connolly SJ et al. Circulation 2008; 118: 2029-37.


RE-LY: mean TTR by country

Wallentin L et al. Lancet 2010; 376: 975–83.


INR control in clinical trial versus clinical practice

1. Kalra L et al. BMJ 2000; 320: 1236-1239 * Pooled data: up to 83% to 71% in

individualized trials. 2. Matchar DB et al. Am J Med 2002; 113: 42-51.


Coagulation cascade

Directthrombin (IIa)inhibitors

Factor Xainhibitors


Novel Oral Anti-coagulants

Direct thrombin inhibitor = dabigatran

Pradaxa®

Boehringer-Ingelheim

Factor Xa inhibitors – rivaroxaban

Xarelto®

Bayer

apixaban edoxaban

Eliquis®

BMS/Pfizer Daiitchi-Sankyo


NOAC in non-valvular AF4 landmark trials

RE-LY* dabigatran

ROCKET-AF** rivaroxaban

ARISTOTLE*** apixaban

ENGAGE-AF (TIMI 48)**** edoxaban

*Connolly SJ et al. N Engl J Med 2009; 361: 1139-51.**Patel MR et al. N Engl J Med 2011; 365: 883-91.***Granger C et al. N Engl J Med 2011; 365: 981-92.****Giugliano RP et al. N Engl J Med 2013; 369: 2093-104.


NOAC – 4 landmark trials

RE-LY dabigatran 150mg BD 19 013

dabigatran 110mg BD

ROCKET-AF rivaroxaban 20mg OD 14 263

ARISTOTLE apixaban 5mg BD 18 201

ENGAGE –AF edoxaban 60mg OD 21 105

edoxaban 30mg OD

(All vs dose-adjusted warfarin INR 2-3)

Total 71 683


NOAC trials – Primary end-point


Stroke or systemic embolism

Ruff CT, Giugliano RP, Braunwald E et al. Lancet published online 4 December 2013.


Secondary efficacy and safety outcomes



Major bleeding



Practical issues with NOACs

- pharmacological

- co-morbid



Pharmacological:

Patient selection Drug selection

Dose selection Adherence errors

Switching Warfarin to NOAC

Switching NOAC to Warfarin

Measuring anti-coagulant effect Drug interactions


Patient selection:New AF patientsAll

Existing Warfarin patientsTTR <60%Stroke/embolism on Warfarin Bleeding on Warfarin Distant laboratoryPoor venous accessPatient preference / means



Drug selection

Savelieva I and Camm AJ. Clin Cardiol 2014; 37: 32-47.


Metabolism/excretion of NOACs

Heidbuchel H et al. Europace 2013; 15: 625-51.


But use reduced dose for:

All patients > 80 years old

Patients 75-80 with HAS-BLED score >3

Body weight < 60kg

Moderate renal dysfunction (Cr Cl 30-50ml/min)

GORD (with dabigatran)

Use full dose as a rule….


Full dose = dabigatran 150mg BD

rivaroxaban 20mg OD

apixaban 5mg BD

edoxaban 60mg OD

Reduced dose = dabigatran 110mg BD

rivaroxaban 15mg OD

apixaban 2.5mg BD

edoxaban 30mg OD

Dose selection


Adherence errors

Missed dose

Double dose

Uncertainty


If a patient misses a dose…..

The half-way rule

Time since missed dose Recommendation

<half-way* The patient should take the ‘missed’ dose

>half-way* The patient should wait until their next scheduled dose

*Half-way = 6 hours for dabigatran and apixaban, 12 hours for rivaroxaban and edoxaban

Huisman M et al. Thromb Haemost 2012; 107: 838-47.


Adherence errors

Missed dose half-way rule

Double dose BD skip next dose

OD take next dose

Uncertainty BD no stat dose

OD stat dose


Stop warfarinAllow INR to

fall below 2.0Start NOAC

Parenteral to NOAC

Start NOAC up to 2 hours before next

parenteral drug dose

Continuous infusions to NOAC

Start NOAC at time of discontinuation of

continuous infusion

Switching patients to NOAC

Warfarin to NOAC

Huisman M et al.

Thromb Haemost2012; 107: 838-47,


Switching from Xa inhibitors

Start warfarin 3 days before stopping Xa


Switching patients from dabigatran

Start Warfarin based on renal function:

CrCl in mL/min Recommendation

≥50 Start VKA 3 days before stopping NOAC

≥30 to <50 Start VKA 2 days before stopping NOAC

15–30 Start VKA 1 day before stopping NOAC

Starting a parenteral anticoagulant:

Dabigatran to parenteral

Start parenteral anticoagulant 12 hours after last dose of NOAC

Huisman M et al. Thromb Haemost 2012; 107: 838-47.


Measuring anti-coagulant effect - dabigatran

4.84.44.03.63.22.82.42.01.61.20.8

0 200 400 600 800 1000Dabigatran plasma concentration (ng/mL)

b12


a

3.6

0.90 200 400 600 800 1000Dabigatran plasma concentration (ng/mL)

d454035302520151050


c

9

6

3

1.2

1.6

2.0

2.4

2.8

3.2

PT (

INR)

EC

T (

rati

o)

aPTT (

rati

o)

TT (

sec)

Multiple dosey = 2.4040 + 0.05851xr2 = 0.8568

Multiple dosey = 0.86 + 0.06873x1/2

r2 = 0.8514



Close correlation between dabigatran plasma concentration and degree of anticoagulant effect

INR is not sufficiently sensitive and cannot be recommended

van Ryn J et al. Thromb Haemost 2010; 103: 1116–27.



Qualitative tests –activated Partial Thromboplastin Time (aPTT)

Thrombin Time (TT)

Quantitative tests–

Ecarin clotting time (ECT)

Hemoclot® thrombin inhibitor assay



Activated partial

thromboplastin time (aPTT)

May be useful in determining

an excess of anticoagulant

activity1,2

Clinically relevant

measurement

An aPTT >80 seconds at

trough (when the next dose

is due) is associated with a

higher risk of bleeding1,3

1. van Ryn J et al. Thromb Haemost 2010; 103: 1116–1127; 2. Liesenfeld K-H et al. Br J Clin Pharmacol 2006; 62: 527–537; 3. Huisman M et al. Thromb Haemost 2012; 107: 838-47.


Measuring anti-coagulant effect -Xa inhibitors

Qualitative

Prothrombin time (PT)

(not INR)

Quantitative

Anti-Xa chromogenic assay


Drug interactions


Drug interactions

Few

Verapamil – strongly accentuates dabigatran and edoxaban

HIV protease inhibitors – strongly accentuates

rivaroxaban and apixaban


Chronic kidney disease

Surgery

Bleeding

Coronary artery disease

Acute stroke

Cardioversion

Malignancy

Practical issues – co-morbid


Chronic kidney disease

CKD is an independent risk factor for stroke in AF

CKD is a risk factor for bleeding on OAC

All NOACs are excreted by kidneys

dabi>edoxa>rivaroxa>apixa

Monitor renal function

No NOACs if on haemodialysis (Rx warfarin)


Interruption for surgery

Bridging is never necessary

When to stop?

When to restart?


Interruption for surgery –when to stop?

Emergency / elective

Bleeding risk of the procedure

Renal function in the case of dabigatran


Classification of bleeding risk

No bleeding risk

Low bleeding risk

High bleeding risk


No bleeding risk

No interruption necessary – operate at trough concentration


Low and high bleeding risk


Interruption for surgery –when to stop?

Dabigatran Low risk High risk

CrCl >80 24 48

50-80 48 72

30-50 72 96

<30 not used

Xa inhibitors

CrCl >30 24 48

15-30 36 48

<15 not used


Interruption for surgery – when to restart?

Complete haemostasis 6-8 hours

Incomplete haemostasis 48-72 hours


Managing bleeding

Patient with bleeding

Mild

• Delay next dose or discontinue treatment as appropriate

Life-threatening

• Consideration PCC or rFVIIa*

• Charcoal filtration

Moderate/severe

• Supportive Rx

• Mechanical compression

• Fluid replacement

• Blood transfusion

• Oral charcoal

• Haemodialysis (dabigatran)

*PCC = prothrombin complex concentrate (Haemosolvex®); rFVIIa = recombinant Factor VIIa (Nova-VII®).

van Ryn J et al. Thromb Haemost 2010; 103: 1116–27.



3 different scenarios:

Patient on OAC for AF develops ACS

Patient with recent ACS / PCI develops AF

Patient with stable CAD develops AF




Warfarin to be continued DAPT started

NOAC to be stopped DAPT+LMWH

If PCI bare metal stent and

radial artery access if possible

Afterwards: triple for 1 month OAC+SAPT for 1 yr

OAC alone



3 different scenarios:


Patient with recent ACS / PCI develops AF




Patient with recent ACS/PCI develops AF

Warfarin must be added to DAPT if <1 month after BMS or <6 months after DES.

If later, consider warfarin alone

warfarin+SAPT

continuing DAPT alone

Xa inhibitor

dabi 110mg BD + SAPT



In deciding, consider….

Stroke risk i.e. CHADSVASc score

Bleeding risk i.e. HAS-BLED score

Athero-thrombotic risk e.g. GRACE score


GRACE* risk score

Age

Heart rate

Systolic BP

Serum creatinine

Killip class

Cardiac arrest at admission

ST deviation

Elevated markers

*Global Registry of Acute Cardiac Events




Switch from aspirin to warfarin alone.

NOAC are likely equivalent or better than warfarin.

Dabigatran does increase MI risk slightly

? combine 110mg BD with aspirin.


Acute stroke

Haemorrhagic – stop OAC immediately

vit K / FFP for warfarin

?PCC / rFVII for NOAC

? Whether to restart after 10-14 days

Ischaemic – thrombolysis contra-indicated

no interruption for TIA / small infarct

3-6-12 days for small/ medium/large


Cardioversion

Thrombo-embolic risks with NOACs are the same as with warfarin


Trials excluded cancer patients

Many cancers increase thrombotic risk

Cancer therapy increases bleeding risk

Cardiologist and oncologist joint decision

Malignancy


Physical approaches1

LAA occlusive devices

Plaato® PLAATO2

Watchman® PROTECT-AF3

Amplatzer cardiac plug®

Surgical interventions

LAA ligation/purse-string/stapling at other Ø LAAOS

LAA snaring/stapling at thoracoscopy LAPTONI

Carotid diverters

1. Savelieva I et al. Annals of Medicine 2007; 39: 371-91. 2. Block PC et al. J Am Coll

Cardiol Intv 2009;

2: 594-600. 3. Holmes DR et al. Lancet 2009; 374: 534-42.


Percutaneous LAA occlusion

Consider with:

Ischaemic stroke despite adequate OAC therapy

Previous intra-cranial haemorrhage

Recurrent GIT bleeding

Co-morbidities e.g. uncontrolled HT, cerebral amyloid angiopathy

Coagulopathies

Lewalter T et al. Europace 2013; 15: 652-6.


Percutaneous LAA occlusion

Complications:

Pericardial effusion / tamponade

Device embolisation

Stroke

Myocardial infarction

prepared by: dr ronnie jardine fcp(sa)

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