Modern Management in

Primary Care (AF1)

Dr Yassir Javaid

Primary Care Cardiovascular Lead

East Midlands Strategic Clinical Network

Dr Ravi Assomull

Consultant Cardiologist

London North West Healthcare NHS Trust

Setting the Scene…..

AF massively increases stroke risk

Increases stroke

risk by 340%

Increases stroke

risk by 240%

Increases stroke

risk by 430%

Increases stroke

risk by 480%

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

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

Stroke severity in patients with AF

% o

f p

ati

en

ts

Disabling Fatal

60%

40%

0%

50%

30%

20%

10%

70%

*The Copenhagen stroke study, a prospective community-based study. n=1,197

**In hospital mortality: 72 deaths, n=217with AF vs. 171 deaths n=968without AF†Discharge to own home: n=104with AF vs. 662 deaths n=968without AF‡Length of hospital stay: 50.4 days with AF vs. 39.8 days without AF

Jorgensen, et al. Stroke 1996;27:1765-9

Among patients who had a stroke, those with AF experienced a:

increase in in-hospital mortality**

40%decrease in the relative chance of discharge to own home†

20%increase in the length of hospital stay‡

…compared to those without AF

AF Related Strokes Are More Severe

Stroke risk similar in persistent and

paroxysmal AF

The risk of stroke with asymptomatic or paroxysmal AF is comparable to that

with persistent AF

Annual risk

of

stro

ke (

%)

Stroke risk category

Low Moderate High0

2

4

6

8

10

12

14 Intermittent AF

Sustained AF

Journal of the American College of Cardiology volume 35, Issue 1, January 2000, Pages 183–187

• Do not offer aspirin monotherapy for AF related stroke prevention

NICE Guideline for AF (June 2014)

See NICE CG180 for full guideline https://www.nice.org.uk/guidance/cg180

Risks of a Fall While on Warfarin

• Absolute risk of subdural haematoma: 0.04%/yr

• Relative risk (RR) of subdural hematoma in someone who falls vs. someone who doesn’t: 1.4

• RR of subdural hematoma in faller on warfarin vs. faller not on warfarin: 3.3

So...

• Would need to fall 295 times a year to outweigh the benefits of warfarin (regardless of age/baseline stroke risk)

• Man-Son-Hing M, et al. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med. 1999;159(7):677–685.

• Tinetti ME, Speechley M, Ginter SF. Risk Factors for Falls among Elderly Persons Living in the Community. N Engl J Med 1988; 319(26):1701-1707.

NICE Guideline for AF (June 2014)

• Do not withhold anticoagulation solely because of risk of having a fall

Stroke Prevention in AF….

NICE Guideline for AF (June 2014)

• CHA2DS2VASc for all patients:• Paroxysmal

• Persistent

• Permanent

• Atrial flutter

• Risk of recurrence after cardioversion back to sinus rhythm

• If CHA2DS2VASc ≥ 2 offer anticoagulation

• If CHA2DS2VASc = 1 consider anticoagulation

– “Offer” = confident that for the vast majority of pts an intervention

will do more good than harm and be cost-effective

– “Consider” = confident that for most pts an intervention will do more

good than harm and be cost-effective

Who should be anticoagulated? (ESC 2012)

Non-valvular AF Valvular AF*

<65 years & lone AF (including female)

No

Assess risk of stroke (CHA2DS2-VASc score)

0 1 ≥2

Assess bleeding risk (HAS-BLED score)Consider patient values and preferences

No antithrombotic therapy

NOAC**

VKA

Yes

** NOAC “broadly preferable” to VKA (INR 2–3) for most patients with non-valvular AF

*AF related to rheumatic valvulardisease (predmoninantly MS) and prosthetic valve

VKA

OAC therapy

Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.

ESC 2016 Recommendations

Eur Heart J doi:10.1093/eurheartj/ehw210.

• Anticoagulation may be with apixaban, dabigatran, rivaroxaban or a vitamin K antagonist

• Discuss the options for anticoagulation with each patient and base the choice on their clinical features and preferences

• If anticoagulation is not tolerated or contraindicated consider left atrial appendage occlusion (LAAO)

NICE Guideline for AF (June 2014)

Valvular vs non-valvular AF

Lip et Al Europace doi:10.1093/europace/euv309

The risk of ischaemic stroke "without" OAC exceeds the

risk of intracranial bleeding "with" OAC*

Relation between risk scores and annual event rates of ischaemic stroke and ICH in relation to use of oral anticoagulation in 159,013 Swedish AF patients followed up for 1.5±1.1 yrs (2005–2008)

CHA2DS2-VASc score

An

nu

al

even

t ra

te

Score

0 1 2 3 4 5 6 7 8+

Stroke [no OAC]

Stroke [OAC]

ICH [OAC]ICH [no OAC]

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%HAS-BLED score

An

nu

al

even

t ra

te0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Score

0 1 2 3 4 5+

Stroke [no OAC]

Stroke [OAC]

ICH [OAC]

ICH [no OAC]

*Except those with a very low risk of stroke

Adapted from Friberg et al. Circulation 2012;125:2298–307.

HAS-BLED score

Letter Clinical characteristic Points awarded

H Hypertension (SBP > 160mmHg) 1

AAbnormal renal and liver function (1 point each) (Creat >200; Br >x2; ALP/AST>x3) 1 or 2

S Stroke 1

B Bleeding diathesis (Prev bleed/unexplained anaemia) 1

L Labile INRs 1

E Elderly (age >65 years) 1

D Drugs or alcohol (1 point each) (≥8 drinks/week) 1 or 2

Maximum 9 points

*This table is based on the likely risk / benefit of warfarin in NVAF patients. The NOACs have been shown to be at least non-inferior to warfarin in terms of reducing ischaemic stroke in NVAF

patients. Dabigatran 150mg has actually been shown to be superior to warfarin in reducing ischaemic stroke.

The NOACs have been shown to be not significantly more hazardous than warfarin in terms of causing major bleeds in NVAF patients. Dabigatran 110mg, apixaban 5mg and edoxaban 60mg

have actually been shown to be associated with significantly fewer major bleeds than warfarin.

Adapted from NICE: Patient Decision Aid – Atrial Fibrillation: medicines to help reduce your risk of a stroke – what are the options; June 2014

Cardiac rhythm assessment

• MANUAL pulse checking will give a strong clue to rhythm

– Now often ignored!

– Is it regular?

– Does the strength of pulse vary?

– What is the rate?

• ECG to monitor or confirm rhythm

SAFE Trial Fitzmaurice BMJ 2007(25 August) 335-383

• Objectives: – Does screening improve detection of AF in primary care?– Opportunistic vs Systematic screening

• Design:– Multicentred Primary Care RCT across 50 practices in England

• Participants:– 14 802 patients ≥ 65 yrs in 25 intervention and 25 control practices

• Results: – Detection rate/year of new AF cases:

• 1.63% (screening practices) vs 1.04% (control practices)(difference 0.59%, 95% CI 0.20% to 0.98%).

• Systematic vs opportunistic screening detected similar numbers of new cases (1.62% v 1.64%, difference 0.02%, –0.5% to 0.5%).

Conclusion: Active screening significantly increases detection. The preferred method of screening in 10 care is opportunistic pulse taking with follow-up ECG

• Anticoagulation may be with apixaban, dabigatran, rivaroxaban or a vitamin K antagonist

• Discuss the options for anticoagulation with each patient and base the choice on their clinical features and preferences

• If anticoagulation is not tolerated or contraindicated consider left atrial appendage occlusion (LAAO)

NICE Guideline for AF (June 2014)

Limitations of warfarin

• Narrow therapeutic window

• Wide variation in metabolism

• Numerous food and drug interactions

• Need for regular coagulation monitoring and dose

adjustment

• Slow onset/offset

• Significant increase in intracranial and other

haemorrhage

Warfarin has a narrow therapeutic window

Based on Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120:897-902

Limitations of warfarin

• Narrow therapeutic window

• Wide variation in metabolism

• Numerous food and drug interactions

• Need for regular coagulation monitoring and dose

adjustment

• Slow onset/offset

• Significant increase in intracranial and other

haemorrhage

Vit K sensitive: VII, IX, X & PT

Apixaban

Rivaroxaban

Apixaban

Edoxaban

Dabigatran

Pivotal Warfarin Controlled Trials

Stroke Prevention in AF

6 Trials of Warfarin vs. Placebo

1989-1993

RE-LY

(Dabigatran)

2009

ROCKET AF

(Rivaroxaban)

2010

ARISTOTLE

(Apixaban)

2011

ENGAGE AF-TIMI 48

(Edoxaban)

2013

Warfarin vs. Placebo

2,900 Patients

NOACs vs. Warfarin

71,683 Patients

Meta-analysis of large NOAC trials shows

favourable risk/benefit ratio over warfarin Ruff et al., The Lancet 2013

ENGAGE AF-TIMI 48

ARISTOTLE

ROCKET AF

RE-LY

Combined

Favours NOAC Favours Warfarin

0.88 (0.75 - 1.02)

0.80 (0.67 - 0.95)

0.88 (0.75 - 1.03)

0.66 (0.53 - 0.82)

0.81 (0.73 - 0.91)

Risk Ratio (95% CI)

p=<0.0001

0.5 1 2

All NOACS: Stroke or Systemic Embolism

n=58,541Heterogeneity p=0.13

[Edoxaban 60 mg]

[Dabigatran 150 mg]

[Rivaroxaban]

[Apixaban]

Meta-analysis of large NOAC trials shows favourable risk/benefit ratio over warfarin, Ruff et al., The Lancet 2013

All-Cause Mortality

Myocardial Infarction

Hemorrhagic Stroke

Ischemic Stroke

0.90 (0.85 - 0.95)

0.97 (0.78 - 1.20)

0.49 (0.38 - 0.64)

0.92 (0.83 - 1.02)

Risk Ratio (95% CI)

p=0.0003

p=0.77

p<0.0001

p=0.10

Favours NOAC Favours Warfarin

0.2 0.5 1 2

Secondary Efficacy Outcomes

Ruff CT, et al. Lancet 2013

ARISTOTLE

ROCKET AF

Combined

Favours NOAC Favours Warfarin

Risk Ratio (95% CI)

0.80 (0.71 - 0.90)

0.71 (0.61 - 0.81)

1.03 (0.90 - 1.18)

0.94 (0.82 - 1.07)

0.86 (0.73 - 1.00)

0.5 1 2

All NOACS: Major Bleeding

p=0.06

RE-LY[Dabigatran 150 mg]

ENGAGE AF-TIMI 48

Ruff CT, et al. Lancet 2013

[Apixaban]

[Rivaroxaban]

[Edoxaban 60 mg]

GI Bleeding

Intracranial

Haemorrhage

1.25 (1.01 - 1.55)

0.48 (0.39 - 0.59)

Risk Ratio (95% CI)

p=0.043

p<0.0001

Favours NOAC Favours Warfarin

0.2 0.5 1 2

Secondary Safety Outcomes

Heterogeneity

ICH, p=0.22

GI Bleeding, p=0.009

Ruff CT, et al. Lancet 2013

0

1

2

3

4

5

Apixaban Warfarin

NOACs vs. Warfarin:Gastrointestinal Bleeding

0

1

2

3

4

5

Rivaroxaban Warfarin

0

1

2

3

4

5

D110 mg D150mg Warfarin

AR

R i

n G

I B

leed

ing

(%

per

year)

ROCKET AF ARISTOTLE RE-LY

Mean CHADS2 = 3.5

P < 0.001

Mean CHADS2 = 2.1

P < 0.001

Mean CHADS2 = 2.1

*

Patel et al. NEJM 2011;365(10):883-91; Connolly et al. NEJM 2009;361(12):1139-51; Granger et al. NEJM 2011;365:981-92

*

Sub-analysis of ROCKET-AF

GI

Ble

ed

ing

Rate

(%

)

0

2

4

With

rivaroxaban

3.6%

With

warfarin

2.6%

Frequency of GI bleeding

higher with rivaroxaban

Nu

mb

er

of

Pati

en

ts

0

5

With

rivaroxaban

With

warfarin

Frequency of Fatal GI bleeding

higher with warfarin

4

3

2

1

GI Bleeding with Rivaroxaban is Less Severe than with Warfarin

Presented during CHEST 2012, the annual meeting of the American College of Chest Physicians, held October 20 -- 25, in Atlanta, Georgia

eGFR vs CrCl

How we should measure renal fct

• BNF: for most drugs eGFR is an adequate estimate but for low therapeutic index and high risk drugs, should use Cockcroft & Gault equation (eCrCl-CG)

• Serum creatinine is derived from muscle mass so the weight element of the equation should be an indication of muscle mass, not excess fat. BNF also states that the weight component of the equation be “ideal body weight” –particularly important in obese patients

http://www.nephron.com/cgi-bin/CGSI.cgi

Case Study – Which anticoagulant?

• Apixaban 5mg bd• Reduce dose to 2.5mg bd if 2 of:

» > 80 years

» Creat > 133 µmol/l

» Weight < 60 kg

or in severe renal impairment (creatinine clearance 15-29 mL/min)

• Dabigatran 150mg bd (Dosette box not an option)• Reduce dose to 110mg bd if any of:

» > 80 years

» HAS-BLED ≥ 3

» Cr-Cl 30-49ml/min

• Edoxoban 60mg od• Reduce dose to 30mg od if 2 of:

» Weight < 60 Kg

» Cr-Cl 15-49ml/min

» Weight < 60 kg

• Rivaroxaban 20mg od• Reduce dose to 15mg od if 2 of:

» Cr-Cl 15-49ml/min

The right dose for the right patient

1. Ezekowitz MD et al. Am Heart J 2009;157:805–10; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–1876; 4.

Rocket Investigators. Am Heart J 2010;159:340-347; 5. Patel MR et al. NEJM 2011;365:883–91; 6. Lopes et al. Am Heart J 2010;159:331-9; 7. Granger et al. N Eng J Med

2011;365:981-92.; 8. Edoxaban SmPC July 2015

Dabigatran1-3 Rivaroxaban4,5 Apixaban6,7 Edoxaban8

Mode of action Thrombin Factor Xa Factor Xa Factor Xa

Half life 12-14 hrs 7-11 hrs 12 hrs 10-14 hrs

Dosing

(in atrialfibrillation)

B.D. O.D. B.D. O.D.

Excretion 85% Renal1/3 Renal2/3 Hepatic

1/4 Renal3/4 Non Renal

1/2 Renal1/2 Non Renal

Form Capsule Tablet Tablet Tablet

Dose

150 mg110 mg (>80 yrs, verapamil or increased bleeding risk)

20 mg15 mg (CrCl 15-49 ml/min)

5 mg 2.5 mg (2 or more:>80yr; weight <60 kg;Cr >133mmol/L) or with severe renal impairment (creatinine clearance 15-29 mL/min)

60 mg 30mg (1 of: <60Kg; CrCl15-49ml/min; P-gpinhibitors)

B.D. = twice daily; O.D. = once daily

Cannot be put in dosette box

Case Study – Monitoring

• Check FBC and LFTs initially and annually

• Reinforce importance of compliance!!!!

• Patient information leaflet and alert card

• Check renal function 6 monthly

Rate and/or rhythm control….

NICE Guideline for AF (June 2014)

• Rate control should be initial 1st line strategy for most AF patients unless:

• AF with reversible cause

• New onset AF (esp if < 65)

• HF thought to be primarily caused by AF

• Clinical judgement suggests rhythm control may be more suitable

• If drug Rx has failed to control symptoms:– Ablation should be:

• offered to patients with paroxysmal AF

• considered for patients with persistent AF

Rhythm control requires anticoagulation for ≥ 3 weeks prior to cardioversion unless AF onset < 48hrs

Subsequent anticoagulation is dependent on stroke risk regardless of perceived effectiveness of rhythm control

Rate control Strategy

[Digoxin should only be considered as monotherapy

in sedentary patients]

First Line monotherapy:

Beta Blocker or Rate-limiting CCB

Atenolol, bisoprolol Diltiazem, verapamil

Aim for ventricular rate 80 - 90 bpm at rest

Journal of the American College of Cardiology

Volume 33, Issue 2, February 1999, Pages 304–310

AF rate control during exercise

European Heart Journal

Digoxin-associated mortality: a systematic review and meta-analysis of the literatureMate Vamos , Julia W. Erath , Stefan H. Hohnloser DOI: http://dx.doi.org/10.1093/eurheartj/ehv143

First published online: 4 May 2015

“The present systematic review and meta-analysis of all available data sources suggest that digoxin use is associated with an increased mortality risk, particularly among patients suffering from AF, (as well as HF)”

Role of Echocardiography

NICE - Echocardiography should be performed in:

• Younger patients when a baseline echo would be useful to guide long term management

• Patients considered for a rhythm control strategy

• Those patients where structural heart disease is suspected eg heart failure or heart murmur

• Those patients where the need for anticoagulation is not clear cut and further refinement of risk is needed

Rule of thumb: An echo is unlikely to influence management if:

Patient is > 75 and asymptomatic and no suspected heart failure or valve disease

AF case detection…..

AF: The Ticking Time Bomb

The burden of AF will rise very sharply

• 13% in the last two decades1

• Estimated to at least double in the next 50 years

56

Year

1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

Pati

en

ts w

ith

AF

(millio

ns)

16

14

12

10

8

6

4

2

0

2.08 2.26 2.44 2.66 2.94 3.333.8

4.344.78 5.16 5.42 5.61

5.15.6

6.16.8

7.58.4

9.4

10.311.1

11.712.1

5.1

5.9

6.7

7.7

8.9

11.7

13.1

14.315.2

15.9

ATRIA* study data2

Mayo Clinic data(assuming no further increase in AF incidence)1

Mayo Clinic data(assuming a continued increase in AF incidence)1

Projected number of adults with AF in

the United States by 20503

*ATRIA = AnTicoagulation and Risk factors In Atrial fibrillation

10.2

1. Miyasaka et al. Circulation 2006;114:119–25.

2. Go et al. JAMA 2001;285:2370–5.

3. Adapted from Savelieva et al. Clin Cardiol 2008;31:55–62.

Who else should we be screening?

• Hypertension

• Structural heart disease (eg heart failure, mitral valve disease)

• Obstructive sleep apnoea

• Use of technology: Portable ECG and leadless patch devices