Post on 05-Feb-2020
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