Dr Pipin Kojodjojo Share more on the topic, Early Treatment of Atrial Fibrillation. Visit our website www.ahvc.com.sg for more info.

1. Dr Pipin Kojodjojo
Senior Consultant
Cardiologist / Cardiac Electrophysiologist
drko.pipin@ahvc.com.sg
linkedin.com/in/pipin-kojodjojo-5611a8228
AF and Hypertension in Daily Primary Care
Early Treatment of Atrial Fibrillation (AF)
February 2022

2. Disclaimer
The content of this presentation has been developed by the speaker to the complete exclusion of Pfizer and
that Pfizer has no influence on the same. Pfizer has merely reviewed the content of the presentation only to
the extent to ensure it meets the specific Pfizer standards but not to ensure that the content or any references,
medical information, facts, views which may have been cited therein are accurate. Any medical information,
facts, views, opinions, and thoughts expressed in this presentation are strictly those of the speaker presenting
the same and do not necessarily reflect or represent the views of, and are not attributable to, Pfizer Singapore
and/or its affiliates.

3. Content
• AF demographics
• Stroke prevention in AF
• Importance of Early Treatment
• Holistic Approach to AF

4. Atrial Fibrillation
Delirium cordis – “dementia of the heart”
• AF – most common sustained arrhythmia in
humans
• Electrical triggers initiate episodes of AF
• Atria undergo structural, electrical and pathological
changes called remodelling
• Result is electrical chaos (atrial activity at 350 – 500
beats per minute)
• Irregular QRS and pulse
1. Fuster V et al. Circulation 2006;114:700–752;
2. Cohen M and Naccarelli GV. J Cardiovasc Electrophysiol 2008;19:885–890

5. Increasing age is a key risk factor for AF
1. Go AS et al. JAMA 2001;285:2370–2375
0
5
10
15
20
Women (n=7,795) Men (n=10,179)
Prevalence
(%)
The ATRIA study1
Age (years)

6. Number of AF patients continues to increase
Year
2.08 2.44
2.26
5.1
5.1
0
2
4
6
8
10
12
14
16
1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
Patients
with
AF
(millions)
5.42
11.7
15.2
4.34
9.4
11.7
3.33
7.5
8.9
2.94
6.8
7.7
8.4
10.2
3.80
4.78
10.3
13.1
5.16
11.1
14.3
5.61
12.1
15.9
5.6
5.9
2.66
6.1
6.7
Olmsted County data, 20061
(assuming a continued increase in AF incidence)
ATRIA study data, 20002
Olmsted County data, 20061
(assuming no further increase in AF incidence)
1. Miyasaka Y et al. Circulation 2006;114:119–125; 2. Go AS et al. JAMA 2001;285:2370–2375

7. All you need to confirm a diagnosis of AF - ECG
Characterised as irregular baseline on ECG wth no organised atrial
activity and irregularly timed QRS complexes

8. Disruptive wearable technology – earlier diagnosis

9. 30 seconds of AF recorded on an Apple Watch

10. Earlier diagnosis of AF: Opportunistic
Screening with devices
• 184 Canadian family physicians provided with
Kardia ECG device for 3 months
• 30 seconds recording for all patients > 65 years
old, not known to have AF
• 42% of eligible patients (n = 7585) were screened
• AF detected in 6.2% (n = 471) and OAC started in
270 patients
• Opportunities exist to perform such screening in
pharmacies, nursing facilities, supermarkets etc.
Godin et al. Screening for Atrial Fibrillation Using a Mobile, Single-Lead Electrocardiogram in Canadian Primary Care Clinics Canadian Journal
of Cardiology 2019
Ping An Good Doctor 1 minute clinic

11. AF screening in villages of rural India
Soni et al. Age-and-sex stratified prevalence of atrial fibrillation in rural Western India: Results of SMART-
India, a population-based screening study IJC 2019

12. 3 reasons why atrial fibrillation (AF) is important?
1) It is very, very common
• More common as we get older
• 15-20% of people above the age of 80
2) AF Increase risk of death by 200% and stroke by 500%
• 1 in 4 strokes caused by AF
• Strokes caused by AF are more disabling (leading form of adult disability)
3) AF can be difficult to detect
• > 80% of patients have no symptoms and therefore are unaware of their condition
• If symptoms are present, the most common is palpitations
• The ECG is only abnormal when AF is happening; so a normal ECG does not rule out AF
Common + Dangerous
+ Hard to Find +
Expensive to Treat
= MAJOR
HEALTHCARE ISSUE

13. How does AF cause strokes?

14. PROTECT
THE
BRAIN
“Regardless of whether the treatment strategy is pursued…the need for anticoagulation is
based on stroke risk and not on whether sinus rhythm is maintained.”

15. ARISTOTLE: Apixaban was superior to warfarin in preventing stroke or systemic
embolism
Adapted from Granger et al. N Engl J Med 2011;365:981-92.
Months
Patients
with
event
(%)
Apixaban
Warfarin
0 6 12 18 24 30
0
1
2
3
4
HR 0.79 (95% CI: 0.66-0.95)
p<0.001 for non-inferiority
p=0.01 for superiority
21% RRR
No. at risk
Apixaban 9,120 8,726 8,440 6,051 3,464 1,754
Warfarin 9,081 8,620 8,301 5,972 3,405 1,768

16. * Major bleeding was defined according to ISTH criteria
Adapted from Granger et al. N Engl J Med 2011;365:981-92.
ARISTOTLE: Apixaban significantly reduced the risk of major bleeding* versus
warfarin
Patients
with
event
(%)
Months
0 6 12 18 24 30
0
2
4
6
8
Apixaban
Warfarin
31% RRR
HR 0.69 (95% CI: 0.60-0.80);
p<0.001
No. at Risk
Apixaban 9088 8103 7564 5365 3048 1515
Warfarin 9052 7910 7335 5196 2956 1491

17. ARISTOTLE: Apixaban was superior to warfarin in reducing all-cause mortality
*Key secondary efficacy endpoint
Figure created from data in Granger et al. N Engl J Med 2011;365:981-92.
All-cause mortality*
0
1
2
3
4
3.94%
669/9081 3.52%
603/9120
11% RRR HR: 0.89
95% CI: 0.80-0.998;
p=0.047
Warfarin Apixaban
Event
rate
(%
/
year)

18. AVERROES: Apixaban vs Aspirin
Randomized, phase III, double-blind, double dummy, superiority trial
*Patients with at least 2 of the following criteria: age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dl
Connolly SJ et al. N Engl J Med 2011;364:806–817
Non-valvular
AF plus
at least one additional
risk factor for stroke
AND have been
shown to be or are
expected to be
unsuitable for VKA
therapy
End
of
treatment
Apixaban 5 mg bid (94%)
Apixaban 2.5 mg bid* (6%)
ASA 81–324 mg od
R
N=5,599
Follow-up
Primary efficacy: composite of stroke (ischaemic or
haemorrhagic) or systemic embolism

19. AVERROES: primary efficacy endpoint
Apixaban
n (% per yr)
Aspirin
n (% per yr) HR 95% CI p-value
Primary efficacy: stroke or
systemic embolism
51 (1.6%) 113 (3.7%) 0.45 0.32–0.62 <0.001
Stroke 49 (1.6%) 105 (3.4%) 0.46 0.33–0.65 <0.001
Ischaemic stroke 35 (1.1%) 93 (3.0%) 0.37 0.25–0.55 <0.001
Haemorrhagic stroke 6 (0.2%) 9 (0.3%) 0.67 0.24–1.88 0.45
Unspecified 9 (0.3%) 4 (0.1%) 2.24 0.69–7.27 0.18
Systemic embolism 2 (0.1%) 13 (0.4%) 0.15 0.03–0.68 0.01
Connolly SJ et al. N Engl J Med 2011;364:806–817

20. AVERROES: safety endpoint
Outcome
Apixaban
n (% per yr)
Aspirin
n (% per yr) HR 95% CI p-value
Major bleeding* 44 (1.4%) 39 (1.2%) 1.13 0.74– 1.75 0.57
Intracranial 11 (0.4%) 13 (0.4%) 0.85 0.38–1.90 0.69
Subdural# 4 (0.1%) 2 (0.1%) – – –
Other intracranial#,‡ 1 (<0.1%) 2 (0.1%) – – –
Extracranial or unclassfied 33 (1.1%) 27 (0.9%) 1.23 0.74– 2.05 0.42
Gastrointestinal 12 (0.4%) 14 (0.4%) 0.86 0.40– 1.86 0.71
Non-gastrointestinal 20 (0.6%) 13 (0.4%) 1.55 0.77– 3.12 0.22
Fatal 4 (0.1%) 6 (0.2%) 0.67 0.19– 2.37 0.53
Non-major clinically relevant
bleeding
96 (3.1%) 84 (2.7%) 1.15 0.86–1.54 0.35
Minor 188 (6.3%) 153 (5.0%) 1.24 1.00–1.53 0.05
*Principal safety outcome in ITT population, defined as clinically overt bleeding accompanied by one or more of
the following: a decrease in the haemoglobin level of ≥2 g/dl over a 24-hour period, a transfusion of ≥2 units of
packed red cells, bleeding at a critical site or fatal bleeding. #HRs and p-values were not calculated because there
were so few events. ‡Excluding haemorrhagic stroke and subdural bleeding Connolly SJ et al. N Engl J Med 2011;364:806–817

21. Management of Atrial Fibrillation
Catheter Ablation
AVN Ablation +
Pacemaker
Surgical Maze
Diagnosis of AF
PROTECT THE BRAIN TREATING SYMPTOMS
Anti-Arrhythmic
Drugs
Novel Anticoagulants
Left Atrial Appendage
Occlusion
TREAT CO-MORBIDITIES

22. Catheter ablation is significantly more successful for rhythm control of paroxysmal
AF – 70% of PAF patients do not respond to AAD
Jais P et al. Catheter Ablation Versus Antiarrhythmic Drugs for Atrial Fibrillation: The A4 Study. Circulation 2008
Wilber D et al. Comparison of AA Drug Therapy and Radiofrequency Catheter Ablation in patients with
paroxysmal AF. JAMA 2010

23. Ablation as the Initial Therapy for PAF –EARLY-AF
Andrade et al. Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation. NEJM 2021
303 PAF patient who have never
received rhythm control randomized to
either:
1. Anti-arrhythmic drugs (Class I / III)
2. PVI with a cryoballoon
Median time from AF diagnosis – 1 yr
Primary endpoint – treatment success
at 12 months (freedom from repeat
ablation, use of AAD after 3 months in
the ablation arm, >30s AT/AF using a
loop recorder, use of cardioversion)
• 1 ablation only, off AAD in 3 months
• 3 procedural complications in the ablation group: 3 phrenic
nerve palsies all resolved
• Symptomatic recurrence: 11% vs 26.2%

24. Ablation as the Initial Therapy for PAF – STOP AF First
Wazni et al. Cryoballoon Ablation as the Initial Therapy for AF. NEJM 2021
203 PAF patient who have never
received rhythm control randomized to
either:
1. Anti-arrhythmic drugs (Class I / III)
2. PVI with a cryoballoon
Primary endpoint – treatment success at
12 months (freedom from repeat
ablation, use of AAD after 3 months in
the ablation arm, >30s AT/AF during
holter monitoring, use of cardioversion)
1 ablation only, off AAD in 3 months
• 2 procedural complications in the ablation group: 1
phrenic nerve palsy, 1 pericardial effusion

25. Diagnosis-to-Ablation Time as a modifiable success factor in
treatment of AF – think door to balloon time for the atria!
Chew et al. Diagnosis-to-Ablation Time and Recurrence of Atrial Fibrillation Following Catheter Ablation: A
Systematic Review and Meta-Analysis of Observational Studies. Circ EP 2020

26. Long Terms Outcomes of Persistent AF Ablation are sub-optimal
Schreiber et al. Five-Year Follow-Up After Catheter Ablation of Persistent Atrial Fibrillation Using the Stepwise
Approach and Prognostic Factors for Success Circulation AE 2015
Predictors of recurrence: Failure to terminate AF, number of procedures, female sex, structural heart disease

27. AF is a progressive, chronic disease
Chang E. et al. A Stochastic Individual-Based Model of the Progression of Atrial Fibrillation in Individuals and
Populations. PLOS ONE 2016

28. 66% persistent AF
OAC stopped at physician’s
discretion in rhythm control arm
Most strokes occurred when
warfarin was stopped /
subtherapeutic
62.6% in rhythm control arm
were in SR at 5 years
Wyse DG et al A comparison of rate and rhythm control in patients with atrial fibrillation. NEJM 2002
Rate versus Rhythm Control: AFFIRM

29. Early Rhythm-Control Therapy in Patients with AF: EAST-AFNET4
• 2789 patients with early AF (diagnosis within 1 year) to receive either early
rhythm control or usual care – 135 sites in 11 European countries – median
follow-up of 5.1 years
• Early rhythm control – AAD or ablation after randomization
• Usual care – management of AF related symptoms (rate control)
• Primary endpoint – composite of death from cardiovascular causes / stroke;
hospitalisation with HF / ACS
• Primary safety endpoint – death, stroke, adverse events from rhythm control
Kirchhof P et al Early Rhythm-Control Therapy in Patients with AF. NEJM 2020

30. Early Rhythm-Control Therapy in Patients with AF: EAST-AFNET4
• 36 days since AF diagnosis, 30% asymptomatic, > 90% OAC, 88% hypertensive, mean age 70,
mean CHADVASC of 3.4
• 82.1% in SR at the end of 2 years in early RC arm, 60.5% in usual care arm
Kirchhof P et al Early Rhythm-Control Therapy in Patients with AF. NEJM 2020

31. Early Rhythm-Control Therapy in Patients with AF: EAST-AFNET4
Kirchhof P et al Early Rhythm-Control Therapy in Patients with AF. NEJM 2020
HR = 0.79
• 21% reduction in CV death, HF
hospitalisation, ACS and stroke
• No difference in overall primary
safety outcome (16.6% vs 16.0%)
• 4.9% non-fatal adverse events due to
AAD in rhythm control arm (1.4% in
usual care)
• 0.8% non-fatal complication rate in
those having AF ablation for rhythm
control

32. ESC 2020 AF Guidelines advocates rhythm therapy in
early AF and earlier role for ablation
Eur Heart J, Volume 42, Issue 5, 1 February 2021, Pages 373–498

33. Management of Atrial Fibrillation
Catheter Ablation
AVN Ablation +
Pacemaker
Surgical Maze
Diagnosis of AF
PROTECT THE BRAIN TREATING SYMPTOMS
Anti-Arrhythmic
Drugs
Novel Anticoagulants
Left Atrial Appendage
Occlusion
TREAT CO-MORBIDITIES

34. Atrial Degeneration
(Substrate Remodeling)
Ageing
Heart
Failure
Valvular
Disease
Heart
Surgery
Coronary
Disease
Alcohol
Excess
Hypertension
Diabetes
Thyroid
Disease
Sleep
Apnoea
Obesity
ATRIAL
FIBRILLATION
AF is the final common endpoint of multiple diseases that
affect atrial health

35. Question
If multiple conditions impair atrial health, thus causing AF……..
Can we better treat or eradicate these conditions to improve
atrial health and prevent AF?

36. At least 50% of AF Asian patients have moderate – severe OSA
Limited efficacy of AF ablation in untreated severe OSA patients
Matiello et al. Low efficacy of AF ablation in severe OSA patients. Europace 2010
Neilan et al. Effect of Sleep Apnea and CPAP on Cardiac Structure and Recurrence of AF. JAHA 2013

37. • 6 hospitals in Australia recruited AF patients who had 10 or more standard drinks per
week (1 bottle of red wine – 8) were asked whether they were willing to consider
abstinence
• 697 patients were asked – 70% declined

38. Effect of alcohol abstinence in drinkers with AF
• 140 patients were randomized to
either
• Abstain for alcohol for 6 months
(87.5% reduction in consumption)
• Continue drinking (19.5%
reduction)
• Primary Endpoint – Time to AF
recurrence
Voskoboinik et al Alcohol Abstinence in Drinkers with AF. NEJM 2020

39. Impact of weight loss to prevent AF recurrence :
Lessons from LEGACY
Pathak et al. Long-Term Effect of Goal-Directed Weight Management in an Atrial Fibrillation Cohort
A Long-Term Follow-Up Study (LEGACY) JACC 2015
• 355 AF patients offered
weight management
• Escalating treatments such as
AAD, ablation based on
symptom control
• 5 year follow-up

40. Intensive BP lowering reduces incidence of AF : SPRINT
Events per 1000 patient
years:
Intensive BP lowering – 6.2
Standard BP lowering – 8.3
HR 0.74
(95% CI 0.56 – 0.98)
P value = 0.037
Soliman et al. Effect of Intensive Blood Pressure Lowering on the Risk of Atrial Fibrillation.
Hypertension 2020

41. Impact of Modifying Co-Morbidities on AF
Risk Factors Impact on AF Risk
Diabetes 1% increase in HbA1c increases AF risk by 13%
Alcohol Consumption 8% increase in AF risk per 1 drink / day compared to non-drinkers
Sedentary lifestyle 10% reduction in AF risk > 9 MET-hr / week
Stress 23% increase risk of AF with negative emotions (stress, anger, anxiety)
Happiness - protective
Obesity 49% increase in AF risk for obese
Smoking 32% increase in AF risk for ex-smokers
105% increase in AF risk for current smokers
Hypertension 11% increase in AF for each 10mmHg
Obstructive sleep apnoea 120% increase in AF risk – > 50% of AF patients have OSA

42. Framework for Coronary Artery Disease
Treatment Modalities
• Risk factor modification
– smoking cessation,
exercise, diet
• Medications – statins,
aspirin, anti-anginals
• Invasive therapies –
CABG, PCI

43. Adopt the same framework when you think about AF
Treatment Modalities
• Risk factor modification –
smoking cessation,
exercise, diet, screen for
OSA, DM, HTN
• Medications – SGLT2i,
ARB, anticoagulants, anti-
arrhythmic
• Invasive therapies –
Catheter Ablation, Left
atrial appendage
occluders

44. ABC Pathway for Integrated Care of Atrial Fibrillation
Lip G. The ABC pathway: an integrated approach to improve AF management. Nature Reviews Cardiology 2017

45. Take home messages
• We will look after more and more AF patients. Please screen opportunistically
• Anticoagulation is key to stroke prevention. DOAC are gold standard therapy
and aspirin does not work!
• AF is a progressive, chronic disease – it does not get better or go away
• Please treat AF early and proactively – rhythm control improves survival and
reduces strokes (above and beyond anticoagulation) – EAST-AFNET4
• Treatment modalities work synergistically – need for holistic approach