Early Rhythm-control

Therapy In Patients With

Atrial Fibrillation
Supervisor:
Dr. dr. Jajang Sinardja, Sp.JP., FIHA., FAsCC., FAPSIC

EAST-AFNET 4
DOI: 10.1056/NEJMoa2019422
This article was published on August 29, 2020 Copyright © 2020 Massachusetts Medical Society.
 GROUP 4

Medical
Staff
Member Name Member Name Member Name
dr. Mohammad Almuhaimin dr. Fiya Muhartini dr. Ceasar Abdilla Rahman
 INTRODUCTION
Early Rhythm Control In Atrial Fibrilation

TABLE OF METHODS
Study design, Sample, and Characteristics

CONTENTS RESULTS
Primary and Secondary Outcome

DISCUSSION
Comparison and Conclusion
EAST-AFNET 4
INTRODUCTION
Terapi kontrol Perawatan
irama dini Biasa

Obat antiaritmia dan

ablasi fibrilasi Outcomes
 • Kondisi jantung dimana terjadi
gangguan pada:
-Pembentukan impuls Pacemaker

ARITMIA -Konduksi impuls

-Kombinasi keduanya
Akibatnya mengganggu laju dan atau
waktu kontraksi otot jantung untuk
mempertahankan curah jantung normal
 ATRIAL FIBRILASI
DEFINISI

Fibrilasi atrium adalah takiaritmia supraventrikular yang

khas, dengan aktivasi atrium yang tidak terkoordinasi
menyebabkan kontraksi yang sangat cepat dan tidak
teratur (fibrilasi),akibatnya darah terkumpul di atrium dan
tidak benar-benar dipompa ke ventrikel
Pada elektrokardiogram (EKG), ciri dari FA adalah tiadanya konsistensi
gelombang P, yang digantikan oleh gelombang getar (fibrilasi).
Pada fungsi NAV yang normal, FA biasanya disusul oleh respons ventrikel
yang ireguler, dan seringkali cepat biasanya melebihi 450 x / menit.
 • Framingham Heart Study yang
merupakan suatu studi kohor pada
tahun 1948 dengan melibatkan 5209
subjek penelitian sehat (tidak menderita
penyakit kardiovaskular) menunjukkan
bahwa dalam periode 20 tahun, angka
kejadian FA adalah 2,1% pada laki-laki
EPIDEMIOLOGI dan 1,7% pada perempuan
• Dari studi observasional
(MONICAmultinational MONItoring of
trend and determinant in
CArdiovascular disease) pada populasi
urban di Jakarta menemukan angka
kejadian FA sebesar 0,2% dengan rasio
laki-laki dan perempuan 3:2
•Fibrilasi atrium menyebabkan
peningkatan mortalitas dan morbiditas,
termasuk stroke, gagal jantung serta
penurunan kualitas hidup. Pasien
dengan FA memiliki risiko stroke 5 kali
lebih tinggi dan risiko gagal jantung 3
kali lebih tinggi dibanding pasien tanpa
FA
 PREDISPOSISI

• Genetik : mutasi pada gen yang mengode peptida

atrial natriuretik,mutasi loss-of-function pada gen
kanal natrium SCN5A,atau gain-of-function pada
gen kanal kalium.Selain itu, beberapa gen PITX2
dan ZFHX3
• Usia
ETIOLOGI
• Peningkatan tekanan atau resistensi atrium
•Peningkatan katub jantung
•Kelainan pengisian dan pengosongan ruang
atrium
•Hipertrofi jantung
•Kardiomiopati
•Hipertensi pulmo (COPD dan cor pulmonary
chronic)
•Tumor intracardiac
• Proses Infiltratif dan Inflamasi
-Pericarditis atau miocarditis
-Amiloidosis dan sarcoidosis
-Faktor peningkatan usia
∙ Proses Infeksi
• Kelainan Endokrin :Hipertiroid, Feokromotisoma
• Neurogenik :Stroke, Perdarahan Subarachnoid ,
Iskemik Atrium ,Infark miocardial
• Obat-obatan :Alkohol, Kafein
 GEJALA KLINIS

• lebih dari 90% episode dari atrial fibrilasi

tidak menimbulkan gejala
• Peningkatan denyut jantung,
ketidakteraturan irama jantung dan
ketidakstabilan hemodinamik
• pusing, kelemahan, kelelahan, sesak
nafas dan nyeri dada
 KLASIFIKASI
• Secara klinis FA dapat dibedakan menjadi lima jenis menurut waktu
presentasi dan durasinya
1. FA yang pertama kali terdiagnosis : pasien yang pertama kali
datang dengan manifestasi klinis FA, tanpa memandang durasi atau
berat ringannya gejala yang muncul.
2. FA paroksismal adalah FA yang mengalami terminasi spontan
dalam 48 jam, namun dapat berlanjut hingga 7 hari
3. FA persisten adalah FA dengan episode menetap hingga lebih dari
7 hari atau FA yang memerlukan kardioversi dengan obat atau listrik.
4. FA persisten lama (long standing persistent) adalah FA yang
bertahan hingga ≥1 tahun, dan strategi kendali irama masih akan
diterapkan
5. FA permanen
• Terdapat beberapa kategori FA tambahan menurut
ciri-ciri dari pasien
- FA sorangan (lone): FA tanpa disertai penyakit
struktur kardiovaskular lainnya, termasuk
hipertensi, penyakit paru atau abnormalitas
anatomi jantung seperti pembesaran atrium kiri,
dan usia di bawah 60 tahun
- FA non-valvular: FA yang tidak terkait dengan
penyakit rematik mitral, katup jantung protese atau
operasi perbaikan katup mitral
- FA sekunder : penyakit katup disebut FA valvular
Berdasarkan kecepatan laju respon ventrikel
(interval RR) maka FA dapat dibedakan:
• FA dengan respon ventrikel cepat: Laju ventrikel >100x/ menit
FA dengan respon ventrikel normal: Laju ventrikel 60- 100x/menit
• FA dengan respon ventrikel lambat: Laju ventrikel <60x/ menit
Patofisiologi Atrial Fibrilasi
ANIMATION VIDEO
PENEGAKAN DIAGNOSIS
EVALUASI KLINIS / RENCANA TINDAK LANJUT
 TATALAKSANA ATRIAL FIBRILASI
(OBAT ANTIARITMIA)

Sumber : Lilly, LS. Pathophysiology of Heart Disease 4th ed. Lippincott & Wilkins.
 Agen antiaritmia untuk mempertahankan irama sinus

Sumber : 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary
 Untuk ventricular rate control pada AF

Sumber : 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary
 Pencegahan thromboembolisme

• Skor CHA2 DS2 –VASc (Congestive heart failure, Hypertension,

Age ≥75 years (skor 2), Diabetes mellitus, Stroke history (skor 2),
peripheral Vascular disease, Age between 65 to 74 years, Sex
Category (female)

Sumber : 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary
• Antagonis vitamin K
(AVK)
• Antikoagulan Baru (AKB)
: Dabigatran Etexilate,
Rivaroxaban, Apixaban
 Tatalaksana untuk jangka panjang

•Ablasi atrium kiri

•Ablasi dan modifikasi nodus
atrioventikular (NAV)
•Terapi tambahan (upstream therapy)
EAST-AFNET 4
METHODS
 Study Design
The trial is an international, investigator-initiated, parallel-group, randomized,
open blinded outcome- assessment trial.
• Patients were randomly assigned in a  Total screened: 2789
1:1 ratio to receive early rhythm control
or usual care  Total number of enrollees: 1395 assigned
to early rhythm control and 1394 assigned
 antiarrhythmic drugs or atrial fibrillation ablation to usual care
(n = 1,395)
 rate-control therapy without rhythm-control therapy  Duration of follow-up: 5.1 years (median)
(n = 1,394).  Mean patient age: 70 years
• The trial was planned by the Atrial Fibrillation  Percentage female: 46.2%
Network (AFNET) and the European Heart
Rhythm Association  Percentage male: 53.8%

Follow Up : Every 6 months, trial sites mailed questionnaires to all patients to obtain information on
hospitalizations and cardiovascular events. At 1 and 2 years, an in-person interview, physical
examination, and ECG were performed. The MoCA, EQ-5D, SF-12, and echocardiography were
repeated at 2 years.
 Outcomes and Adverse Events
Primary Outcome Secondary Outcome
A. Secondary outcomes reported here include each
A. The first primary outcome was component of the first primary outcome such as
a composite of death from rhythm, left ventricular function, quality of life
The primary safety outcome was a composite of
cardiovascular causes, stroke
(either ischemic and
(assessed with the European Quality of Life–5
Dimensions [EQ-5D] visual analogue scale and
death from any cause, stroke, or prespecified
hemorrhagic), or hospitalization
with worsening of heart failure
the 12-Item Short-Form General Health Survey
[SF-12]),

serious adverse events ofB.special

or acute coronary syndrome, interest
atrial fibrillation–
analyzed in a time-to-event
capturing
related symptoms (assessed as
the European Heart Rhythm Association [EHRA]
complications of rhythm-control
analysis. score),
B. The second primary outcome
therapy.
was the number of nights spent C. cognitive function (based on the Montreal
in the hospital per year Cognitive Assessment [MoCA]) at 2 years.
 Inclusion criteria:
Age greater than 65 years,
with 2 following criteria
- female sex,
Age ≥18 who had early
- heart failure,
atrial fibrillation (defined as
- hypertension,
atrial fibrillation (diagnosed
- diabetes mellitus,
≤12 months before
- severe coronary artery
enrollment)
disease,

01 02 03 04
And
- chronic kidney disease [glomerular
Older than 75 years had a filtration rate, 15 to 59 ml per minute
previous transient per 1.73 m2 of body-surface area]
ischemic attack or stroke - and left ventricular hypertrophy
(diastolic septal wall width, >15 mm)
 Screening,
Randomization,
Treatment, and
Follow-up
 Characteristics of the
Patients at Baseline

* Plus–minus values are means ―SD. Definitions of clinical

measures are provided in Table S1. ACE denotes angiotensin-
converting enzyme,
IQR interquartile range, NOAC non–vitamin K antagonist oral
anticoagulant, and VKA vitamin K antagonist.
† The body-mass index is the weight in kilograms divided by the
square of the height in meters. Data were missing for 7 patients
assigned
to early rhythm control and for 6 patients assigned to usual care.
‡ Data on median days since atrial fibrillation diagnosis were
missing for 2 patients assigned to early rhythm control and for 1
patient assigned
to usual care.
§ The absence of symptoms was defined as a European Heart
Rhythm Association (EHRA) score of I. The EHRA score
categorizes symptoms
related to atrial fibrillation into four classes from I
(asymptomatic) to IV (severe symptoms at rest).
¶ At least mild cognitive impairment was defined as a Montreal
Cognitive Assessment (MoCA) score of less than 26. The
MoCA score provides
an overall assessment of cognitive function. Scores range from
0 to 30, with lower scores indicating worse cognitive function.
‖ Data on blood pressure were missing for 9 patients assigned to
early rhythm control and 4 patients assigned to usual care.
** Stable heart failure was defined as New York Heart
Association stage II or a left ventricular ejection fraction of less
than 50%.
†† CHA
EAST-AFNET 4
RESULTS
 RESULTS
28 July 2011 - 30 Desember 2016
Total patients were screened  2789
 1395 assigned to early rhythm control and 1394
assigned to usual care
Demographic and clinical characteristics were
generally well balanced between the groups
 Primary Outcomes
 First-primary-outcome event was found to have occurred less often in patients
assigned to early rhythm control than in patients assigned to usual care (hazard
ratio, 0.79; 96% confidence interval [CI], 0.66 to 0.94; P = 0.005)

 The effect of early rhythm control on the first primary outcome remained stable
after adjustment for relevant covariates (hazard ratio, 0.78; 95% CI, 0.66 to 0.92;
P = 0.004)

 In Secondary Primary Outcome : There was no significant difference in the mean

(±SD) number of nights spent in the hospital between the treatment groups (early
rhythm control, 5.8±21.9 days per year; usual care, 5.1±15.5 days per year; P =
0.23)
 Primary and Secondary Outcome

* Plus–minus values are means ±SD. Data in columns 2 and 3 are observed data, and data in column 4 are model-based effect estimates. There were no significant differences in the key secondary
outcomes between the treatment groups, with two exceptions: more patients assigned to early rhythm control were in sinus rhythm at 2 years, and a slightly greater improvement in the 12-Item Short-
Form Health Survey (SF-12) mental score at 2 years was found in the group assigned to usual care. All 95% confidence intervals for secondary end points were not adjusted for multiplicity and should
not be used to infer definitive treatment effects. The results for additional secondary outcomes are provided in the Supplementary Appendix.
† The treatment effect is expressed as the median unbiased estimate of the hazard ratio and 96% confidence interval, which were calculated on the basis of Tsiatis, Rosner, and Mehta stagewise
ordering that adjusts for the group-sequential design.24 P = 0.005 for the betweengroup comparison.
‡ The treatment effect is expressed as the hazard ratio and 95% confidence interval, which were calculated with a Cox regression with treatment group as the fixed factor and site as the shared frailty
term.
§ The treatment effect is expressed as the incidence rate ratio and 99% confidence interval, which were calculated with a mixed negative binomial model with treatment group as the fixed factor, the
log of follow-up time as the offset, and site as a random effect. P = 0.23 for the between-group comparison.
¶ The treatment effect is expressed as the adjusted mean difference and 95% confidence interval, which were calculated with a mixed linear model with the corresponding baseline measurement and
treatment group as the fixed effects and site as a random effect, analyzed after multiple imputation of missing values in survivors.
‖ The European Quality of Life–5 Dimensions (EQ-5D) assesses state of health on visual analogue scale from 0 (very bad health) to 100 (perfect health); values were defined as 0 for nonsurvivors.
** Scores on the SF-12 range from 0 to 100, with lower scores indicating worse functioning.
†† The treatment effect is expressed as the odds ratio and 95% confidence interval, which were calculated with a mixed logistic regression including treatment group and the corresponding baseline
assessment as fixed factors and site as a random effect, analyzed after multiple imputation of missing values in survivors.
‡‡ The absence of symptoms was defined as an EHRA score of I.
 Secondary Outcomes
 Left ventricular function and cognitive function were stable at
2 years, with no evidence of significant differences between
the treatment groups

 Most patients in both groups were free from atrial fibrillation–

related symptoms at 2 years, and the change from baseline
in atrial fibrillation–related symptoms (EHRA score) and
quality of life (EQ-5D score) did not differ significantly
between the groups
* Plus–minus values are means ±SD. Data in columns 2 and 3 are observed data, and data in column 4 are model-based effect estimates. There were no significant differences in the key secondary
outcomes between the treatment groups, with two exceptions: more patients assigned to early rhythm control were in sinus rhythm at 2 years, and a slightly greater improvement in the 12-Item Short-
Form Health Survey (SF-12) mental score at 2 years was found in the group assigned to usual care. All 95% confidence intervals for secondary end points were not adjusted for multiplicity and should
not be used to infer definitive treatment effects. The results for additional secondary outcomes are provided in the Supplementary Appendix.
† The treatment effect is expressed as the median unbiased estimate of the hazard ratio and 96% confidence interval, which were calculated on the basis of Tsiatis, Rosner, and Mehta stagewise
ordering that adjusts for the group-sequential design.24 P = 0.005 for the betweengroup comparison.
‡ The treatment effect is expressed as the hazard ratio and 95% confidence interval, which were calculated with a Cox regression with treatment group as the fixed factor and site as the shared frailty
term.
§ The treatment effect is expressed as the incidence rate ratio and 99% confidence interval, which were calculated with a mixed negative binomial model with treatment group as the fixed factor, the
log of follow-up time as the offset, and site as a random effect. P = 0.23 for the between-group comparison.
¶ The treatment effect is expressed as the adjusted mean difference and 95% confidence interval, which were calculated with a mixed linear model with the corresponding baseline measurement and
treatment group as the fixed effects and site as a random effect, analyzed after multiple imputation of missing values in survivors.
‖ The European Quality of Life–5 Dimensions (EQ-5D) assesses state of health on visual analogue scale from 0 (very bad health) to 100 (perfect health); values were defined as 0 for nonsurvivors.
** Scores on the SF-12 range from 0 to 100, with lower scores indicating worse functioning.
†† The treatment effect is expressed as the odds ratio and 95% confidence interval, which were calculated with a mixed logistic regression including treatment group and the corresponding baseline
assessment as fixed factors and site as a random effect, analyzed after multiple imputation of missing values in survivors.
‡‡ The absence of symptoms was defined as an EHRA score of I.
EAST-AFNET 4
DISCUSSION
 DISCUSSION
Previous Trials
Early rhythm control did not affect the number of nights
spent in the hospital. (8,13)
comparing rate-control and rhythm-control strategies did not
show better outcomes with rhythm control than with rate
control.(7,8,12,13)
 rhythm-control therapy with the antiarrhythmic drug
dronedarone was found to reduce the risk of death or
hospitalization for cardiovascular causes (6).
most patients in both treatment groups in our trial continued to receive anticoagulation, rate control, and treatment of
concomitant cardio- vascular conditions, maintaining their protective effects.
This Trial
Rhythm-control therapy in all patients with early atrial
fibrillation and concomitant cardiovascular conditions was
associated with a lower risk of death from cardiovascular
causes, stroke, or hospitalization for heart failure or acute
coronary syndrome than usual care over a follow up time of
more than 5 years.
trial included atrial fibrillation ablation, a powerful rhythm-
control therapy (5,26).
The majority of patients in that trial had had atrial fibrillation
for less than 1 year
Most patients (>70%) were asymptomatic at 1 and 2 years
in both treatment groups, and the magnitude of change in left
ventricular function did not differ between the groups at 2
years, which indicates that both rate control and rhythm
control can control symptoms and maintain car- diac function
in patients with early atrial fibril- lation.
 LIMITATIONS
1. The trial compared two treatment strategies that necessitated an
open trial design. Blinded, central assessment of primary outcomes
was used to minimize bias.
2. The trial was not primarily designed to assess the safety and
effectiveness of specific components of early rhythm control.
3. This trial enrolled only patients with early atrial fibrillation, and thus
the results may not be generalizable to patients in whom rhythm-
control therapy that includes atrial fibrillation ablation is initiated later.
4. did not collect detailed information on recurrent atrial fibrillation in
both groups, and therefore our data on percentages of patients with
sinus rhythm are not comparable to data on recurrent atrial fibrillation
from other rhythm-control trials. (5,11,26).
 THANK
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