This 40-year-old man presented with night sweats, hemoptysis, dyspnea and weight loss. Imaging showed a cavitary lung lesion and filling defects in the main pulmonary artery suggestive of a pulmonary embolism. Further PET-CT imaging and biopsy revealed primary pulmonary artery angiosarcoma. This is a rare and aggressive malignancy with poor prognosis. Treatment is largely palliative.

1. EAST-AFNET 4 TRIAL
DR.GOPIDI APARANJI
SRI JAYADEVA INSTITUTE OF CARDIOVASCULAR SCIENCES &
RESEARCH, BANGALORE
NEJM AUGUST 29,2020.

3. INTRODUCTION
 Atrial fibrillation (AF) is the most common sustained arrhythmia.
 It causes discomfort and reduced quality of life in affected patients.
 Even with current guideline-based management, patients with atrial fibrillation
have stroke, acute coronary syndrome, heart failure, and cardiovascular death at
a rate of approximately 5% of patients per year.
 35 to 50% of patients with atrial fibrillation who receive adequate
anticoagulation either receive inpatient therapy or die within 5 years.

4. BACKGROUND

5. BACKGROUND
 Maintenance of sinus rhythm could prevent the adverse outcomes related to AF.
 Previous trials have not shown superiority of rhythm control with antiarrhythmic drugs
over rate control in patients with established atrial fibrillation.
 Limitations of the previous trials
1. Discontinuation of oral anticoagulation in patients with sinus rhythm.
2. Limited effectiveness of rhythm control therapy in an era before catheter ablation.

6. RATIONALE FOR THE EAST TRIAL
Can rhythm control therapy improve outcomes in AF patients?
 Rhythm control therapy although potentially capable of eliminating the
arrhythmia, is only recommended to control AF related symptoms.
 ATHENA Trial- Dronedarone reduced the primary outcome of unplanned
cardiovascular hospitalizations or all cause death by 24% compared to placebo
and reduced stroke and CV death in secondary analysis.
 PALLAS Trial – Dronedarone increased deaths, strokes and heart failure
hospitalizations.

7.  Small trials have suggested that atrial fibrillation ablation may improve left
ventricular function and may reduce the risk of adverse outcomes in patients
with atrial fibrillation and heart failure.
 Some reports have shown that low rates of stroke and death associated with
rhythm-control therapy including atrial fibrillation ablation.
 AF has profound effects on atrial structure and function.
 Usually AF Induced atrial damage develops within 1st few weeks of AF.

8.  The risk of cardiovascular complications and mortality associated with AF is
highest in the first year after the initial diagnosis (Early AF).
 Early rhythm control therapy could preserve atrial structure and function and
maintain sinus rhythm more effectively than delayed rhythm control.
 Catheter ablation and new antiarrhythmic drugs have enhanced the
potential effectiveness and safety of rhythm control therapy.

9.  The aim of the present study (EAST-AFNET 4) was to test whether a strategy of
early rhythm-control therapy that includes atrial fibrillation ablation would be
associated with better outcomes in patients with early atrial fibrillation than
contemporary, evidence-based usual care.

10. STUDY DESIGN
 EAST- AFNET 4 – International, investigator initiated, multicenter, prospective,
parallel-group, open, blinded-outcome assessment, randomised trial.
 Population studied:
 Sample size: 2789 patients
 Study period from July 28, 2011 to December 30, 2016.
 Conducted across 135 sites in Europe.

11. INCLUSION AND EXCLUSION CRITERIA

12. Trial Intervention
 Treatment of cardiovascular conditions, anticoagulation, and rate control were
mandated in all patients.
 Patients were randomly assigned in a 1:1 ratio to receive early rhythm control or
usual care.
 Early rhythm control therapy - Antiarrhythmic drugs or atrial fibrillation
ablation, as well as cardioversion of persistent atrial fibrillation, to be initiated
early after randomization.
 Patients were asked to transmit a patient-operated single-lead
electrocardiogram (ECG) (Vitaphone) twice per week and when symptomatic to
detect recurrent AF.

13.  USUAL CARE – Patients were initially treated with rate-control therapy
without rhythm-control therapy.
 Rhythm-control therapy was used only to mitigate uncontrolled atrial
fibrillation–related symptoms during adequate rate-control therapy.

14. EAST TRIAL FLOW CHART

15. FOLLOW-UP
 All patients were followed up by yearly visits plus a questionnaire at 6
months intervals.
 Follow–up was continued for all patients until the end of the trial, death,
or withdrawal from the trial.
 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.

16. OUTCOMES AND ADVERSE EVENTS
 Primary outcome
1. The first coprimary outcome was a composite of death from
cardiovascular causes, stroke (either ischemic and hemorrhagic), or
hospitalization with worsening of heart failure or acute coronary
syndrome.
2. The second coprimary outcome was the number of nights spent in the
hospital per year.

17.  Secondary outcomes
1. All cause death
2. Each component of the first primary outcome
3. Rhythm (progression of AF)
4. Left ventricular function by echo
5. Quality of life and cognitive function
 Primary safety outcome
1. Composite of death, stroke, or serious adverse events related to rhythm-control
therapy

18. STATISTICAL ANALYSIS
 The trial was designed as an event-driven trial.
 The first and second primary outcomes were tested independently for differences between the
treatment groups at an overall two-sided type 1 error rate of 4% for the first primary outcome and
1% for the second primary outcome to reach an overall type 1 error rate of 5%.
 A between group difference of 20% in the annual rate of the first primary outcome was deemed a
clinically relevant difference.

19.  The analyses of the primary outcomes included all patients who underwent
randomization and at least one follow-up assessment.
 All analyses were conducted with Stata software, ver sion 16.1 (StataCorp), and
R software, version 3.6.1
 2 Sided p value of 0.05 was considered to indicate statistical significant

20. RESULTS
 For the intention to treat (ITT) population, a total of 2789 subjects were
randomly assigned to Early rhythm control (n = 1395) or usual care (n = 1394).
 Treatment of cardiovascular conditions, anticoagulation, and rate control were
mandated in all patients.
 Demographic and clinical characteristics were well balanced between the
groups.

21. Demographic and clinical characteristics of the patients at baseline

22.  Almost all patients (1323 [94.8%]) who were randomly assigned to early rhythm
control received an antiarrhythmic drug or underwent atrial fibrillation ablation.
 At 2 years, 908 of 1395 patients (65.1%) were still receiving rhythm-control therapy.
 Usual care group -1335 (95.8%) of the 1394 patients in this group had their condition
managed without rhythm-control therapy.
 at 2 years, 1191 of the 1394 patients (85.4%) were still not receiving rhythm-control
therapy .
 At 2 years, 1020 of 1159 patients (88.0%) assigned to early rhythm control and 1065
of 1171 patients (90.9%) assigned to usual care were still taking oral anticoagulants.

25. Primary outcomes
 The trial was stopped for efficacy at the third interim analysis after a median follow-up of 5.1
years per patient.
 A first-primary-outcome event occurred in 249 patients assigned to receive early rhythm control
(3.9 per 100 person-years) and in 316 patients assigned to receive usual care (5.0 per 100
person-years).
 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)

26.  Second 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 safety outcome - did not differ significantly between the treatment groups (early
rhythm control, 231 patients; usual care, 223 patients).
 Mortality was similar in the two treatment groups, and stroke occurred less frequently
among patients assigned to early rhythm control than among those assigned to usual care.

27.  Serious adverse events related to rhythm-control therapy were more common in the group
assigned to early rhythm control but were infrequent.
SECONDARY OUTCOMES
1. Left ventricular function and cognitive function were stable at 2 years, with no evidence of
significant differences between the treatment groups.
2. Most patients in both groups were free from atrial fibrillation–related symptoms at 2
years.

30. Primary safety outcome

31.  Previous studies comparing rate-control and rhythm-control strategies did not show better outcomes
with rhythm control than with rate control.
 In present study , initiating 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 (absolute difference in risk, 1.1 events per 100 person-years).
 Early rhythm control did not affect the number of nights spent in the hospital in contrast to previous
trials.
DISCUSSION

32.  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.
 present study included atrial fibrillation ablation, that works synergistically with
antiarrhythmic drugs and It is contributed to the superiority of early rhythm control in this
trial.
 In contrast to previous trials, most patients in both treatment groups in this present trial
were continued to receive anticoagulation, rate control, and treatment of concomitant
cardiovascular conditions, maintaining their protective effects.

33.  Present study enrolled patients with early atrial fibrillation and initiated rhythm control therapy
shortly after the diagnosis of atrial fibrillation and 54% of the patients were in sinus rhythm at
enrollment.
 ATHENA Trial- Dronedarone reduced the primary outcome of unplanned cardiovascular
hospitalizations or all cause death by 24% compared to placebo and reduced stroke and CV death in
secondary analysis.
 The majority of patients in that trial had atrial fibrillation for less than 1 year (68% of the 2859
patients in whom the duration of atrial fibrillation was known), and 75% of the patients were in
sinus rhythm at enrollment.

34.  PALLAS Trial – Dronedarone increased deaths, strokes and heart failure hospitalizations.
 Tested in patients with chronic AF and almost no patients were in sinus rhythm at the time
of enrollment.
 There were no significant differences between the treatment groups with respect to the
primary safety outcome in the present study.
 Early rhythm control was associated with more adverse events related to rhythm-control
therapy than was usual care, but such events were uncommon.

35.  Early initiation of rhythm-control therapy, guidance on the safe use of antiarrhythmic
drugs and the availability of atrial fibrillation ablation may have contributed to the low
incidence of adverse events associated with rhythm-control therapy in the present study
as compared with previous trials.

36. STUDY LIMITATIONS
1. This study compared two treatment strategies that necessitated an open trial design, Blinded, central
assessment of primary outcomes was used to minimize bias.
2. Present study 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.
3. All enrolled patients were deemed eligible for either rate-control or rhythm control therapy, which
probably excluded the most symptomatic patients.

37.  Present study did not collect detailed information on recurrent atrial fibrillation in both
groups, and therefore this data on percentages of patients with sinus rhythm are not
comparable to data on recurrent atrial fibrillation from other rhythm-control trials.

38. CONCLUSION
 Early initiation of rhythm-control therapy was associated with less frequent cardiovascular
events than usual care in patients with early atrial fibrillation and cardiovascular conditions
without affecting the number of nights spent in the hospital.
 The early rhythm-control strategy was associated with more adverse events related to
rhythm-control therapy, but the incidence of the overall safety outcome events was similar
in the two groups.

39. Thank you

40. IMAGE CHALLENGE
FORTY-YEAR-OLD MAN WITH DYSPNOEA, HAEMOPTYSIS AND
NIGHT SWEATS

41. CLINICAL INTRODUCTION
 A 40-year-old man presented with a 1-month history of night sweats, haemoptysis,
dyspnoea and weight loss.
 Non smoker.
 Physical examination was unremarkable.
 He was hemodynamically stable.
 He was anaemic with a haemoglobin of 10 g/L and
his D-dimer was elevated at 1.32 µg/mL.

42.  12 lead ECG showed sinus rhythm with no abnormalities.
 Chest radiograph (CXR) was performed.
 Transthoracic echocardiography revealed normal right ventricular size and systolic function
with a step-up, distally, in pulmonary arterial (PA) velocity from 0.7 m/s to 3.2 m/s.
 CT pulmonary angiogram (CTPA) was subsequently performed.
 The findings of the CTPA prompted further assessment with a positron emission
tomography (PET)-CT .

44. QUESTION
 What is the likely diagnosis?
A. Right upper lobe bronchopneumonia.
B. Submassive pulmonary embolism.
C. Right upper lobe squamous cell carcinoma.
D. Primary pulmonary artery angiosarcoma.
E. Giant cell pulmonary arteritis.

46. ANSWER D
 First, in CXR - a cavitating lesion can be seen in the right upper lobe raising the question of
potential malignancy or atypical pneumonia.
 The CTPA then demonstrated extensive main and right PA opacification.
 The lesion seen on CXR was also seen on the CTPA and was presumed to be a metastasis.

47.  A PET-CT was performed and there was increased fluorodeoxygenase (FDG)
uptake within the PA.
 While abnormal FDG uptake can be seen in PE, these findings prompted further
investigation to rule in/out a PA neoplasm.
 Percutaneous transfemoral biopsy of the PA lesion was done.
 Histological findings consisted of marked pleomorphism and abnormal mitoses,
confirming high grade primary PA angiosarcoma .

49.  Invasively, there was a gradient of 43 mm Hg across the lesion and
inserted a palliative 24×45 mm CP stent from his left to main PA, with a
subsequent improvement in his functional status.
 He declined chemotherapy and died acutely 10 months later.

50. DISCUSSION
 Primary PA angiosarcoma is a rare vascular malignancy, with a median survival of 7 months.
 Angiosarcoma presents in middle age (40-65years).
 The tumor grows rapidly and produces local invasion and distant metastasis.
 Vascular occlusion is the main cause of death.
 Compared with patients with solitary lesions, patients with multiple lesions had a poorer
prognosis because of the rapid progression of multiple lesions and less effective clinical
treatment.

51.  primary pulmonary angiosarcoma showing multiple infiltration or consolidation
suggests a prognostic indicator for an unfavorable outcome.
 Diagnosis requires multi- modality imaging and tissue histopathology.
 The proliferation of variably sized vascular channels with irregular branching,
epithelioid‐like endothelial lining of vascular spaces, abundant cytoplasm with
pleomorphic nuclei and prominent nucleoli, and mitotic figures in atypical fashion
are typical pathological features of pulmonary angiosarcoma.

52.  Immunohistochemical examination is essential to confirm diagnosis.
 Among the various immunohistochemical markers used for classification, CD31,
CD34, and factor VIII‐related antigen are considered specific for diagnosis.
 There is no standard treatment regimen specifically for pulmonary epithelioid
angiosarcoma.
 Treatment is largely palliative.

53.  Surgical resection, radiation, and chemotherapy have all been attempted.
 Surgery has been the mainstay for locally confined disease.
 Several previous studies have shown that angiosarcoma is radiosensitive.
 Chemotherapy has also been reported to be effective.
 Two chemotherapeutic combinations have demonstrated partial and full effects:
doxorubicin/ifosfamide and docetaxel/gemcitabine.

54. THANK YOU