Medical Journal Presentation

1. JOURNAL PRESENTATION
Dr. Ahmed Shahed
Resident Medical Officer
Department of Medicine
Holy Family Red Crescent Medical College Hospital.

2. Comparison of the efficacy and safety of new oral
anticoagulants with warfarin in patients with atrial
fibrillation: a meta-analysis of randomised trials
Christian T Ruff, MD, Robert P Giugliano, MD, Eugene Braunwald, MD, Elaine B Hoffman,
PhD, Naveen Deenadayalu, MPH, Michael D Ezekowitz, MBChB, A John Camm, MD,
Jeffrey I Weitz, MD, Basil S Lewis, MD, Alexander Parkhomenko, MD, Takeshi Yamashita,
MD and Elliott M Antman, MD
The Lancet
Volume 383, Issue 9921, Pages 955-962 (March 2014)
DOI: 10.1016/S0140-6736(13)62343-0

3. Contents
Over view about
Atrial Fibrillation
Journal Presentation

4. Over view about AF
What is AF?
How do the electrical signals works?
What happens in AF?
What are the symptoms of AF?
What causes AF?
What triggers AF?
What are risks of AF?
What test might be needed?
What is the treatment for AF?
Mechanism of action of Warfarin and New oral anticoagulant drugs.

5. Atrial Fibrillation
 Atrial fibrillation (AF) is an atrial
tachyarrhythmia characterised by
predominantly uncoordinated atrial activation
with consequent deterioration of atrial
mechanical function.

7. How do the electrical Signal
works?

8. Classification of AF
Terminology Clinical features Pattern
Initial event (first
detected episode)
Symptomatic
Asymptomatic
Onset unknown
May or may nor
reoccur
Paroxysmal Spontaneous
termination <7
days and most
often <48 hours
Recurrent
Persistent Not self-
terminating
Lasting >7 days or
prior cardioversion
Recurrent
Permanent
(‘accepted’)
Not terminated
Terminated but
relapsed
No cardioversion
attempt
Established

9. Dizziness Tiredness
Chest pain and Shortness of
breath
Palpitations
Symptoms of AF

10. What causes AF
Heart
Causes
• High Blood Pressure, MI, Heart Surgery,
Heart Valve disease, Congenital heart
disease, Cardiomyopathy.
Lung
Causes
• Pulmonary embolism, Asthma,
Emphysema, COPD, Pneumonia and Lung
Cancer.
Others
• Hyperthyroidism, ‘Lone’ AF, DM,
Imbalance of K+, Mg2+,Ca2+.

11. What Triggers AF?
Alcohol, Coffee,Tea,
Fizzy drinks
Overweight
Taking Illegal
drugs(amphetamines,
cocaine), Smoking.

12. What are the risk of AF?
Stroke
Heart Failure

13. What is the Treatment for AF
Drug
treatment
Beta-Blocker
Calcium
channel
blocker
Anti
arrrhythmic
Cardioversion
Chemical (eg:
Amiodarone,
Flecainide)
Mechanical
(200j
>360j>360j)
Others
Catheter
ablation
Insertion of an
artificial
pacemaker
device.
Prevention of
Blood Clots
Warfarin
Newer
anticoagulants
Aspirin
Heparin

14. Mechanism of action of Warfarin
and New oral anticoagulant
drugs.

15. NOAC

16. European Society of Cardiology Guideline
Risk Factors
For Stroke and Thrombo-embolism in Non-valvular AF
Risk Factor Score
Congestive heart failure/LV dysfunction* 1
Hypertension* 1
Age >75** 2
Diabetes Mellitus* 1
Stroke / TIA / Thrombo-embolism** 2
Vascular Disease* 1
Age 65-74* 1
Sex category (i.e. female sex)* 1
Maximum Score 9
Note: maximum score is 9 since age may contribute 0,1, or 2 points
* ‘Clinically relevant non-major’ risk factor
** “Major” risk factor
Camm AJ. Europace. 2010 Oct;12(10):1360-420. Pub Med PMID: 20876603.
CHA2DS2-VASc and Stroke Rate

17. Journal Presentation
Background
Methods
Findings
Interpretation
Conclusion

18. Background
Largest trial uptodate
comparing the
efficacy and safety of
Four NOAC with
warfarin in patients
with AF.

19. Limitations of warfarin
• Narrow therapeutic index
• Frequent monitoring and dose adjustment
• Drug interaction

20. Advantages of NOAC
Rapid onset and
offset of action
Absence of
effect of dietary
vitamin K intake
on their activity
Fewer drug
interactions
Treatment
monitoring not
required.

21. Drugs approved
Dabigatran
Rivaroxaban
Apixaban

22. Aim of the paper
 Assess the relative benefits of NOAC
in key subgroups
 Assess the effect of these drugs on
important secondary outcomes
 To provide clinicians an alternative
therapeutic option to reduce the risk of
stroke in patients with AF

23. Study selection
RE-LY
(Dabigatran150
&110mg)
ROCKET AF
(Rivaroxaban),
ARISTOTLE
( Apixaban),
ENGAGE AF-
TIMI 48
(Edoxaban
60mg & 30mg).
 RE-LY : Randomized evaluation of long term Anticoagulation therapy.
 ROCKET AF : Direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in AF.
 ARISTOTLE : Reduction of stroke and other thromboembolic events in AF.
 ENGAGE AF-TIMI 48 : Anticoagulation with factoe Xa next generation in AF thrombolysis in MI study 48. Largest of all four trials.

24. Methods
Started from Jan1, 2009, to Nov 19, 2013 limiting
searches to phase 3.
Randomised trials of patient with AF who were
randomised to receive NOAC or Warfarin.
Meta-analysis of all 71,683 participants
42411 received NOAC
29272 received Warfarin

25.  This paper assessed the comparative
efficacy and safety for stroke or
systemic embolic events and for major
bleeding in various clinical subgroups

26. ROCKET-AF and ARISTOTLE included patient with systemic embolism, ROCKET-AF included
patient with LV EF <35%,ARISTOTLE Included those with LV EF <40%, RE-LY and ARISTOTLE
<50 ml/min,50-80ml/min,>80ml/min. RE-LY, ARISTOTLE, AND ENGAGE AF TIMI 48 Patients who
used VKAs for >61 days. ROCKET >6Weeks

27. Outcomes
The main outcomes were
 stroke and systemic embolic events,
 Ischaemic stroke
 Myocardial Infarction
 Haemorrhagic stroke
 Major bleeding
 Intra cerebral Haemorrhage
 Gastrointestinal bleeding

28. Findings

29. Figure 1
Stroke or systemic embolic events
Data are n/N, unless otherwise indicated. Heterogeneity: I2=47%; p=0·13. NOAC=new
oral anticoagulant. RR=risk ratio. *Dabigatran 150 mg twice daily. †Rivaroxaban 20 mg
once daily. ‡Apixaban 5 mg twice daily. §Edoxaban 60 mg once daily.
NOAC significantly reduced the composite of stroke or systemic embolic events
by 19%

30. Figure 2
Secondary efficacy and safety outcomes
Data are n/N, unless otherwise indicated. Heterogeneity: ischaemic stroke I2=32%, p=0·22;
haemorrhagic stroke I2=34%, p=0·21; myocardial infarction I2=48%, p=0·13; all-cause mortality
I2=0%, p=0·81; intracranial haemorrhage I2=32%, p=0·22; gastrointestinal bleeding I2=74%,
p=0·009. NOAC=new oral anticoagulant. RR=risk ratio.
NOAC were also associated with a significant reduction in all cause mortality.
The drugs were similar to warfarin in the prevention of ischaemic stroke and MI
NOAC were however assoc, with increased GI bleeding

31. Figure 3
Major bleeding
Data are n/N, unless otherwise indicated. Heterogeneity: I2=83%; p=0·001.
NOAC=new oral anticoagulant. RR=risk ratio. *Dabigatran 150 mg twice daily.
†Rivaroxaban 20 mg once daily. ‡Apixaban 5 mg twice daily. §Edoxaban 60 mg once
daily
A substantial reduction in ICH was observed which included hgic stroke,
subdura, epidural and subarachnoid bleeding

32. Figure 4
Source: The Lancet 2014; 383:955-962 (DOI:10.1016/S0140-6736(13)62343-0)
Terms and Conditions
Figure 4
Stroke or systemic embolic events subgroups (A) and major bleeding subgroups (B)
Data are n/N, unless otherwise indicated. No data available from RE-LY for the following major bleeding
subgroups: sex, creatinine clearance, diabetes, and CHADS2 score. For ROCKET AF no major bleeding data
available in the TTR and diabetes subgroup and major and non-major clinically relevant bleeding was used for
subgroups of age, sex, CHADS2 score, and creatinine clearance. NOAC=new oral anticoagulant. RR=risk ratio.
TIA=transient ischaemic attack. VKA=vitamin K antagonist. TTR=time in therapeutic range

33. Interpretation of low dose NOAC
Similar efficacy to warfarin for composite of
stroke or systemic embolic events
Increase in ischaemic stroke and MI
compared to warfarin
Large decrease in haemorrhagic stroke
Significant reduction in all causes of
mortality.

34. Low dose regimens might be
an appealing option for frail
patients or for those who
have a high risk for bleeding
with full dose anticoagulation.

35. Merits of this paper
The first to show the relative
efficacy and safety of NOAC
is consistent across a broad
range of vulnerable patients

36. Interpretation
This meta-analysis is the first to include
results from all four new oral
anticoagulants studied in the pivotal
phase 3 clinical trials for stroke
prevention in patients with AF. NOAC
showed a favourable risk benefit profile
with significant reductions in stroke, ICH,
and mortality with similar major bleeding
as warfarin, but increased
gastrointestinal bleeding.

37. Conclusion
“Our findings offer clinicians
a more comprehensive
picture of new oral
anticoagulants as a
therapeutic option to reduce
the risk of stroke in this
patient population”

38. Criticism
The CHADS VAS score was not
mentioned although the individual
components were analyzed.

40. Bleeding Risk Scores Widely
Used in AF
1. Gage BF, et al. Am Heart J. 2006 Mar;151(3):713-9. PMID: 16504638. Pub Med PMID:16504638.
2. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. Chest. 2010 Nov;138(5):1093-100. PMID:20299623.
3. Fang MC, et al. J Am Coll Cardiol. 2011 Jul 19;58(4):395-401. Pub Med PMID:21757117.
HAEMORRHAGES1
HASBLED2
ATRIA Score3

41. Bleeding Risk Scores in AF
ATRIA HAS-BLED HEMORR2
HAGES
Anemia1 3 Hypertension4 1 Hepatic10 or
Renal disease2
1
1
Severe renal disease2 3 Abnormal Renal5 or
Liver function6
1
1 Ethanol abuse 1
Age ≥75 yrs 2 Stroke 1 Malignancy 1
Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1
Hypertension3 1 Labile INR8 1 Reduced platelet number
or function11 1
Elderly (>65 yrs) 1 Rebleeding12 2
Drugs9 or
Alcohol
1
1 Hypertension4 1
Anemia13 1
Genetic factors14 1
Excessive fall risk15 1
Stroke 1
Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000–000. 2012 Jul 24. [Epub ahead of print]
Online Appendix. PMID: 22858389.
1. Hemoglobin <13 g/dl men; <12 g/dl women
2. Estimated glomerular filtration rate <30 ml/min or dialysis-dependent
3. Diagnosed hypertension
4. Systolic blood pressure >160 mmHg
5. Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 mmol/L
6. Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal,
in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)
8. Unstable/high INRs or poor time in therapeutic range (eg <60%)
9. Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc.
10. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl
11. Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia
12. Prior hospitalization for bleeding
13. Most recent hematocrit <30 or hemoglobin <10 g/dl
14. CYP2C9*2 and/or CYP2C9*3
15. Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls

42. Pharmacokinetics of NOACs
Kaatz S, et al. Am J Hematol. 2012 May;87 Suppl 1:S141-5. Pub Med PMID: 22473649.
Apixaban Dabigatran Rivaroxaban
Direct factor inhibition Xa IIa Xa
Bioavailability (Frel) 80% 6% 80%
Peak action (tmax) 1–3 hr 1–3 hr 1–3 hr
Protein binding 84% 35% 92–95%
Renal clearance 25% 80% 33%
Elimination half life with creatinine
clearance > 80 ml/min 15.1 hr 13.8 hr 8.3 hr
Elimination half life with creatinine
clearance 50–79 ml/min 14.6 hr 16.6 hr 8.7 hr
Elimination half life with creatinine
clearance 30–49 ml/min 17.6 hr 18.7 hr 9.0 hr
Elimination half life with creatinine
clearance < 30 ml/min 17.3 hr 27.5 hr 9.5 hr

43. Comparison of agents
Dabigatran Rivaroxaba
n
Apixaban
Target Factor IIa Factor Xa Factor Xa
FDA Indications Nonvalvular AF Nonvalvular AF
Ortho VTE Proph
Acute Treatment
VTE
Nonvalvular AF
Prodrug Yes No No
Dosing Twice daily Daily, with food Twice daily
Onset 1-2 hrs 2-4 hrs 3-4 hrs
Half-life (h) 14–17 7–11 8–14
Renal Adjustment ↓ 15-29ml/min
Avoid < 15 ml/min
Avoid < 30 ml/min Avoid < 15 ml/min
Drug Interactions P-gp CYP3A4/P-gp CYP3A4/P-gp

44. Meta-analysis of Efficacy and Safety
of New Oral Anticoagulants
Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354..
Dabigatran, Rivaroxaban, Apixaban,Edoxaban vs. Warfarin in AF patient
All cause stroke/SEE
Ischemic and unspecified stroke
Hemorrhagic stroke

45. GI Bleeding
Meta-analysis of Efficacy and Safety
of New Oral Anticoagulants
Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients
Major bleeding
Intracranial bleeding
Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3):453-60. Pub Med PMID: 22537354.

46. Determine stroke/thromboembolic risk
High risk:
• Previous
ischaemic
stroke/TIA or
thromboembolic
event
• Age >75 with
hypertension,
diabetes or
vascular disease
• Clinical evidence
of valve disease,
heart failure, or
impaired left
ventricular function
on
echocardiography
Moderate
risk:
• Age >65 with
no high risk
factors
• Age <75 with
hypertension,
diabetes or
vascular
disease
Low risk:
• Age <65 with
no moderate or
high risk factors
Patients with AF

47. Determine stroke/thromboembolic risk
High
risk
Moderate
risk
Low
risk
Consider anticoagulation
Consider anticoagulation
or aspirin
Aspirin 75 to 300 mg/day
if no contraindications
Contraindications to
warfarin?
Warfarin, target INR = 2.5
(range 2.0 to 3.0)
Reassess risk stratification
whenever individual risk
factors are reviewed
N
O
YES
Patients with AF

48. European Society of Cardiology
Guidelines
Risk Category
CHA2DS2-
VASc
Score
Recommended
Antithrombotic Therapy1
One ‘major’ risk factor
or > 2 ‘clinically
relevant non-major’ risk
factors
> 2 OAC
One ‘clinically relevant
non-major’ risk factor’
1
• Either OAC or aspirin 75-325 mg daily
• Preferred: OAC rather than aspirin
No risk factors 0
• Either aspirin 75-325 mg daily or no
antithrombotic therapy
• Preferred: no antithrombotic therapy
rather than aspirin
Approach to Thromboprophylaxis in Patients
with AF
1. Camm AJ. Europace. 2010 Oct;12(10):1360-420. Pub Med PMID: 20876603.
2. Connolly SJ, et al. N Engl J Med 2009;361:1139–1151. PMID: 19717844.
Risk of Bleeding HAS-BLED Score Dabigatran Dosage2
Low risk 0–2 150 mg b.i.d.
Measurable risk, or 1 clinically-
relevant non-major risk factor ≥3 110 mg b.i.d.

49. ACCP Guidelines
Level of Risk
ACCP
Recommendation Alternative*
Not
Recommended
Low Risk
(CHADS2 = 0)
No Therapy Aspirin Oral anticoagulation
or combination
therapy with aspirin
and clopidogrel
Intermediate Risk
(CHADS2 = 1)
Oral anticoagulation Aspirin with
clopidogrel
Aspirin
High Risk
(CHADS2 = 2)
Oral anticoagulation
(dabigatran 150 mg
b.i.d. vs. VKA**)
Aspirin with
clopidogrel
Aspirin
You JJ, et al. Chest. 2012 Feb;141(2 Suppl):e531S-75S. Pub Med PMID: 22315271.
*For patients with AF unsuitable for, or who refuse, oral anticoagulant (for reasons other than concerns about major bleeding)
**VKA = adjusted-dose vitamin K antagonist
For patients with Nonrheumatic AF, including those with Paroxysmal
AF

50. 2011 ACCF/AHA/HRS
Guidelines
Risk Category
1
Recommended Therapy
No risk factors Aspirin, 81 to 325 mg daily
One moderate risk factor Aspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5)
Any high risk factor or
> 1 moderate-risk factor
Warfarin (INR 2.0 to 3.0, target 2.5)*
Antithrombotic Therapy for Patients with Atrial Fibrillation
1. Fuster V. Circulation. 2011 Mar 15;123(10): Pub Med PMID: 21382897.
2. Wann LS, et al. J Am Coll Cardiol. 2011 Mar 15;57(11):1330-7. Pub Med PMID: 21324629.
2011 Focused Update Recommendation Class I
2
Comments
Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic
thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or
systemic embolization who do not have a prosthetic heart valve or hemodynamically significant
valve disease, severe renal failure (creatinine clearance <15 mL/min) or advanced liver disease
(impaired baseline clotting function). (Level of Evidence: B)
New Recommendation
Less Validated /
Weaker Risk Factors
1
Moderate Risk Factors High Risk Factors
Female gender Age >75 years Previous stroke, TIA or embolism
Age 65 to 74 years Hypertension Mitral stenosis
Coronary artery disease Heart failure Prosthetic heart valve*
* If mechanical valve, target international normalized ratio (INR) >
2.5Thyrotoxicosis LV ejection fraction <35%
Diabetes mellitus

51. Canadian Cardiovascular
Society Guidelines
OAC*
CHADS2 = 1
Assess Thromboembolic Risk
(CHADS2)
Skanes AC, et al. Can J Cardiol. 2012 Mar-Apr;28(2):125-36. Pub Med PMID: 22433576.
OAC
CHADS2 = 2
*ASA is a
reasonable
alternative
for some as
indicated by
risk/benefit
No anti-
thrombotic ASA OAC*
No
additional
risk factors
for stroke
Either
female sex
or
vascular
disease
Age > 65 yrs
or
combination
female sex
and
vascular
disease
CHADS2 = 0
*ASA is a
reasonable
alternative
for some as
indicated by
risk/benefit
No anti-
thrombotic ASA OAC*
No
additional
risk factors
for stroke
Either
female sex
or
vascular
disease
Age > 65 yrs
or
combination
female sex
and vascular
disease
CHADS2 = 0
When OAC therapy is indicated,
most patients receive:
• Dabigatran, rivaroxaban,
or apixaban (after Health
Canada approval)
• In preference to warfarin
• Conditional Recommendation,
High-Quality Evidence
Increasing stroke risk

52. Optimal Candidates for
Warfarin
Patients who:
• Have (borderline) renal
insufficiency
• Are taking stable dose
of warfarin and do not
find INR testing
burdensome
• Have access to self-
testing machine
• Are concerned about
the lack of an
evidence-based
reversal strategy

53. Optimal Candidates for New
Drugs
Patients who:
• Find INR testing burdensome
• Despite adherence to provider
recommendations, have low ‘time-in-
range’
• Can afford (or arrange to get) the new
drugs
• Have normal renal function
Price: (India)
• Rivaroxaban: 300Tk/Tablet (OD)
• Dabigatran: 200 Tk/Tablet (BD)
• Apixaban : 250Tk/Tablet (BD)