4.
Meta-analysis is a systematic review of a focused topic
in the literature that provides a quantitative estimate
for the effect of a treatment intervention or exposure
Meta-analysis
Mark W. Russo How to Review a Meta-analysis.Gastroenterology & Hepatology Volume
3, Issue 8 August 2007
5.
AF is defined as a cardiac arrhythmia with the following
characteristics:
The surface ECG shows ‘absolutely’ irregular RR intervals
There are no distinct P waves on the surface ECG
The atrial cycle length is usually variable and <200 ms (>300
bpm).
Atrial Fibrillation-definition
6. Previous stroke or TIA
Age > 75
Structural heart disease
Hypertension
Previous MI
Moderate to severe LV dysfunction in echo
Complex aortic plaque in TOE
Marked LA enlargement(>5.0 cm)
Risk factors for stroke in AF
Diabetes-Not a convincing
predictive factor
Michael Hughes et al. Stroke and thromboembolism in atrial fibrillation: A systematic
review. Thromb Haemost 2008; 99: 295–304
7.
CHADS2 score
C Congestive Heart Failure 1 point
H Hypertension 1 point
A Age75 y 1 point
D Diabetes 1 point
S2 Stroke 2 points
Score 0=aspirin
Score 1=aspirin or oral anticoagulation
Score 2=oral anticoagulation
8.
CHADS2 & Stroke rate
Validation of clinical classification schemes for predicting stroke: results from the
National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870
9.
CHA2DS2-VASc Score
C Congestive Heart Failure 1 point
H Hypertension 1 point
A2 Age_75 y 2 points
D Diabetes 1 point
S2 Stroke 2 points
V Vascular disease 1 point
A Age_65 y 1 point
Sc Sex category, female 1 point
Score 0= no therapy or aspirin (no therapy preferred)
Score 1= aspirin or oral anticoagulation (oral anticoagulation preferred)
Score 2= oral anticoagulation
10.
Mason et al CHA2DS2-VASc Score and Anticoagulation for Atrial Fibrillation. The
American Journal of Medicine, Vol 125, No 6, June 2012
11.
HAS-BLED
H Hypertension 1
A Abnormal renal and liver function(1
point each)
1 or 2
S Stroke 1
B Bleeding 1
L Labile INRs 1
E Elderly (>65 years) 1
D Drugs or alcohol (1 point each) 1 or 2
Score > 3 is high risk for bleeding
14.
For patients with AF, (including paroxysmal AF) who are at
low risk of stroke (eg, CHADS2 score=0), we suggest no
therapy rather than antithrombotic therapy (Grade 2B)
For patients who do choose antithrombotic therapy, we
suggest aspirin (75 mg to 325 mg once daily) rather than oral
anticoagulation (Grade 2B) or combination therapy with
aspirin and clopidogrel (Grade 2B)
Antithrombotic Therapy for Atrial Fibrillation
ACCP guidelines 9th ed.
CHEST 2012; 141(2)(Suppl):e531S–e575S
15.
Who are at intermediate risk of stroke (eg, CHADS2 score=1),
we recommend oral anticoagulation rather than no therapy
(Grade 1B) . We suggest oral anticoagulation rather than
aspirin or combination therapy(Grade 2B).
For patients who are unsuitable for or choose not to take an
oral anticoagulant, we suggest combination therapy with
aspirin and clopidogrel rather than aspirin(Grade 2B)
Antithrombotic Therapy for Atrial Fibrillation
ACCP guidelines 9th ed.
CHEST 2012; 141(2)(Suppl):e531S–e575S
16.
Who are at high risk of stroke (eg, CHADS2 score= 2), we
recommend oral anticoagulation rather than no therapy
(Grade 1A) , aspirin or combination therapy(Grade 1B).
For patients who are unsuitable for or choose not to take an
oral anticoagulant, we recommend combination therapy with
aspirin and clopidogrel rather than aspirin(Grade 1B)
Antithrombotic Therapy for Atrial Fibrillation
ACCP guidelines 9th ed.
CHEST 2012; 141(2)(Suppl):e531S–e575S
17.
For patients with AF, (including paroxysmal AF) for
recommendations in favor of oral anticoagulation we suggest
dabigatran 150 mg bd rather than adjusted-dose warfarin
(target INR range, 2.0-3.0) (Grade 2B)
Exception: AF with MS, AF with CAD
Antithrombotic Therapy for Atrial Fibrillation
ACCP guidelines 9th ed.
CHEST 2012; 141(2)(Suppl):e531S–e575S
18.
AF and Mitral Stenosis: warfarin (INR-2.0 to 3.0)
AF with stable CAD: warfarin (INR-2.0 to 3.0)
AF with high risk and 1st month of bare metal stent or 3 to 6 month
of drug eluting stent: triple therapy (warfarin, aspirin,
clopidogrel).
After this period till 12 motnhs: warfarin and aspirin/clopidogrel
After 12 months: same as AF with stable CAD
Antithrombotic Therapy for Atrial Fibrillation
ACCP guidelines 9th ed.
CHEST 2012; 141(2)(Suppl):e531S–e575S
19.
AF with low/intermediate risk till 12 months of stent: dual
antiplatelet therapy
After this period: same as AF with stable CAD
AF with acute CAD, no stent, till 12 months: warfarin plus
aspirin/clopidogrel
After this period: same as AF with stable CAD
Antithrombotic Therapy for Atrial Fibrillation
ACCP guidelines 9th ed.
CHEST 2012; 141(2)(Suppl):e531S–e575S
20.
In pts “unsuitable” for oral anticoagulation due to a
specific risk of bleeding, patient preference or physician
preference
Reduced the risk of major vascular events (6.8% vs 7.6%
per year), especially stroke(2.4% vs 3.3% per year)
Increased the risk of major hemorrhage (2.0% vs 1.3% per
year)
ACTIVE-A (Effect of Clopidogrel Added to Aspirin in
Patients with Atrial Fibrillation) trial
Class IIb in 2011 ACCF/AHA/HRS Focused Update on the Management of Patients
With AFib
22.
Warfarin
Vitamin K antagonist
Oral, i.v, rectal-bioavailability nearly complete
T1/2=25 to 60 hours (≈40 hours), duration of action= 2 to 5
days
Monitoring: PT(INR)
Antidote: Vitamin K1(phytonadione), FFP
Vitamin K antagonist
23.
Genotype testing for CYP2C9 and VKORC1 (FDA
suggested)
Slow onset and offset of action (TTI)
Narrow therapeutic range
Regular monitoring (TTR)
Drug interactions
Problems with warfarin
TTI- Time To INR
TTR- Time in Therapeutic Range
24.
Direct Thrombin inhibitors:
Ximelagatron
Dabigatran
Factor Xa inhibitors:
Rivaroxaban
Apixaban
Edoxaban
New OAC
25. Direct Thrombin inhibitor (both free and clot bound IIa)
T1/2=12 – 17 hours
GFR >30ml/min:150 mg bd, GFR 15 to 30 ml/min: 75 mg bd
90-95% unchanged in urine, rest in bile. Dialysable.
PT, aPTT, TT
No antidote. Prothrombin concentrate or rVIIa may be used.
RE-ALIGN trial: significantly more thromboembolic events and
excess of major bleeding in patients with prosthetic heart valves
Dabigatran
26.
Randomized Evaluation of Long Term Anticoagulation Therapy
N Engl J Med 2009; 361:1139-51(RE-LY; dabigatran)
Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment
Group
27.
As compared to warfarin(1.69% per year of 1⁰ outcome):
Dabigatran 110 mg- similar rate(1.53% per year) of stroke
and systemic embolism, lower rates of major haemorrhage.
Dabigatran 150 mg-lower rates(1.11% per year) of stroke
and systemic embolism, similar rates of major
haemorrhage
Randomized Evaluation of Long Term Anticoagulation Therapy
N Engl J Med 2009; 361:1139-51(RE-LY; dabigatran)
28. Reversible Factor-Xa inhibitor, activity also on thrombin and
factor VII
T1/2=5-13 hours
20 mg od, if GFR 30 to 49 ml/min: 15 mg od
CYP3A4 metabolism, 70% renal and 30%fecal elimination
No antidote. Prothrombin concentrate or rVIIa may be used.
Monitoring: anti Factor Xa assay, PT, aPTT
It is not for patients with artificial heart valves
Rivaroxaban
29.
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition
Compared with Vitamin K Antagonism for Prevention of Stroke
and Embolism Trial in Atrial Fibrillation
(ROCKET AF) N Engl J Med 2011;365:883-91
30.
1.7% per year vs 2.2% per year (P<0.001 for non-inferiority)
2.1% per year vs 2.4% per year (P = 0.12 for superiority)
There was no significant between-group difference in the risk
of major bleeding, although intracranial and fatal bleeding
occurred less frequently in the rivaroxaban group
Funded by Johnson & Johnson and Bayer
Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition
Compared with Vitamin K Antagonism for Prevention of Stroke
and Embolism Trial in Atrial Fibrillation
(ROCKET AF) N Engl J Med 2011;365:883-91
31.
Reversible Factor-Xa inhibitor
T1/2=8-15 hours
5 mg bd
CYP3A4 metabolism. 30% renal and 70% fecal elimination
Minimal p-gp interaction
Anti factor Xa assay, PT, aPTT
No antidote
Apixaban
32.
Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) N Engl J Med 2011;365:981-92.
33.
Apixaban reduced the risk of (in comparison to warfarin)
stroke or systemic embolism by 21%
major bleeding by 31% and
death by 11%.
Apixaban (5mg bd/ 2.5 mg bd in subsets) was superior to
warfarin
Funded by Bristol-Myers Squibb and Pfizer
Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) N Engl J Med 2011;365:981-92.
34.
Reversible Factor Xa inhibitor
T1/2=9-10 hours
50% renal clearance
60 mg od
Anti factor Xa assay, PT, aPTT
No antidote
Edoxaban
35.
Effective Anticoagulation with Factor Xa Next Generation in
Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48
(ENGAGE AF–TIMI 48) N Engl J Med 2013;369:2093-104
36.
Effective Anticoagulation with Factor Xa Next Generation in
Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48
(ENGAGE AF–TIMI 48) N Engl J Med 2013;369:2093-104
37.
Both (30mg & 60mg) once-daily regimens of edoxaban were
noninferior to warfarin with respect to the prevention of
stroke or systemic embolism and were associated with
significantly lower rates of bleeding and death from
cardiovascular causes
Funded by Daiichi Sankyo Pharma Development
Effective Anticoagulation with Factor Xa Next Generation in
Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48
(ENGAGE AF–TIMI 48) N Engl J Med 2013;369:2093-104
38.
Novel Oral Anticoagulants in Atrial Fibrillation: A
Meta-analysis of Large, Randomized, Controlled Trials
vs Warfarin
Ariel Dogliotti, Ernesto Paolasso, Robert P. Giugliano. Clin. Cardiol. 36, 2, 61–67 (2013)
40.
To assess the relative benefit of new oral
anticoagulants in key subgroups
And to assess the effects on important secondary
outcomes.
Aim
41.
Search: Medline from Jan 1, 2009, to Nov 19, 2013
Limited to phase 3, RCTs of patients with atrial fibrillation
who were randomised to receive new oral anticoagulants
or warfarin, and
Trials in which both efficacy and safety outcomes were
reported for their comparison
Study selection
42.
Pre specified analysis of the four phase 3 randomised trials
ROCKET AF
ARISTOTLE
RE LY
ENGAGE AF TIMI 48
Study selection
46.
1) Meta analysis done for both higher doses (dabigatran 150
mg bd and edoxaban 60 mg od) combined with the single
doses studied in ROCKET AF(rivaroxaban 20 mg od) and
ARISTOTLE(apixaban 5 mg bd)
2) In a separate analysis a meta-analysis of the two lower
doses (dabigatran 110 mg bd and edoxaban 30 mg od)
Statistical Analysis
47.
Statistical Analysis
Two sensitivity analyses were also done:
1) A meta-analysis of only the factor Xa inhibitors, with
removal of the thrombin inhibitor dabigatran
2) An analysis combining all doses of all drugs (both high
and low doses of dabigatran and edoxaban with
rivaroxaban and apixaban)
51.
Age (<75 vs ≥75 years)
Sex
H/O previous stroke or
TIA,
H/O diabetes,
Renal function (creatinine
clearance <50 ml/min, 50–
80 ml/min, >80 ml/min),
CHADS2 risk score (0–1, 2,
3–6),
VKA status at study entry
(naive or experienced), and
Centre-based time in
therapeutic range (threshold
of <66% vs ≥66%)
Subgroup analysis
Compared efficacy and safety in important clinical subgroups
54.
Stroke and systemic embolic events were significantly
reduced in patients receiving new oral anticoagulants.
This benefit was mainly driven by substantial protection
against haemorrhagic stroke, which was reduced by half
Significant reduction in all cause-mortality compared with
warfarin
Discussion
55.
For the prevention of ischaemic stroke, the new oral
anticoagulants had similar efficacy to warfarin
Reduced ischaemic stroke by two-thirds compared with placebo
Low dose regimen have a similar efficacy to warfarin for
protection against all stroke or systemic embolic events.
However, they are not as effective for protection against
ischaemic stroke in particular
Discussion
56.
Favourable safety profile compared with warfarin
However, they were associated with an increase in
gastrointestinal bleeding
Low dose regimen have a safer profile than warfarin
Consequently, they might be an appealing option for frail
patients or for those who have a high risk for bleeding with
full-dose anticoagulation
Discussion
57.
Statistical heterogeneity across the trials-complete
uniformity can show consistency in bias rather than
consistency in real effects, so some heterogeneity is
expected
Data from only clinical trials, which could affect the
generalisability of the results- results of phase 4
surviellance
Potential Limitations
59. 1. Is this article from a peer reviewed
journal?
Yes(go on) No(stop)
2. Is the location of the study similar to
mine so the results, if valid, apply to
my practice?
Yes(go on) No(stop)
3. Is the study sponsored by an
organization that may influence the
study design or results?
Yes(pause) No(stop)
4. Will this information, if true, have a
direct impact on the health of my
patients, and is it something they will
care about?
Yes(go on) No(stop)
5. Is the problem addressed one that is
common to my practice, and is the
intervention Or test feasible and
available to me?
Yes(go on) No(stop)
6. Will this information , if true, will
require me to change my current
practice?
Yes(go on) No(stop)