new oral anticoagulants versus warfarin-appraisal
TRANSCRIPT
JOURNAL CLUB
Presented by: Dr.Venugopalan.G, JRPreceptor: Dr. Pradeep Behl, SR
Department of Geriatric Medicine
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
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
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
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=aspirinScore 1=aspirin or oral anticoagulationScore 2=oral anticoagulation
CHADS2 & Stroke rate
Validation of clinical classification schemes for predicting stroke: results from theNational Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870
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
Mason et al CHA2DS2-VASc Score and Anticoagulation for Atrial Fibrillation. The American Journal of Medicine, Vol 125, No 6, June 2012
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
ESC guidelines 2010
ESC guidelines 2010
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
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
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
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
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
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
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) trialClass IIb in 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With AFib
Oral Anticoagulants
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
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 INRTTR- Time in Therapeutic Range
Direct Thrombin inhibitors:
Ximelagatron
Dabigatran
Factor Xa inhibitors:
Rivaroxaban
Apixaban
Edoxaban
New OAC
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
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
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)
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
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
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
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
Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) N Engl J Med 2011;365:981-92.
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.
Reversible Factor Xa inhibitor
T1/2=9-10 hours
50% renal clearance
60 mg od
Anti factor Xa assay, PT, aPTT
No antidote
Edoxaban
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
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
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
Novel Oral Anticoagulants in Atrial Fibrillation: A Meta-analysis of Large, Randomized, Controlled
Trials vs WarfarinAriel Dogliotti, Ernesto Paolasso, Robert P. Giugliano. Clin. Cardiol. 36, 2, 61–67 (2013)
To assess the relative benefit of new oral
anticoagulants in key subgroups
And to assess the effects on important
secondary outcomes.
Aim
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
Pre specified analysis of the four phase 3
randomised trials
ROCKET AF
ARISTOTLE
RE LY
ENGAGE AF TIMI 48
Study selection
Stroke and systemic
embolic events,
Ischaemic stroke,
Haemorrhagic stroke,
All-cause mortality,
Myocardial infarction,
Major bleeding,
Intracranial haemorrhage
(including haemorrhagic
stroke, epidural, subdural
and subarachnoid
haemorrhage), and
Gastrointestinal bleeding
Outcomes
Efficacy Safety
Median follow-up: 1.8 to 2.8 years
Participants
71,68342,411 29,272
Novel oral anticoagulants Warfarin
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
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)
Stroke or systemic embolic events
Secondary efficacy and safety outcomes
Major bleeding
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 analysisCompared efficacy and safety in important clinical subgroups
Stroke or systemic embolic events in subgroup
Major bleeding in subgroup
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
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
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
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
Antidote
Cost
Safety
Compliance
Realiability?
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