new oral anticoagulants versus warfarin-appraisal

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

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)



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)



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



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



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



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

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?

The way ahead…

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)

THANK YOU

new oral anticoagulants versus warfarin-appraisal

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