Anticoagulation in atrial fibrillation -...

+ Faculty/Presenter Disclosure

Faculty: Sudeep Shivakumar

Relationships with commercial interests:

Grants/Research Support: N/A

Speakers Bureau/Honoraria: Boehringer Ingelheim, Bayer

Inc, Leo Pharma

Consulting Fees: N/A

Other: N/A

+ Disclosure of Commercial Support

No commercial support

+ Mitigating Potential Bias

No input into slides or content of talk by anyone but

the speaker

+

Anticoagulants: When and what to use

Family Medicine Assembly, NSCFP

September 27th, 2013

Dr. Sudeep Shivakumar, Hematology

Dalhousie University

+ Objectives

To review indications for anticoagulation

To discuss the new oral anticoagulants

To discuss the management of bleeding

+ Overview

Anticoagulants are widely used

Vitamin K antagonists used to be the only oral option

Times are changing…

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+

+ Overview

Big advantage:

No lab monitoring

Big disadvantage:

No lab monitoring

Unpredictability of coagulation tests

But very predictable action

No reversal agents

But ?less bleeding

Variety of different agents with different characteristics

+ Indications for anticoagulation

Atrial fibrillation

DVT/PE

Mechanical heart valves

No evidence for new anticoagulants as of yet

+ Atrial fibrillation

Most common cardiac rhythm disorder

Affects >10% in those > 80 years old

Krahn et al, Am J Med, 1995

Incidence of atrial fibrillation in 4000 male air crew recruits

+ Atrial fibrillation

Lifetime risk for a 40 year old is ~25% (Framingham1)

Independent risk factor for ischemic stroke

Rate of stroke in those not on antithrombotic therapy is ~4.5%/year

Increases the risk of stroke 5x across all age groups

Incidence of stroke increases with age2

1.3% per year for those aged 50-59

5.1% per year for those aged 80-89

2Frost, Am J Med, 2000

1Wolf, Stroke, 1991

+ Pathogenesis of stroke

Multifactorial

Blood stasis

Especially in the left atrial appendage

Can lead to thrombus formation

?possibly due to LA shape and presence of trabeculations

Increased erythrocyte aggregation

Fibrillating atrium leads to altered LAA flow and uncoordinated LA

systole

Thought to lead to low shear rate and increased RBC aggregation

Hypercoagulable state

Mechanism not entirely understood

+ Prevention of thromboembolism

Warfarin and aspirin both extensively studied

Both significantly reduce the incidence of stroke in non-valvular

atrial fibrillation

Both approved as antithrombotic therapy for atrial fibrillation

+ Compared to placebo…

Aspirin

Meta-analysis of 6 RCT’s comparing ASA to placebo in atrial fibrillation

ASA reduced the incidence of stroke or TIA by 22 %

Warfarin

Various studies have compared warfarin to placebo in atrial fibrillation

Warfarin reduced the incidence of stroke by 68 %

3x as effective as ASA

For those 65-75 years old with no other risk factors

Risk of stroke 4.3% per year with no therapy

Risk of stroke 1.4% per year with aspirin

Risk of stroke 1.1% per year with warfarin

Hart, Ann Int Med, 1999

+ Warfarin compared to ASA

Consistent benefit for warfarin seen

Pooled analysis of 5 RCT’s comparing warfarin to ASA in non-

valvular AF (over 4000 patients):

Adjusted-dose warfarin significantly reduced stroke risk in patients

compared to placebo or ASA

However, risk of bleeding higher with warfarin:

Absolute rate increase of major bleeding was 0.9 events per 100

patient years

2.2 events per 100 patient years in warfarin arm vs. 1.3 events per

100 patients years in ASA arm

Atrial Fibrillation Investigators, Arch Int Med, 1994

+ Who is at risk for stroke?

Many risk factors for embolization in atrial fibrillation have been

evaluated

Multivariate risk models have been devised

Pooled analysis from the Atrial Fibrillation Investigators (AFI)

Stroke Prevention in Atrial Fibrillation (SPAF)

ACC/AHA/ESA guidelines

ACCP guidelines

Framingham study community risk model

CHADS2 score

+ CHADS2 score

Generated from independent clinical predictors from the AFI

and SPAF

Tested and validated in other cohorts

Best validated in various patient populations

More effective than other models in comparison studies

Simple to remember

Simple to use

Gage et al, JAMA, 2001

+ CHADS2 score

Score

CHF or LV dysfunction 1

Hypertension 1

Age > 75 1

Diabetes 1

Stroke/TIA 2

•Score of 0 to 1

•1.5 to 2.5% risk per year of stroke

•Score of 2 or greater

•4.0 to 18.2% risk per year of stroke

+

+ Venous thromboembolism

Deep venous thrombosis Pulmonary embolism

+

Venous thromboembolism

Known predisposing conditions – Virchow’s triad:

Venous stasis

Hypercoagulability Vessel wall injury

+ Venous thromboembolism

Not uncommon

Longitudinal investigation of thromboembolism etiology (LITE) study1

>21 000 participants

Cohort study

Incidence of 1st time VTE = 1.92 per 1000 person years

Major cause of morbidity and mortality

JAMA study2 looking at post-mortems of 3 412 hospitalized patients between 1966 and 1980

6% of deceased patients had evidence of massive pulmonary embolism

Most common preventable cause of in-hospital death

1Cushman, Am J Med, 2004

2Dismuke, JAMA, 1986

+ Pulmonary embolism

Untreated PE

Mortality rate of ~30%1

Most die within hours of diagnosis

Treated PE

Prospective NEJM study looked at 399 patients with newly

diagnosed PE

94% received anticoagulant treatment

Only 2.5% (10 patients) died of PE

Treatment of PE is life-saving!

1Dalen, Prog Cardiovasc Dis, 1975

2Carson,NEJM, 1992

+ Anticoagulants in DVT/PE

Goals of treatment:

Short term:

Prevent the extension of thrombus and embolization for DVT

Reduce mortality for PE by reducing recurrent events

Relief of symptoms

Long term:

Prevent recurrent events

+ Anticoagulants

Substance that prevents clotting

Usually by inhibiting steps in the coagulation cascade

Heparins

LMWHs

Vitamin K antagonists

Direct thrombin inhibitors

Factor Xa inhibitors

Other targets

+ Warfarin

Oral vitamin K antagonist

Been in use since the 1950’s

Effect measured by the INR

Reduces stroke risk in atrial fibrillation by 68%

Also used for treatment of DVT/PE and prevention of

thrombosis with mechanical valves

Frost, Am J Med, 2000

+ New anticoagulants

Many new targets being explored

Eg. thrombin, factor Xa, tissue factor, protein C, factor V and VIII

Increasing data on:

Dabigatran – oral direct thrombin inhibitor

Rivaroxaban – oral factor Xa inhibitor

Apixaban – oral factor Xa inhibitor

+ New anticoagulants

Leung, The Hematologist, 2011

+ Dabigatran

Pharmacokinetics

Half life 12-17 hours

Time to peak, plasma 1 hour

Not recommended for CrCl <30

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+ Dabigatran

Approved by Health Canada for atrial fibrillation

Covered by MSI if not able to tolerate warfarin

Not approved for VTE treatment

Costs $3.20 per day

+ Factor Xa inhibitors

•Lack of direct thrombin inhibition = less bleeding?

+ Rivaroxaban

Oral, direct factor Xa inhibitor

Fixed, once-daily dosing

Predictable pharmacokinetics

Half life 7-11 hours

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+ Rivaroxaban

Approved for atrial fibrillation

Approved for DVT and PE

No bridging with LMWH needed

15 mg po BID x 3 weeks, then 20 mg po OD

~$2.84 per day

+ Apixaban

Oral, direct factor Xa inhibitor

Primary difference from rivaroxaban is mode of excretion

More hepatobiliary excretion than renal

+

+ Apixaban

Primary outcome = stroke or systemic thromboembolism

1.6% with warfarin

1.27% with apixaban

Major bleeding

3.09% with warfarin

2.13% with apixaban

Decreased intracranial and GI bleeding

Now approved for atrial fibrillation in Canada

+ Bleeding

~2% of patients/year on long term anticoagulants will end up

with a major bleed requiring medical attention

Holding anticoagulants is the first step, but often other steps

are needed

Depends on anticoagulant

+ Warfarin

Clear options for reversal:

Vitamin K

Fresh frozen plasma

Prothrombin complex concentrates

+

+ Vitamin K for those with high INRs

but no bleeding

For patients taking VKAs with INRs between 4.5 and 10 and

with no evidence of bleeding, we suggest against the routine

use of vitamin K (Grade 2B)

For patients taking VKAs with INRs > 10.0 and with no

evidence of bleeding, we suggest that oral vitamin K be

administered (Grade 2C)

CHEST guidelines, 2012

+ Bleeding with warfarin

Vitamin K

5-10 mg if acute bleed

Takes ~1 day to reverse effect

Fresh frozen plasma

Large volume

Incomplete reversal

Prothrombin complex concentrate

Works within 1 hour

More effective than plasma at reversing INR

Small volume

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http://www.gov.ns.ca/health/nspbcp/

+

http://www.gov.ns.ca/health/nspbcp/

+ Reversal of new anticoagulants

Warfarin had several predictable options for reversal:

Vitamin K

Fresh frozen plasma

Activated prothrombin complex concentrates

No reversal agents for new anticoagulants

However, lower risk of bleeding

+ Bleeding

Dabigatran, rivaroxaban and other new agents

No known antidotes

Half-lives roughly 7-17 hours

Supportive care

Blood product support

Fresh frozen plasma

Can consider dialysis with dabigatran

+ Reversal of new anticoagulants

Suggested approach:

Transfuse as necessary

Packed red blood cells

Platelets as needed

Fresh frozen plasma as needed

Consider use of other blood products

?Prothrombin complex concentrates

?Activated factor VIIa – should it even be offered?

Cochrane review showed increased rate of arterial thrombosis

No good evidence!

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+ Perioperative management of

warfarin

Warfarin confers increased risk of bleeding

Needs to be stopped for many procedures or surgeries

Given long half life, warfarin needs to be stopped 5 days before

surgery

+ Perioperative management of new

oral anticoagulants

No data

However, stopping dabigatran or rivaroxaban 48 hours before

surgery seems reasonable

Based on half life less than 17 hours

As long as CrCl >50 ml/min

Monographs do suggest minimum of 24 hours

Not evidence based as of yet

In practice, appears to be safe

Ongoing studies based on creatinine clearance

+

Renal function

(CrCl)

Estimated

half-life (hrs)

Stop dabigatran before surgery

higher-risk for bleeding

low-risk for bleeding

≥50 mL/min (mild dysfunction or normal)

14-17 2-3 days 1 day

30 to <50 mL/min (moderate dysfunction)

18-24 4 days 2-3 days

<30 mL/min (severe dysfunction)

>24 >5 days 2-5 days

Van Rijn J, et al. Thromb Haemost 2010;103:1116 Douketis JD. Curr Pharm Des 2010;16:3436

Pre-operative Management of Dabigatran

+ Post-operative management

Standard bleeding risk and good hemostasis

Dabigatran may be resumed the same evening after a minimum of 6

hours post-op

75 mg for the first post-op dose and then the usual maintenance

dose

High bleeding risk (e.g. vascular surgery, neurosurgery, etc)

Resume dabigatran on POD 2 or 3

Incomplete hemostasis

Delay dabigatran until no drainage or other evidence of bleeding

Do not use dabigatran if bowel paralysis (consider LMWH or UFH)

+ Summary

New anticoagulants are increasingly being used

Dabigatran, rivaroxaban and apixaban are approved for stroke

prevention in atrial fibrillation

No reversal agents as of yet, so supportive care only for

bleeding complications

However, trend towards less bleeding with all new agents

Stopping novel agents 48 hours before surgery is reasonable,

as long as renal function is adequate

+ Thank you!

shivakumars@cdha.nshealth.ca