New Anticoagulants: When and Why Should I Use Them? Disclosures

(1)

Winship Cancer Institute

of Emory University

New Anticoagulants: When and Why Should I Use Them?

Christine L. Kempton, MD, MSc

Associate Professor of Pediatrics and Hematology and Medical Oncology

Hemophilia of Georgia, Inc , Directors Chair in Hemostasis

Disclosures

• Nothing relevant to disclose.

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Venous Thromboembolism (VTE)

• Overall annual incidence 1/1000 persons

•

Increases with age: 5/1000 persons annually in people over 80 years of age

• Location

•

Pulmonary embolism (PE) – 2/3

•

Deep venous thrombosis (DVT) – 2/3

• Mortality within one month of diagnosis:

•

DVT – 6%

•

PE – 12%

• Long-term complications

•

DVT- post-thrombotic syndrome occurs in 20-50%

•

PE- chronic pulmonary hypertension occurs in 2-4%

Yeh et al. Blood 2014 pre-published

Old Oral Anticoagulants: Warfarin

• First approved for medical use in 1954

• Inhibits vitamin K reductase (VKOR)

•

Prevents carboxylation of clotting factors II, VII, IX, and X

•

Partially decarboxylated proteins have less clotting activity

• Metabolised by cytochrome P450 (CYP)

•

particularly CYP2C9

• Limitations:

•

Food-drug interactions

•

Drug-drug interactions

•

Delayed onset of action

•

Variability of response monitoring

• Safety and efficacy dependent on therapeutic INR

Hirsh et al. Circulation 2003; 107: 1692-1711

(3)

Factor IXa Factor VIIIa Factor XIa

Fibrinogen Factor IX

Factor Xa Factor Va

Thrombin Prothrombin

Fibrin Factor X

4 Rivaroxaban

Apixiban Edoxaban

Dabigitran Factor VIIa

Tissue Factor

Novel Oral Anticoagulants (NOAC)

Dabigitran Rivaroxaban Apixiban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa

Pro-drug Yes No No No

Elimination half-life

14-17 hrs 7-11 hrs 8-14 hrs 5-11 hrs Bioavailability

%

3-7 80 66 45

Protein Binding %

35 >90 ~85 40-59

Route of elimination

Urine ~80%, feces ~20%

Urine ~66%, feces ~30%

Urine ~25%, feces ~70%

Urine ~35%

Feces ~60%

Dosing Twice/day Once/day* Twice/day Once/day Substrate of

CYP enzymes

No Yes (CYP3A4,

CYP2J2)

Yes (CYP3A4)

Yes (CYP3A4) Substrate of

P-glycoprotein

Yes Yes Yes Yes

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Indications for Use

Non- valvular A. Fib

VTE prevention

Initial VTE Treatment

VTE

Secondary Prevention

Dabigitran + - +

(after 5-10 days

of parenteral AC)

+

Rivaroxaban + + + +

Apixiban + + * *

Edoxaban * - *

(after 5-10 days of

parenteral AC)

*

*FDA application pending

Treatment of Acute VTE: Efficacy

VTE Recurrence

HR (95% CI) NOAC Warfarin

Dabigitran- RE-COVER Study

¹

; n=1274

2.4% 2.1% 1.10 (0.65-1.84)

Rivaroxaban-EINSTEIN Study

²

; n=3449

2.1% 3.0% 0.68 (0.44-1.04)

Rivaroxaban-EINSTEIN PE Study

³

; n=4832

2.1% 1.8% 1.12 (0.75-1.68)

Apixiban-AMPLIFY Study

⁴

; n=5244

2.3% 2.7% 0.84 (0.60-1.18)

Edoxaban-Hokusai-VTE Study

⁵

; n=4921

3.2% 3.5% 0.89 (0.70-1.13)

1. Schulman et al. NEJM. 2009;361:2342-52 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97

4. Agnelli et al. NEJM 2013; 1369:799-808

5. Houkusai VTE Investigators. NEJM 2013;369:1406-15

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Treatment of Acute VTE: Safety

Major Bleeding Clinically Relevant Non-Major Bleeding

NOAC Warfarin HR (95% CI)

NOAC Warfarin HR (95% CI) Dabigitran- RE-COVER

Study¹; n=1274

1.6% 1.9% 0.82 (0.45- 1.48)

4.0% 7.8% -

Rivaroxaban-EINSTEIN Study²; n=3449

1.8% 1.2% 0.65 (0.33- 1.30)

7.3% 7.0% -

Rivaroxaban-EINSTEIN PE Study³; n=4832

1.1% 2.2% 0.49 (0.31- 0.79)

9.5% 9.8% -

Apixiban-AMPLIFY study⁴; n=5244

0.6% 1.8% 0.31* (0.17- 0.55)

3.8% 8.0% 0.48

(0.38-0.60) Edoxaban-Hokusai-VTE

study⁵; n=4921

1.4% 1.6% 0.84 (0.59- 1.21)

8.1% 8.6% -

*p <0.001

1. Schulman et al. NEJM. 2009;361:2342-52 2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. EINSTEIN PE Investigators NEJM 2012;366:1287-97

4. Agnelli et al. NEJM 2013; 1369:799-808

5. Houkusai VTE Investigators. NEJM 2013;369:1406-15

Dabigitran

Rivaroxaban Apixiban

Dabigitran

Rivaroxaban Apixiban

Dentali F, Circulation 2012;126:2381-2391

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Secondary Prevention of VTE: Efficacy

VTE Recurrence

HR (95% CI) NOAC Placebo

Dabigitran-RE-MEDY &

RE-SONATE

¹

; n=2856

1.8% 5.6%* 0.08 (0.02-0.25)

Rivaroxaban-EINSTEIN Study

²

n=1196

1.3% 7.1% 0.18 (0.09-0.39)

Apixiban-AMPLIFY EXT

³

; 2.5mg n=2482

1.7%^ 8.8% 0.19 (0.11-0.33)

*Warfarin treated group1.3%, HR 1.44 (95% CI 0.78-2.64)

^Apixiban 2.5 mg and 5.0 mg similar

1. Schulman et al. 2013;368:709-18

2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808

Secondary Prevention of VTE: Safety

Major Bleeding Clinically Relevant Non-Major Bleeding

NOAC Place bo

HR (95% CI)

NOAC Placebo HR (95% CI)

Dabigitran-RE-MEDY

& RE-SONATE

¹

; n=2856

0.9% 0 - 5.0% 1.8% 2.92 (1.52-

5.60)

Rivaroxaban- EINSTEIN Study

²

n=1196

0.7% 0 - 5.4% 1.2% -

Apixiban-AMPLIFY EXT

³

; 2.5mg n=2482

0.2% 0.5% 0.49 (0.09- 2.64)

3.0% 2.3% 1.29**

(0.72-2.33)

^Apixiban 2.5 mg and 5.0 mg similar

1. Schulman et al. 2013;368:709-18

2. EINSTEIN Investigators. NEJM 2010;363:2499-510 3. Agnelli et al. NEJM 2013; 1369:799-808

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Agnelli et al. NEJM 2013; 1369:799-808

Patient Selection

Use Avoided:

• PE with hemodynamic instability

• Significant risk of bleeding

• Recent trauma or surgery

• CrCl < 30 ml/min

• Hepatic dysfunction (Child- Pugh B)

• Pregnancy

• Active cancer

• High-risk settings such as HIT or antiphospholipid syndrome

• Concurrent use of :

•

Strong inhibitors/inducers of CYP3A4 and P-glycoprotein

Use with Caution:

• Advanced age > 75 years

• Extremes of weight < 60 or >

150 kg

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INR Control

Good Poor

Lifestyle burden

Low High

May benefit

Limited benefit May benefit No benefit

Adherence

Patients Currently on Warfarin

NOAC Selection

• Preference for once daily vs. twice daily dosing: Favors rivaroxaban and edoxaban

•

Rivaroxaban should be taken with food

• Ability to use an all oral regimen at diagnosis: Favors rivaroxaban and apixiban

• Low renal clearance- Avoid dabigitran and favor apixiban

• History of coronary artery disease—Avoid dabigitran

• Upper GI complaints - Avoid dabigitran

• Recent GI bleed- Favors apixiban

• Clinical setting is extended treatment for secondary prevention—Favors apixiban

• CYP3A4 interaction-Favors dabigitran

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Monitoring

• Acute Treatment:

•

Early follow-up if discharged from the ED

•

Follow-up at times of transition (apixiban: 7 days, rivaroxaban: 21 days)

• Extended Treatment

•

Follow-up to assess adherence, efficacy, side effects, stability of renal/liver function

•

Every 3-12 months, depending on renal function

• Laboratory monitoring

•

Approved kits for rivaroxaban (anti-Xa assay) and dabigitran (anti-IIa assay)

•

Not recommended for routine monitoring

•

Potential uses:

•

Emergent surgery or other invasive procedure

•

Failure of efficacy or safety

•

Anticipated alterations of pharmacokinetics or pharmacodynamics

Practical Issues

• Switching from warfarin to NOAC:

•

Stop warfarin and start NOAC when INR < 2.0

•

Likely after 2-3 missed doses depending on the INR at cessation of warfarin

• Encourage use of Medic Alert that identifies NOAC use

• Discuss importance of adherence:

•

Use of pill box essential

•

Take at similar time each day

• Missed dose:

•

< 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose, then take dose

•

> 12 hours (daily dosing) and 6 hours (BID dosing) from missed dose—skip the dose

•

Do not double up

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Bleeding Management

•

No reversal agent currently available, but new agents are in development

Factor Xa inhibitors Direct Thrombin Inhibitors

Normalization of hemostasis

12-24h CrCl > 80 mL/min: 12-24h CrCl 50-80 mL/min: 24-36h CrCl 30-50 mL/min: 36-48h CrCl < 30 mL/min: > 48h General measures Hold medication, local hemostatic measures,

transfusion therapy as need for anemia and thrombocytopenia, tranexamic acid

Increase clearance -- Hemodialysis

Promote hemostasis

Prothrombin complex concentrates (PCC) (25 U/kg), activated PCC (aPCC) (50 U/kg), or rFVIIa (90 mcg/kg)-no clinical data

Heidbuchel et al. Eur Heart J 2014 pre-published

Peri-operative Management

•

Post-operative

•

Restart NOAC once full anticoagulation is allowed—likely 48-72 hours after major surgery

•

May need prophylactic anticoagulation with LWMH in the immediate post- operative period until able to resume full dose anticoagulation

• Pre-operative: Low vs. high surgical bleeding risk

Dabigitran Apixiban Edoxaban Rivaroxaban

Low High Low High Low High Low High

CrCl > 80 mL/min > 24h > 48h > 24 h > 48h ND ND > 24 h > 48h CrCl 50-80 mL/min > 36h > 72h > 24 h > 48h ND ND > 24 h > 48h CrCl 30-50 mL/min > 72h > 120h > 24 h > 48h ND ND > 24 h > 48h

ND=no data

Heidbuchel et al. Eur Heart J 2014 pre-published Prescribing information

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Summary

• New oral anticoagulants …

•

offer a real alternative to warfarin therapy for a large number of patients.

•

are efficacious for:

•

Treatment of acute VTE: DVT and hemodynamically stable PE.

•

Secondary prevention of recurrent VTE.

•

are as safe or safer than warfarin.

•

are more convenient and less burdensome than warfarin.

• Patients not appropriate for NOACs include those with:

•

Severe renal or liver impairment

•

Cancer

•

Extremes of weight

•

Pregnant

•

Significantly advanced age

•