The New Oral Anticoagulants:

Handle with CarePhilip C. Comp, M.D., Ph.D.

October 18, 2013

Speaker for dabigatran (Pradaxa®) and rivaroxaban (Xarelto®)

Anticoagulant Quiz• Which commonly used anticoagulant does

not require laboratory monitoring? • Which anticoagulant has no antidote?• The dose of which anticoagulant depends on

renal function?

(Enoxaparin, Lovenox®)

Edoxaban

The New Oral Anticoagulants

Dabigatran (Pradaxa®)Inhibits thrombinTwice a dayAtrial fibrillation

Apixaban (Eliquis®)Inhibits factor XaTwice a dayAtrial fibrillation

Rivaroxaban (Xarelto®)Inhibits factor XaOnce a dayAtrial fibrillation; DVT/PE treatment;Reduction in risk of DVT/PE (after 6 mn Tx);Hip/Knee prophylaxis;

Canine Model of Blood Coagulation

Factor IX Factor X PROTHROMBIN

Canine Model of Blood Coagulation

Effect of Warfarin

Factor IXa Factor Xa THROMBIN

Canine Model of Blood CoagulationOral Anti-Xa

Factor IXa Factor Xa THROMBIN

Canine Model of Blood CoagulationOral Anti-thrombin

Factor IXa Factor Xa THROMBIN𝐝𝐚𝐛𝐢𝐠𝐚𝐭𝐫𝐚𝐧rivaroxaban

apixaban

There is no free lunch

The effectiveness of an anticoagulant must be weighed against the risk of bleeding

Bleeding

Thrombosis

Apixaban, Dabigatran and Rivaroxaban

• Oral• Short half-lives• Renal clearance• No INRs• No food interactions• Few drug interactions

Prevention of Stroke-Apixaban

Granger et al. NEJM 3654: 981-92, 2011Number needed to treat/1.8 years: 167

Atrial Fibrillation- Dabigatran

Connolly et al. NEJM 361, 2009

35% RRR

!

Number needed to treat/ 2 years: 88

Atrial Fibrillation- Rivaroxaban

CPatel et al. NEJM 365: 883-91, 2011Number needed to treat/1.6 years: 135

Atrial Fibrillation- Dabigatran

Modified from Connolly et al. NEJM 361, 2009

STRO

KENo Treatment Warfarin

Dabigatran

Number needed to treat NT 88 v. warfarin

No Tr

eatm

ent

CHADS2 Scores

0-1 33%2 35%3-6 33%

ESTIMATE 5% risk/yearIn a non-treated group

Percentage of AF patients with stroke per year

No treatment 5.0%Warfarin 1.6%Dabigatran 1.0%

~

Modified from Connolly et al. NEJM 361, 2009

3.4%

0.6%68% of strokes gone; 32 occur

80% of strokes gone; 20 occur

100 strokes occur

STROKE = Ischemic Stroke and Hemorrhagic Stroke*

*Subdural hematomas, epidural hematomas, subarachnoid hematomas and intracerebral hemorrhage

Stroke rates (percent/year)

All Stroke Hemorrhagic Stroke

Time INR in 2-3 range

Dabigatran/ Warfarin

1.44/1.57 0.10/0.38 64

Rivaroxaban/Warfarin(as treated)

2.61/3.12 0.5/0.7 55

Apixaban/ Warfarin

1.19/1.51 0.24/0.47 62

Bleeding and death rates (percent/year)

Major Bleeding

Death

Dabigatran/ Warfarin

3.11/3.36 3.64 /4.13

Rivaroxaban/Warfarin(as treated)

3.60/3.40 1.90/2.20

Apixaban/ Warfarin

2.13/3.09 3.52/3.94

Bleeding Event Rate (%/year)Intracranial Gastrointestinal

Apixaban 0.33 0.76Warfarin 0.80 0.86

Dabigatran 0.30 1.51Warfarin 0.74 1.02

Rivaroxaban 0.77 3.15Warfarin 1.18 2.16

N Engl J Med 2011;365:981-92N Engl J Med 2009;361:1139-51.N Engl J Med 2011;365:883-91.

NNT with dabigatran for 1 year to prevent one adverse event compared to warfarin

NNT

Stroke or systemic embolus

172

Intracranial bleeding 227

Major bleeding 154

Life-threatening bleeding

286

Nature Reviews Cardiology 7, 10-11 (January 2010)

Can atrial fibrillation studies be directly compared?

Mean Age and CHADS2 Score

Apixaban 70y 2.1 ± 1.1

Rivaroxaban 73y 3.5 ± 0.94

Dabigatran 72y 2.1 ± 1.1

Direct comparison of strokes and bleeding between studies is difficult.

CHF 1Hypertension 1Age > 75 1Diabetes 1Prior stroke 2

New oral agents in atrial fibrillation

Apixaban superior to warfarinRivaroxaban not inferior to warfarinDabigatran superior to warfarin

Davis, N Engl J Med 2012;366:1914-22.

No food interactions

Compare to WARFARIN AND FOOD

Dietitians

CHLOROPHOBIA (fear of the color green)

Green Tea

Green Tea333 liters of green tea contain 1 mg vitamin K

Iceberg Lettuce

New anticoagulants have short half- lives (9-17 hours)

Compliance

Forgetfulness 30%Other priorities 16%Decision to omit doses 11%Lack of information 9% Osterberg l et al. NEJM 353: 487-97 2005

1,800,000 patients prescribed a statin:

Patients filled prescriptions for a mean of 11.4 medications/3 month

10% of patients filled prescriptions for 23 or more medications.

10% had prescriptions written by 4 or more prescribers.

Choudhry NK The Implications of Therapeutic Complexity on Adherence to Cardiovascular Medications. Archives of Internal Medicine 171:814-822, 2011

Retrospective Study of Medication Prescription in Oklahoma City, n=3

• 64 year old man: 14 medications daily; 31 pills• 61 year old woman: 15 medications; 39 pills• 90 year old man: 15 medications; 27 pills

Drugs don’t work in patients who don’t take them C. Everett Koop, M.D.

1916-2013

Typical Clinical Trial Patient

Who is the ideal patient?

• Does not like INRs• Reliable• Well insured

Who will have a bleed?

• Frail (<60 kg)• Reduced creatinine clearance• Over 80 years of age

Harper. Bleeding Risk with Dabigatran in the Frail ElderlyN Engl J Med 2012; 366:864-866

Proper prescriber behavior

• At each visit – Are your taking drug X?• At every visit – Why are you taking drug X?• At each visit – Are you taking X every day?

KIDNEY FUNCTION IS IMPORTANT!CHECK THE CREATININE CLEARANCE

What is the effect of no more INRs?

No more anticoagulation clinics and fewer office visits.Will that reduce compliance?

BOUNCING BEN in a BAD candidate!

00.5

11.5

22.5

33.5

44.5

INR

Who to switch from warfarin

• Not a cure for the bouncing INR• Stroke risk: Least benefit to well controlled

warfarin patients• Fewer potential drug interactions in

polypharmacy patients?

Warfarin > new anticoagulant

Patients angst: Miss INRsMiss food restrictions

If bleeding occurs

Little data availablea. Factor VIIab. Factor VIII Inhibitor Bypassing

Activity (FEIBA)c. Hydration

Fresh frozen plasma and Vitamin K are not the way to go!

Everyone is developing an antidote

Oral anticoagulant inhibits factor Xa

Xa

Inhibitor

Everyone is developing an antidote

A recombinant antidote (DU-176b)

Xa

Surgery while on medication

Dabigatran (100% renal)Rivaroxaban (65% renal clearance)Apixaban (25% renal clearance)

When to stop the medication preoperatively depends on the medication and renal function.

Look it up!

What is the cost per day*

Dabigatran = $9.50Rivaroxaban= $9.46Apixaban = $9.40

*Sam's Club, Northwest Highway, OKC 10/10/13

Advising patients

• Explain they are taking lots of medications – stroke preventers critical • Avoid friendly little black dogs and

get someone else to clean the gutters!

Summary of New Anticoagulants

• Marginally better than warfarin for atrial fibrillation

• No food interactions; few drug interactions• No need for INRs• Short-half life – take regularly• Check creatinine clearance yearly