New Oral Anticoagulants

Pharmacological considerations

New oral anticoagulants

• The “ideal” anticoagulant.

• Metabolic pathways – Drug-drug interactions

• One dose fits all ???

• Special sub-groups of patients.

• NOAC’s-induced bleeding complications – how to treat ?

Why not warfarin ?

• Narrow therapeutic index

• Large inter-individual variability in dose-effect relationship.

• Slow onset of action

• Slow offset of action (pharmacokinetic and pharmacodynamic)

• Multiple drug and dietary interactions

• Requires monitoring to maintain in therapeutic range.

Why not warfarin ?

• Efficacy is dependent upon infrastructure:

• TTR (time in therapeutic range) is

associated with improved safety and

efficacy.

• TTR is improved with specialized AC

programs.

• TTR is improved in countries with

developed health care infrastructure

The “ideal” anticoagulant

• Oral administration.

• Rapid onset/offset of action.

• Wide therapeutic range.

• Predictable therapeutic effect with fixed or weight-based dosing.

• No drug-drug or drug-food interactions.

• No monitoring required (but ability to monitor is desired)

• Easily reversible

• Well defined pharmacokinetics in renal dysfunction.

• Cost-effective.

New Oral Anticoagulants (DOAC’s)

• Direct Thrombin inhibitors:

• Dabigatran (Pradaxa)

• Factor Xa inhibitors:

• Rivaroxaban (Xarelto)

• Apixaban (Eliquis).

DOAC’s mechanism of action

Dabigatra השם הגנרי

n

Rivaroxaba

n

Apixaban

®PRADAXA® XARELTO® ELIQUIS השם המסחרי

Direct thrombin מנגנון פעולה

inhibitor,

reversible

Factor Xa

inhibitor,

reversible

Factor Xa

inhibitor,

reversible

Pro-drug לא לא כן

3-7% זמינות ביולוגית קיבה ריקה 66%

עם אוכל~ 90%50%

זמן מחצית חיים

(שעות)12-14 5-13 8-14

כבדי כבדי כבדי מטבוליזם

לא CYPמטבוליזם י "בעיקר ע

CYP3A4/5

י "בעיקר ע

CYP3A4/5

כן כן כן P-gpסובסטרט של

27% 33% 80% פינוי כלייתי% התאמת מינון

כ "באס

נדרשת נדרשת נדרשת

-מעלה ספיגה בכ אין השפעה השפעה למזון

40%

אין השפעה

DOAC’s – drug interactions

DOAC’s – drug interactions

Dabigatran Drug interactions

*

*

*

*

Trough [dabigatran]

One dose fits all ?

Bleeder ?

Stroke ?

A pre-specified analysis of RE-LY

9183 patients tested on 110 + 150 BID doses

Analyzed-

112 SSE events (1.3%)

323 bleeding events (3.8%)

1◦ outcome – blood level and risk of AE

DAB levels depended on – renal function, age, weight, female gender

3.5%

1%

Source FDA EMA

Dose 150 bid

75 bid ?

150 bid

110 bid

Dose adjustment NO Age > 75

Therapeutic level -- 48-200 ng/ml

Mandatory monitoring ? NO YES

Outcomes in relation to

Renal function

Trial eGFR <50 ml/min Results

RE-LY1,2 3,505 Consistent

results*

ROCKET-

AF3 2,950

Consistent

results**

ARISTOTLE4

3,017

Less bleeding in

patients with

CKD**

NOACs in CKD (eGFR <50 ml/min)

1. Connolly SJ, et al. N Engl J Med 2009;361:1139–1151; 2. Eikelboom JW, et al.

Circulation 2011;123:2363-2372;

3. Patel MR, et al. N Engl J Med 2011;365:883–891; 4. Granger CB, et al. N Engl J Med

2011;365:981–992

* Dose was randomized

**Dose reduced in patients with renal impairment and/or those at risk of

bleeding

Expert Rev Cardiovasc. Ther. 11(8), 2013

NOACs in CKD (eGFR <50 ml/min) Renal function

Age above 75

Trial AGE ≥75 Results

RE-LY1,2 7,258 More Bleedings in

Elderly Patients

ROCKET-

AF3 6,229

Consistent

results

ARISTOTLE4

5,678 Consistent

results

NOACs in Elderly Patients (AGE

≥75)

1. Connolly SJ, et al. N Engl J Med 2009;361:1139–1151; 2. Eikelboom JW, et al.

Circulation 2011;123:2363-2372;

3. Patel MR, et al. N Engl J Med 2011;365:883–891; 4. Granger CB, et al. N Engl J Med

2011;365:981–992

* Dose was randomized

**Dose reduced in patients with renal impairment and/or those at risk

of bleeding

NOACs vs. Warfarin

Stroke in the younger and elderly

Barco S, et al. Hematology 2013; 26: 215-224

NOACs vs. Warfarin

Major bleedings in the younger and elderly

Barco S, et al. Hematology 2013; 26: 215-224

31

OD or BID dosing ?

• Acute vs. chronic disease (adherence > 6 mo)

• Clinical study participation

• Drug schedule

• cost

32

Frost et al. Clinical pharmacology 2014:6

Treatment of bleeding

BLEEDING

GENERAL OTHER REPLACEMENT ANTIDOTE ?

Apixaban Rivaroxaban PRADAXA Measure

NO data Charcoal

Not likely to help. NO data. Hemodialysis

NO data FFP

? ? PCC

? rFVIIa

NA rFX

soon soon soon Antidot

36

• 12 healthy male volunteers

• RCT - crossover

• Rivaroxaban 20 mg OD, dabigatran 150 mg BID

• Received PCC after each anticoagulant

Rivaroxaban

Pradaxa

ETP PT

PTT TT

• 5 patients on dabigatran

• All on 110 mg BID for a median of 27 days Rx duration

• One patient died of bleeding and sepsis

• In 4 bleeding stopped. NO thrombosis at 6m FU

Specific antidote

IDAROCIZUMAB – fully humanized Fab administered IV

High affinity to DAB (X350)

NO pro or antithrombotic effects

Short half life

NO other endogenous targets

344 Idarucizumab, a Specific Antidote for

Dabigatran: Immediate, Complete and Sustained

Reversal of Dabigatran Induced Anticoagulation in

Elderly and Renally Impaired Subjects

IDAROCUZIMAB – 2 RCTs on healthy volunteers and renally impaired (mild-moderate)

Increasing doses 1, 2.5. 2,5 BID, 5 mg

Complete reversal of DAB w/o side effects

Modified factor X (rFX)

Removal of active + GLA binding sites

Xa inhibitor binding not affected

No effect of FX activity when administered alone

43

X X

Specific antidote

ANDEXANATE ALFA – Portola pharmaceuticals

Phase I+II studies – 65 patients

> 90% inhibition of Apixaban within 2 minutes lasting 120 minutes ( with infusion)

No Abs, no thrombosis