New Oral Anticoagulants. Pharmacological considerations

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 doseeffect 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

Apixaban ELIQUIS Factor Xa inhibitor, reversible לא 50% 8-14 Rivaroxaba n XARELTO Factor Xa inhibitor, reversible לא 66% קיבה ריקה 90%~ עם אוכל 5-13 Dabigatra n PRADAXA Direct thrombin inhibitor, reversible כן 3-7% 12-14 כבדי לא כן כבדי בעיקר ע"י CYP3A4/5 כן כבדי בעיקר ע"י CYP3A4/5 כן 27% 33% 80% השם הגנרי השם המסחרי מנגנון פעולה Pro-drug זמינות ביולוגית זמן מחצית חיים )שעות( מטבוליזם מטבוליזם CYP סובסטרט של P-gp % פינוי כלייתי התאמת מינון באס"כ השפעה למזון נדרשת אין השפעה נדרשת מעלה ספיגה בכ- נדרשת אין השפעה

DOAC s drug interactions

DOAC s drug interactions

Dabigatran Drug interactions

* * * *

One dose fits all? Trough [dabigatran] 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

1% 3.5%

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

NOACs in CKD (egfr <50 ml/min) Trial egfr <50 ml/min Results RE-LY 1,2 3,505 ROCKET- AF 3 ARISTOTLE 4 2,950 3,017 Consistent results* Consistent results** Less bleeding in patients with CKD** * Dose was randomized **Dose reduced in patients with renal impairment and/or those at risk of bleeding 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

NOACs in CKD (egfr <50 ml/min) Renal function Expert Rev Cardiovasc. Ther. 11(8), 2013

Age above 75

NOACs in Elderly Patients (AGE 75) Trial AGE 75 Results RE-LY 1,2 7,258 ROCKET- AF 3 ARISTOTLE 4 6,229 5,678 More Bleedings in Elderly Patients Consistent results Consistent results * Dose was randomized **Dose reduced in patients with renal impairment and/or those at risk of bleeding 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

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

OD or BID dosing? 31

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? Measure Charcoal Hemodialysis FFP PCC rfviia rfx Antidot PRADAXA? NA soon Rivaroxaban Apixaban NO data Not likely to help. NO data. NO data soon?? soon 36

12 healthy male volunteers RCT - crossover Rivaroxaban 20 mg OD, dabigatran 150 mg BID Received PCC after each anticoagulant

PT ETP Rivaroxaban Pradaxa 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

Specific antidote Modified factor X (rfx) Removal of active + GLA binding sites Xa inhibitor binding not affected No effect of FX activity when administered alone X X 43

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