new oral anticoagulants - ish.org.iltrial age ≥75 results re-ly1,2 7,258 more bleedings in elderly...
TRANSCRIPT
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New Oral Anticoagulants
Pharmacological considerations
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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 ?
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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.
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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
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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.
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New Oral Anticoagulants (DOAC’s)
• Direct Thrombin inhibitors:
• Dabigatran (Pradaxa)
• Factor Xa inhibitors:
• Rivaroxaban (Xarelto)
• Apixaban (Eliquis).
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DOAC’s mechanism of action
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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
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DOAC’s – drug interactions
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DOAC’s – drug interactions
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Dabigatran Drug interactions
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*
*
*
*
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Trough [dabigatran]
One dose fits all ?
Bleeder ?
Stroke ?
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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
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3.5%
1%
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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
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Outcomes in relation to
Renal function
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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
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Expert Rev Cardiovasc. Ther. 11(8), 2013
NOACs in CKD (eGFR <50 ml/min) Renal function
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Age above 75
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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
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NOACs vs. Warfarin
Stroke in the younger and elderly
Barco S, et al. Hematology 2013; 26: 215-224
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NOACs vs. Warfarin
Major bleedings in the younger and elderly
Barco S, et al. Hematology 2013; 26: 215-224
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31
OD or BID dosing ?
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• Acute vs. chronic disease (adherence > 6 mo)
• Clinical study participation
• Drug schedule
• cost
32
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Frost et al. Clinical pharmacology 2014:6
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Treatment of bleeding
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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
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• 12 healthy male volunteers
• RCT - crossover
• Rivaroxaban 20 mg OD, dabigatran 150 mg BID
• Received PCC after each anticoagulant
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Rivaroxaban
Pradaxa
ETP PT
PTT TT
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• 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
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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
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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
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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
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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