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Apiksaban
Dr. Murat Özdemir
Gazi Üniversitesi, ANKARA
AF Zirvesi, Nisan 2015, ANTALYA
S1
S4
Gln 192
Arg 143 Gly 216
Tyr 99
Phe 174
Trp 215
Cys 220
Cys 191
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Doğrudan faktör Xa inhibisyonu - apiksaban
Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:1238-1247. Ansell J. J Thromb Haemost 2007;5(suppl1):60-64.
Apiksaban
fXa fXa Protrombin Fibrin pıhtısı
Apiksaban pıhtıya veya protrombinaz kompleksine bağlı olan
Faktör Xa’yı inhibe eder
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Apiksaban - farmakokinetik
Emilim
– Tüm GIS boyunca
– Yoğun olarak distal ince barsak ve çıkan kolon
– Zirve plazma konsantrasyonu yaklaşık 3 - 4 saatte
– Gıda varlığından etkilenmez
Lam S. Card in Rev, 2013, e-pub ahead of print. DOI: 10.1097/CRD.0b013e318293d6e6
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Metabolizma/Atılım
–Yarılanma zamanı yaklaşık 12 saat
–CYP3A4 tarafından metabolize edilir – aktif metaboliti
yoktur
–Renal klirens – total klirensin yaklaşık % 27’sinden
sorumlu
–P-glikoprotein substratıdır
Apiksaban - farmakokinetik
Lam S. Card in Rev, 2013, e-pub ahead of print. DOI: 10.1097/CRD.0b013e318293d6e6
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AVERROES çalışması
Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial
Fibrillation Patients Who Have Failed or are Unsuitable for
Vitamin K Antagonist Treatment
Connolly SJ et al. N Engl J Med 2011;364:806–817.
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N=5,599
Aspirin 81–324 mg OD
Apiksaban 5 mg BD (2.5 mg – en az ikisi varsa
Yaş≥80, VA≤60 kg, krea≥1.5mg/dL)
Hasta populasyonu
Nonvalvüler AF ve en az bir inme risk faktörü
Warfarin kullanamamış veya kullanamayacağı düşünülen olgular
Primer sonlanım
İskemik inme, hemorajik inme veya sistemik emboli
AVERROES - tasarım
Connolly SJ et al. N Engl J Med. 2011;364:806–817
Eikelboom JW et al. Am Heart J 2010;159:348–353.e1.
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AVERROES
Ortalama CHADS2 skoru = 2.1
Medyan 1.1 yıl takip sonunda erken sonlandırıldı
Hastaların % 94’ünde apiksaban 5 mg BID
Connolly SJ et al. N Engl J Med 2011;364:806–817
*Clinicaltrials.gov NCT00496769
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AVERROES – İnme ve sistemik emboli
No. at Risk
Aspirin 2791 2716 2530 2112 1543 628
Apixaban 2808 2758 2566 2125 1522 615
HR = 0.45 (95% CI, 0.32–0.62)
0 3 6 9 12 18
0.00
0.01
0.02
0.03
0.04
0.05
Aspirin
Apiksaban
p<0.001
Connolly SJ et al. N Engl J Med 2011;364:806–817
Aylar
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No. at Risk
Aspirin 2791 2738 2557 2140 1571 642
Apixaban 2808 2759 2566 2120 1521 622
AVERROES - Majör kanama
HR = 1.13 (95% CI, 0.74–1.75)
Aspirin
Apiksaban
p=0.57
0 3 6 9 12 18
0.00
0.005
0.010
0.015
0.020
Connolly SJ et al. N Engl J Med 2011;364:806–817
Aylar)
Cu
mu
lati
ve h
azard
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AVERROES – Ciddi yan etkiler
Apiksaban (%) Aspirin (%) p
En az 1 ciddi istenmeyen olay 22.2 27.2 <0.001
Kardiyak sorunlar 11.3 12.1 0.32
Aritmiler 4.3 4.5 0.66
Koroner arter sorunları 2.2 2.5 0.46
Kalp yetmezliği 4.3 4.7 0.53
Gastrointestinal sorunlar 2.4 2.8 0.38
Genel sorunlar 2.4 2.8 0.38
Enfeksiyonlar 4.2 5.3 0.045
Sinir sistemi sorunları 3.0 6.6 <0.001
Yaralanma, prosedürel komplikasyonlar 2.2 2.2 0.97
Connolly SJ et al. N Engl J Med 2011;364:806–817 in supplementary appendix
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Çalışma ilacının kalıcı biçimde bırakılması
2 yılda :
– Apiksaban kolunda % 17.9
– Aspirin kolunda % 20.5
HR = 0.88 (95% CI 0.78-0.99, p=0.03)
Connolly SJ et al. N Engl J Med 2011;364:806–817
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N Engl J Med 2011;365:981-92
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N=18,201
Hasta populasyonu
Nonvalvüler AF ve en az biri :
Yaş ≥ 75
İnme/TIA/emboli öyküsü
Son 3 ayda semptomatik KY veya LVEF ≤ 0.40
Diabetes mellitus
HT
Primer Etkinlik sonlanımı
İnme veya sistemik emboli
Temel Sekonder Etkinlik sonlanımı
Tüm nedenlere bağlı ölüm
Primer emniyet sonlanımı
Majör kanama
ARISTOTLE - tasarım
Warfarin (hedef INR 2.0−3.0)
Apiksaban 5 mg BD
(2.5 mg BD bazı olgularda)†
Randomize
çift-kör,
double-dummy
†en az ikisi: yaş ≥ 80 ; VA ≤ 60 kg; serum kreatinin ≥ 1.5 mg/dL
Granger CG et al. N Engl J Med 2011;10.1056
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% 85 persistan/kalıcı AF
Ortalama CHADS2 skoru =
2.1
% 5 olguda 2.5 mg doz
Takip
– Medyan 1.8 yıl takip
– 69 hasta izlemde kayıp
Warfarin kolunda TTR
Ortalama % 62
İlaç bırakma oranları :
– Warfarin % 27.5
– Apiksaban % 25.3
ARISTOTLE
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ARISTOTLE – İnme veya sistemik emboli
P<0.001 (non-inferiyorite)
HR 0.79 (95% CI, 0.66–0.95); P=0.01 (superiyorite)
No. at Risk
Apiksaban 9120 8726 8440 6051 3464 1754
Warfarin 9081 8620 8301 5972 3405 1768
21% RRR
Ola
y g
örü
len
has
tala
r (
%)
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N Engl J Med 2011;365:981-92
ARISTOTLE
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ARISTOTLE – majör kanama
HR 0.69 (95% CI, 0.60–0.80); P<0.001
No. at Risk
Apiksaban 9088 8103 7564 5365 3048 1515
Warfarin 9052 7910 7335 5196 2956 1491
31% RRR
Ola
y g
örü
len
has
tala
r (
%)
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ARISTOTLE – istenmeyen olaylar
N (%) Apixaban
(N=9088) Warfarin
(N=9052)
İstenmeyen olay - toplam 7406 (81.5) 7521 (83.1)
Ciddi istenmeyen olay - toplam 3182 (35.0) 3302 (36.5)
İstenmeyen olaya bağlı ilaç bırakılması 688 (7.6) 758 (8.4)
Granger CG et al. N Engl J Med 2011;10.1056/NEJMoa1107039 supplementary appendix. NEJM.org 28 August 2011
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ARISTOTLE - sonuç
Warfarine kıyasla apiksaban :
– İnme ve sistemik emboli riskinde % 21 (p=0.01)
– Majör kanama riskinde % 31 (p<0.001)
– Ölüm riskinde % 11 (p=0.047) azalmaya yol açmıştır.
Bulgular tüm alt gruplarda benzer ve tutarlıdır
Apiksabanın kabul edilebilir bir yan-etki profili ve warfarinden daha az
ilaç bırakma oranı vardır
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1.8 yıl süreyle tedavi edilen her 1000 hastada,
warfarine kıyasla apiksaban ile önlenen olaylar :
İnme 6 hastada (hemorajik 4, iskemik 2)
Majör kanama 15 hastada
Ölüm 8 hastada
Granger CG et al. N Engl J Med 2011;10.1056/NEJMoa1107039. NEJM.org 28 August 2011
ARISTOTLE sonuç
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Nonvalvüler AF’da tromboembolinin önlenmesi için öneriler - Genel Sınıf Kanıt
Nonvalvüler AF’da inme riskini belirlemede CHADSVASc skoru önerilir I A
CHADSVASc skoru = 0 ise antitrombotik tedavi önerilmez I A
CHADSVASc skoru ≥ 2 ise;
Warfarin (INR=2-3) veya
Dabigatran veya
Apiksaban veya
Rivaroksaban
I A
CHADSVASc skoru = 1 ise;
Warfarin (INR=2-3) veya
Dabigatran veya
Apiksaban veya
Rivaroksaban
Kanama riski ve hasta tercihi de dikkate alınarak
IIa A
Sadece cinsiyet nedeniyle CHADSVASc skoru = 1 olan olgularda antitrombotik tedavi
verilmemesi düşünülmelidir
IIa B
Hasta herhangi bir OAK kullanmayı reddediyorsa, ASA 75-100 mg + klopidogrel 75 mg
(kanama riski düşükse) veya sadece ASA 75-325 mg düşünülmelidir
IIa B
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Nonvalvüler AF’da tromboembolinin önlenmesi için öneriler – Yeni oral antikoagülanlar Sınıf Kanıt
OAK endikasyonu olan ancak warfarin(INR=2-3) kullanamayan olgularda;
Dabigatran veya
Apiksaban veya
Rivaroksaban
I B
OAK endike olduğunda, olguların çoğunda warfarin(INR=2-3) yerine
Dabigatran veya
Apiksaban veya
Rivaroksaban
düşünülmelidir
IIa A
Dabigatran kullanılacak olursa, olguların çoğunda 150 mg BD dozu düşünülmeli; 110 mg BD
dozu aşağıdaki durumlarda önerilmelidir
Yaş ≥ 80
İlaç etkileşimi (verapamil gibi)
HASBLED skoru ≥ 3
Kreatinin klirensi 30-49 mL/dak
IIa B
Rivaroksaban kullanılacak olursa, olguların çoğunda 20 mg OD dozu düşünülmeli; 15 mg OD
dozu aşağıdaki durumlarda önerilmelidir
HASBLED skoru ≥ 3
Kreatinin klirensi 30-49 mL/dak
IIa C
Yeni oral antikoagülan kullanılan olgularda böbrek fonksiyonları başlangıçta ve izlemde yılda
bir kreatinin klirensi hesaplanarak değerlendirilmelidir. Başlangıçta orta derecede böbrek
fonksiyon bozukluğu olanlarda takipte yılda 2-3 değerlendirme önerilir
IIa B
Kreatinin klirensi 30 mL/dak altında olanlarda yeni oral antikoagülanlar kullanılmamalıdır III A
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(Circ Heart Fail. 2013;6:451-460.)
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Tüm kanamalar
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İlaç etkileşmeleri
Kuvvetli CYP3A4 ve P-Gp inhibitörü alanlarda doz 2.5 mg olmalı
– Ketokonazol, itrakonazol, ritonavir, klaritromisin
Kuvvetli CYP3A4 ve P-Gp indükleyicilerinden uzak durulmalı
– Rifampin, karbamezapin, fenitoin
Kanama riskinin artabileceği durumlar
– ASA, diğer antikoagülanlar, DAPT, NSAID
Önemli etkileşim yok
– Famotidin, atenolol, digoksin, amiodaron
Lam S. Card in Rev, 2013, e-pub ahead of print. DOI: 10.1097/CRD.0b013e318293d6e6
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Uyarılar
Ciddi KC yetmezliğinde kullanılmamalı
Gebelikte kategori B
Kr klirensi < 15 mL/dak veya diyaliz – kullanılmamalı
Lam S. Card in Rev, 2013, e-pub ahead of print. DOI: 10.1097/CRD.0b013e318293d6e6
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Kontrendikasyonlar
Valvüler AF
Protez kapak
Allerji
Aktif kanama
Lam S. Card in Rev, 2013, e-pub ahead of print. DOI: 10.1097/CRD.0b013e318293d6e6
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Koagülasyon izlemi - Lab
INR uygun değil
aPTT uygun değil
Anti Fxa aktivitesi ?
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Anti FXa aktivitesi apiksabanın plasma düzeyleri ile yakın
direkt ilişki gösterir
Anti-faktör Xa chromogenic assay (Diagnostica Stago Rotachrom® Heparin)
apiksabanın plazma düzeylerini değerlendirmek için uygun olabilir
0 100 200 300 400 500 600 700 800 900 0
100
200
300
400
500
600
700
800
900
Apiksaban plazma düzeyi (ng/ml)
An
ti-X
a (
ap
ixab
an
un
it)
(ng
/ml)
r2=0.8794
Barrett et al. Thromb Haemost 2010;104:1263-71
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Anti- FXa aktivitesi
Klinik olaylarla korelasyon net değil
Doz modifikasyonuna kılavuzluk edemez
Kullanılabileceği durumlar
– Kompliyansın kontrolü
– Doz aşımı
– Acil durumlar – kanama, acil cerrahi gereksinimi gibi
Jimenez D. Adv Ther 2012;29:187
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Doz aşımı veya kanama
Antidot yok
– PCC
– aFVII
– TDP
Antikoagülan etki son dozdan sonra 24 saat devam
eder
Diyaliz faydalı değil
Aktif kömür
Lam S. Card in Rev, 2013, e-pub ahead of print. DOI: 10.1097/CRD.0b013e318293d6e6
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Pratik ipuçları
Girişim öncesi ne zaman kesilmeli ?
– Yüksek kanama riskli girişim – 48 saat
– Düşük kanama riskli girişim - 24 saat
Warfarinden geçiş – INR < 2.0 olunca
Lam S. Card in Rev, 2013, e-pub ahead of print. DOI: 10.1097/CRD.0b013e318293d6e6
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