Anticoagulant Usage for Mechanic Cardiac Valve Replaced Patients and Warfarin Resistance

Abstract

Objectives:  To evaluate the treatment choices applied to patients with mechanical heart valves who were determined as resistant to warfarin.

Materials and Method: The study comprised 40 patients (22 male, 18 female; mean age 58.15 years) who had been fitted with mechanical heart valves and were under International Normalised Ratio (INR) monitoring between 2006 and 2014. Until the target level was achieved, INR monitoring was applied once a week and thereafter once a month. The INR target values were applied as 2-3 for mechanical valves in the aorta position and as 2.5-3.5 for mechanical valves in other positions and for high-risk patients. Patients using a weekly dose of <75mg warfarin were evaluated as the normal dose group and those using ≥ 75mg warfarin were evaluated as the high dose group. 

Results: The INR monitoring period of the patients ranged from 1 month to 28 years (mean 10.22 years). The normal dose group comprised 36 patients (90%) and the high dose group 4 (10%). In 3 of the high dose group, the target INR values were obtained with an increased dose of Coumadin and in 1 patient, the target INR level was reached with 300mg/day acetyl salicylic acid together with warfarin. 

Conclusion: Warfarin resistance in individuals using anti-coagulant medications has been reported at approximately 5%. There are acquired and genetic factors which affect the warfarin dose. When warfarin resistance is encountered, firstly the patient must be questioned in detail as to medication compatibility for concomitant diseases and interaction of diet or medications with warfarin. When it has been determined that these factors are not present, then genetic factors should be considered. Increased treatment dose for patients determined as warfarin-resistant should be a combination of warfarin with low molecular weight heparin or combined clopidogrel and acetyl salicyclic acid. 

 

Keywords

• Warfarin, Warfarin resistance

Mekanik Kalp Kapaklı Hastalarda Antikoagülan Kullanımı ve Warfarin Direnci

Öz

Amaç: Mekanik kalp kapağı olan hastalarda warfarin direnci olanlar  tespit edildi ve bu hastalarda uygulanan tedavi seçenekleri değerlendirildi.

Materyal ve Metot: Çalışmaya 2006-2014 yılları arasında ınr takipleri yapılan mekanik kalp kapağı takılmış 40 hasta (18 kadın, 22 erkek; ortalama yaş 58,15) dahil edildi. Inr takipleri hedef düzey tutturulana kadar haftada bir kez daha sonra ayda bir yapıldı. Hedef ınr olarak aort pozisyonundaki mekanik kapaklar için  2- 3,  diğer pozisyonlardaki mekanik kapaklar ve yüksek riskli hastalarda 2,5 – 3,5 değerleri uygulandı. Haftada 75 mg altı dozlarda warfarin kullanan hastalar normal doz grubu, 75 mg ve üstü dozlarda warfarin kullanan hastalar ise yüksek doz grubu olarak değerlendirildi.

Bulgular: Hastaların ınr takip süreci 1 ay ile 28 yıl arasında değişiyordu ( ortalama 10,22 yıl).  Normal doz grubu olarak değerlendirilen haftada 75 mg dan az warfarin kullanan hasta sayısı 36 idi(%90). Yüksek doz grubu olarak değerlendirilen haftada 75 mg dan fazla warfarin kullanan hasta sayısı 4 idi(%10). Yüksek doz grubundaki hastalardan 3 ünde hedef INR değerleri coumadin doz artımı ile sağlandı, bir hastada ise warfarin ile birlikte günde 300 mg asetil salisilik asit kullanılarak hedef INR düzeyine ulaşıldı.

Sonuç: Antikoagülan ilaç kullanan kişilerde warfarin direnci sıklığı yaklaşık %5 dir. Warfarin dozunu etkileyen edinsel ve genetik faktörler vardır. Warfarin direnci ile karşılaşıldığında öncelikli olarak ayrıntılı bir şekilde hastanın ilaç alımına uyumu, eşlik eden hastalıklar, warfarin ile etkileşen diyet ve ilaç alımı sorgulanmalı, bu faktörlerin mevcut olmadığı tesbit edildiğinde genetik faktörler akla gelmelidir. Warfarin direnci tespit edilen hastalarda uygulanan tedavi doz artımı, kombine düşük molekül ağırlıklı heparin kullanımı ya da warfarinin clopidogrel ve asetil salisilik asit ile kombine edilmesidir.

 

Anahtar Kelimeler

• Warfarin, Warfarin direnci

Kaynakça

1. Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic therapy in children. Chest 2001;119:344- 70.
2. Hirsh J, Dalen J, Anderson DR, Puller L, Bussey H, Ansell J et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001;119:8-21.
3. Ansell J, Hirsh J, Dalen J, Bussey H, Anderson D, Poller L et al.Managing oral anticoagülant therapy. Chest 2001; 119:22-38.
4. Gage BF, Lesko LJ.Pharmacogenetics of Warfarin :regulatory, scientific and clinical issues. J Thromb Thrombolysis 2008;25:45-51.
5. D’Andrea G, D’Ambrosio R, Margaglione M. Oral anticoagulants: pharmacogenetics. Relationship between genetic and non-genetic factors. Blood Rev 2008;22:127-40.
6. Oldenburg J, Watzka M, Rost S, Müller CR. VKORC1:molecular target of coumarins. J Thromb Haemost 2007;5:1-6.
7. Orsi FA, Annichino Bizzacchi JM, de Paula EV. VKORC1 V66M mutation in African Brazilian patients resistant to oral anticoagulant therapy. Thromb Res 2010;126:206-10.
8. Vaquez SR, Rondina MT, Pendleton RC. Azathioprine-induced Warfarin resistance. Ann Pharmacother 2008;42:1118-23.

9. Dickerson RN, Garmon WM, Kuhl DA, Minard G, Brown RO. Vitamin K-independent Warfarin resistance after concurrent administration of Warfarin and continuous enteral nutrition. Pharmacotherapy 2008;28:308- 13.
10. Carr ME, Klotz J, Bergeron M. Coumadin resistance and the vitamin supplement ‘Noni’. Am J Hematol 2004;77:103.
11. Demirbağ R.Warfarin kullanan hastalarda genotip tayini istenmeli mi? Türk Kardiyol Dern Arş 2010;38:283- 4.
12. Kosaki K, Yamaghishi C, Sato R.1173C>T polymorphism in VKORC1 modulates the required Warfarin dose. Pediatr Cardiol 2006;27:685-88.
13. Nowak –Gottl U, Dietrich K, Schaffranek D. In pediatric patients ,age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes Blood 2010;116:6101-5.
14. Marusic S, Gojo-Tomic N, Franic M, Bozina N.Therapeutic efficacy of acenocoumarol in a Warfarin- resistant patient with deep venous thrombosis:a case report.Eur J Clin Pharmacol 2009;65.1265-6.
15. Bodin L, Horellou MH, Flaujac C. A vitamin K epoxide reductase complex subunit -1 (VKORC1) mutation in a patient with vitamin K antagonist resistance. J Thromb Haemost 2005;3:1533-5.