Anticoagulanti Orali Diretti
Apixaban is an oral highly selective, reversible direct inhibitor of activated factor X (Fxa) with a half-life of 9-14 hours and an oral bioavailability of approximately 50%. It binds to both free and clot bound Factor Xa. It has been approved in Europe, Canada and United States for thromboprophylaxis in patients undergoing total knee or total hip replacement surgery, for prevention of stroke and systemic embolism in patients with non valvular atrial fibrillation, with one or more risk factors as a previous stroke, a previous transient ischemic attack (TIA), age =/ > 75 years, hypertension, diabetes mellitus, symptomatic heart failure (Class NYHA =/ > 2). (For New York Heart Association Classification see section on “Indications”) for treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) and also for prevention of recurrent DVT and PE. Apixaban has been compared to enoxaparin for the prevention of venous thromboembolism in patients undergoing a knee or a hip replacement surgery in the ADVANCE trials (1) (NEJM 2009 vol. 361 pp. 594-604) (2) (The Lancet 2010 vol. 375 pp. 807-815) (3) (NEJM 2010 vol. 363 pp. 2487-2498) and the results were favorable to the use of apixaban.
In the ARISTOTLE trial, (4) (NEJM 2011 vol. 365 pp. 981-992) apixaban has been compared to warfarin for prevention of stroke and systemic thromboembolism in patients with non valvular atrial fibrillation.
In the AMPLIFY trial, (5) (NEJM 2013 vol. 369 pp. 799-808) apixaban has been compared to standard therapy with enoxaparin and warfarin in the treatment of acute venous thromboembolism.
In the AMPLIFY-EXTENSION trial, (6) (NEJM 2013 vol. 368 pp. 699-708) apixaban was compared to placebo in patients with venous thromboembolism who had already completed 6 to 12 months of anticoagulation therapy and the study was continued for 12 months.
In the ADOPT trial, (7) (NEJM 2011 vol. 365 pp. 2167-2177) the use of an extended thromboprophylaxis with apixaban for 30 days in patients with acute medical illness has been investigated.
In the APPRAISE-2 study, (8) (NEJM, 2011 vol. 365 pp. 699-708) apixaban has been compared to placebo in patients on standard antiplatelet therapy, with a recent acute coronary syndrome (ACS)
All these trials and their results with a critical review, will be discussed in the sections “Indications” and “Conclusions” . Use of apixaban must be avoided with concomitant use of potent inhibitors of CYP3A4 or P-glicoprotein (P-gp) as azole antimicotics and protease HIV inhibitors,and with strong inducers of CYP3A4 and P-glicoprotein(P-gp) such as carbamazepine, phenytoin, phenobarbital, dexamethasone, rifampicine etc. (see section on “Contraindications”). At the moment a phase 3 study designed to test an antidote to the factor Xa inhibitor met its primary efficacy end point, according to an announcement from Portola Pharmaceuticals. An intravenous bolus of andexanet alfa, "immediately and significantly" reversed the anticoagulation of apixaban in the ANNEXA-A study, the company reported. In total, 33 healthy volunteers in the study were treated with apixaban 5 mg twice daily for four days and then randomized to andexanet alfa 400 mg. or placebo. Given the positive results, Portola plans to file an application with the US Food and Drug Administration (FDA) for accelerated approval. (see section on "Adverse reactions") Recently in November 2014, The New England Journal of Medicine published a letter in which a new small synthetic, water-soluble, cationic molecule, PER977 (Arizapine) that is designed to bind specifically to unfractioned heparin (UF) and low molecular weight heparin (LMWH) through non-covalent hydrogen bonding and charge-charge interactions, also binds in a similar way to the new oral factor Xa inhibitors, edoxaban, rivaroxaban and apixaban, and to the oral thrombin inhibitor dabigatran, antagonizing their anticoagulant effect. (9) (New England Journal of Medicine 2014 vol. 371 pp. 2141-2142) For details, see review on Dabigatran, section on "Adverse reactions".
The time in therapeutic range (TTR) in all the studies which involved the DOACs was quite low (55-64%) and far below the 80% achieved, using the INR self-testing with online remote monitoring and management (STORM2) (10) (Journal of Thrombosis and Thrombolysis 2011 vol. 31 (3) pp. 265-274). In the EAA study (11) (Journal of Thrombosis and Haemostasis 2014 vol. 12 pp.1193-1195) using warfarin, the incidence of overall events (% per year) for stroke, major bleedings, minor bleedings and death were 0.30, 0.86, 2.70 and 0.75 per year respectively, that is much less compared with the incidence observed in patients treated with warfarin in DOACs trials. In addition, the annualized incidence of intracranial hemorrhage (ICH) was much lower in atrial fibrillation patients taking warfarin, in the SPORTIF III trial (0.53%) (12) (Lancet 2003 vol. 362 pp. 1691-1698), in the SPORTIF V trial (0.28%) (13) (JAMA 2005 vol. 293 pp. 690-698), in a Cochrane review 0.30% (14) (Cochrane Database of Systematic Reviews 2005 Issue 3 Art. No. CD001927), in another Cochrane Review 0.45% (15) (Cochrane Darabase Review 2007 Issue 3 Art. No. CD006186) than the incidence of ICH in patients taking warfarin in DOACs trials. For this reason, also the statement that DOACs cause less intracranial hemorrhages than warfarin must be taken with caution. As demonstrated in the recent EAA study (11) (Journal of Thrombosis and Haemostasis 2014 vol. 12 pp. 1193-1195), a state of the art laboratory control of warfarin reduces in an impressive manner all the bleeding and thrombotic adverse events. In the so called "real world", at least in western european countries and north america, it is not anymore possible to accept a not optimal laboratory control of vitamin K antagonists treatment, because of the great number of specialized anticoagulation clinics. All the clinicians involved in the oral anticoagulant therapy should refer their patients to these anticoagulation clinics. Only in this manner it is possible to obtain an optimal laboratory control of vitamin K antagonists treatment and consequently to use DOACs in selected cases only. In addition, differently from vitamin K antagonists with the use of DOACs we do not have a laboratory value that will be able to let we know if the patient can receive a surgical procedure without any bleeding. On the contrary, with the use of INR we certainly can say that with a value < 1.4 the patient can receive a major surgery too. (16) (Journal Watch, September 30, 2014 Reader Comments, Vincenzo Marottoli)
The health and the life of our patients is so an important issue that cannot be prevaricated by our personal career and economic interests.
1 ) Lassen Michael Rud, Raskob Gary E., Gallus Alexander et al. : Apixaban or enoxaparin for thromboprophylaxis after knee replacement. New England Journal of Medicine 2009; 361 : 594-604
2 ) Lassen Michael Rud, Raskob Gary E., Gallus Alexander et al. : Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2) : a randomised double-blind trial. The Lancet 2010; 375, issue 9717 : 807-815
3 ) Lassen Michael Rud, Gallus Alexander, Raskob Gary E. : Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. New England Journal of Medicine 2010; 363 : 2487-2498
4 ) Granger Christopher B., Alexander John H., McMurray John J.V. et al. : Apixaban vesus warfarin in patients with atrial fibrillation. New England Journal of Medicine 2011; 365 : 981-992
5 ) Agnelli Giancarlo, Buller Harry R., Cohen Alexander et al. : Oral apixaban for the treatment of acute venous thromboembolism. New England Journal of Medicine 2013; 369 : 799-808
6 ) Agnelli Giancarlo, Buller Harry R., Cohen Alexander et al. : Apixaban for extended treatment of venous thromboembolism. New England Journal of Medicine 2013; 368 : 699-708
7 ) Goldhaber Samuel Z., Leizorovic Alain, Kakkar Ajay K., et al. : Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. New England Journal of Medicine 2011; 365 : 2167-2177
8 ) Alexander John H., Lopes Renato D., James Stefan et al. : Apixaban with antiplatelet therapy after acute coronary syndrome. New England Journal of Medicine 2011; 365 : 699-708
9 ) Ansell Jack E., Bakhru Sasha H., Grosso Michael et al. : Use of PER977 to reverse the anticoagulant effect of edoxaban. New England Journal of Medicine 2014; 371 : 2141-2142
10 ) Bussey Henry I. : Transforming oral anticoagulation by combining international normalized ratio (INR) self testing and online automated management. Journal of Thrombosis and Thrombolysis 2011; 31 (3) : 265-274
11 ) Poller L., Jespersen J and Ibrahim S. : Warfarin or dabigatran for treatment of atrial fibrillation. Journal of Thrombosis and Haemostasis 2014; 12 : 1193-1195
12 ) Executive steering committee on behalf of the SPORTIF III investigators . Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with nonvalvular atrial fibrillation (SPORTIF III) : randomised controlled trial. Lancet 2003; 362 : 1691-1698
13 ) Executive steering committee for the SPORTIF V investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. A randomised trial. JAMA 2005; 293 : 690-698
14 ) Aguilar M.I., Hart R. : oral anticoagulation for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2005; Issue 3 Art. No. : CD001927. DOI: 10.1002/14651858.CD001927.pub2
15 ) Aguilar M.I., Hart R., Pearce L.A. : Oral anticoagulants versus antiplatelet therapy for preventing styroke in patients
with non-valvular atrial fibrillation and no history of stroke or vtransient ischemic attacks. Cochrane Database of Systematic Reviews 2007, Issue 3 Art. No. : CD006186. DOPI: 10.1002/14651858.CD006186.pub2
16 ) Green David : Are new oral anticoagulants safer than vitamin K antagonists? Journal Watch, September 30, 2014 Readers Comments,Vincenzo Marottoli http://jwatch.org/na35816/2014/09/30/are-new-oral-anticoagulants-safer-vitamin-K-antagonists