Abstract

Acenocoumarol and phenprocoumon are the other two vitamin K antagonists that are used in the treatment of venous thromboembolic disease, thromboembolic prophylaxis of atrial fibrillation and of cardiac valve replacement.
Acenocoumarol is the second vitamin K antagonist used in Europe after warfarin, and phenprocoumon is used pricipally  in Germany and Holland. Because of their narrow therapeutic range,many patients have bleedings of variable severity or have recurrent thrombotic events. As for warfarin, patients treated with these drugs need an individual dose guided by laboratory monitoring of prothrombin time by INR. Also for acenocumarol and phenprocoumon there are many interactions with some foods and many drugs that are about the same observed with warfarin. As we discussed in the review “ Warfarin part I”,(see abstract) and in the reviews about new oral anticoagulants, comparing these last drugs with the old vitamin K antagonists, there is not a clear clinical advantage of new oral anticoagulants over vitamin K antagonists in west countries that have a good clinical and laboratory control of oral anticoagulant therapy, especially in specialized anticoagulation clinics, also if influential medical thought leaders are out in force to exert their influence in convincing other physicians and especially patients, of the enthusiastic pharmacologic properties of these new class of drugs and of the fact that these drugs do not need laboratory control. In fact, also if new oral anticoagulants have a predictable pharmacokinetics and pharmacodynamics, there are not only many particular circumstances in which we need a laboratory control, but also in normal circumstances, as for example 1-2 weeks after the beginning of the treatment, when a “steady state” is reached,  we need a laboratory control to know the drug concentration in that particular patient we are treating. Again, every two or three months, it is better to control patients who are taking these drugs, not only clinically, but by a laboratory test too. For all these reasons, these new oral anticoagulants can be used only in a restricted number of cases, as in patients who cannot reach the specialized anticoagulation clinics for personal or health problems, in patients who have a very unstable INR when they are in therapy with vitamin K antagonists, in patients who refuse a blood test every 3-4 weeks, or in patients who had an intracranial bleeding while they were in therapy with vitamin K antagonists, because of the high percentage of recurrence when they restart vitamin K antagonists therapy again, as demonstrated in the Italian Collaborative CHIRONE (Cerebral Haemorrhage In patients Restarting Oral aNticoagulant thErapy)     study (1) (Neurology 2014 vol. 82 pp. 1-7) All the clinical studies in which the new oral anticoagulants were studied, were sponsored by drug manufacturers. Obviously this created a bias, because from the authors, analyzing the results, were emphasized some statistical parameters as Relative Risk reduction (RRR) and not other parameters as Absolute Risk Reduction (ARR) and its opposite that is the Number Needed to Treat (NNT) (2) (Canadian Medical Journal Association 2004 vol. 171 pp. 353-358)  that really give a true interpretation of the clinical results. What we really need are manufacturer independent trials sponsored by governmental agencies, also if this will cost a great amount of public money. The most important adverse reaction of these vitamin K antagonists as for warfarin is bleeding but,differently from the new oral anticoagulants that have not an antidote commercially available to reverse their anticoagulant effect, we can use Prothrombin Complex Concentrates (PCCs) to reverse the anticoagulant effect of these vitamin K antagonists not only in case of an important bleeding, but also in case of an emergency surgery. All these vitamin K antagonist as warfarin exert their anticoagulant effect inhibiting the γ-carboxylation of vitamin K-dependent clotting factors II, VII, IX, X, and vitamin K dependent proteins C, S, Z, osteocalcin and the GLA matrix,  whereas the pharmacokinetic properties differ distinctly. As for warfarin the interference of these drugs with Osteocalcin and  with the GLA matrix can be responsible for important clinical effects such as osteoporosis and heart valves calcification respectively.  As for warfarin, before starting a therapy with these vitamin K antagonists, we must carefully evaluate the bleeding and the thrombotic risk of a patient using our clinical judgement and some bleeding and thrombotic scores. Now a new vitamin K antagonist, tecarfarin, has been developed. This new drug avoids cytochrome P450 (CYP) related  metabolism and transport by P-glycoprotein (P-gp) which are a major cause of safety and efficacy problems related to the use of warfarin but, also to a less extent, to the use of DOAs. For this, tecarfarin does not interfere with other drugs and furthermore can be administered to patients with severe chronic renal insufficiency (CrCl < 30 ml/min) without problems because it is not excreted via the kidney. Current data indicates that tecarfarin may not require frequent monitoring unlike warfarin. (3) (www.armetheon.com)
 

References :

1 )  Poli Daniela, Antonucci Emilia, Dentali Francesco et al.  : Recurrence of ICH after resumption of anticoagulation with VK antagonists. CHIRONE Study.  Neurology 2014; 82 : 1-7
2 )  Barratt Alexandra, Wyer Peter C, Hatala Rose et al.  : Tips for learners of evidence-based medicine : Relative risk reduction, absolute risk reduction and number needed to treat. Canadian Medical Journal Association 2004; 171 (4) :
353-358
3 )  Press Release : A novel oral anticoagulant to be developed for patients with prosthetic heart valves or chronic renal dysfunction : www.armetheon.com : March 8, 2013


 

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