Abstract

Warfarin is a vitamin K antagonist that is used for prevention or treatment of venous thromboembolic disease, thromboembolic prophylaxis of atrial fibrillation and of cardiac valve replacement,and occasionally after myocardial infarction.  At the moment, it is the most used oral anticoagulant in the world, also if the new oral anticoagulants prescribed principally by cardiologists and internists are becoming  new drugs used in some indications in which warfarin is normally used, principally in non valvular atrial fibrillation.
Two recent meta-analyses have been published.  In the meta-analysis published on (1) The Lancet on line on December 4, 2013, the efficacy and the safety of new oral anticoagulants have been compared with warfarin in patients with atrial fibrillation, and a significant reduction in the relative risk of stroke, intracranial hemorrhage (ICH) and mortality has been reported. The authors emphasize a halving of the relative risk of ICH. In the meta-analysis published on (2) JAMA Neurology 2013 vol. 70 pp. 1486-1490, the authors studied the risk of ICH in patients with atrial fibrillation treated with new oral anticoagulants and in patients treated with warfarin. They have also reported a relative risk reduction of ICH of about 50%. In these cases is crucial to look at absolute, and not relative risks of each drug.  If we look at absolute risk reduction of ICH,  we can see that in the JAMA Neurology meta-analysis, the absolute risk  was 0.58% with new oral anticoagulants (NOA) and 1.24% with warfarin. So the absolute risk reduction between the two groups was only 0.66%. For 151 of 152 patients treated, there was no difference between NOA and warfarin. This means that a patient enrolled in the three randomized clinical trials has a 99.4% chance of not having an ICH on a NOA, compared to a 98.8% chance of not having one on warfarin. In the Lancet meta-analysis there were 911 stroke or systemic embolism events in patients treated with NOA and 1107 in patients treated with warfarin. The absolute risk reduction was 0.7% . In this case, 141 of 142 patients treated with NOA received no benefit over warfarin.  In this meta-analysis a patient with atrial fibrillation has a 96.9% chance of not having an embolic event on a NOA drug, compared to a 96.2% chance of not having one on warfarin. (3) (www.medscape.com/viewarticle/818013) Papers that emphasize Relative Risk Reduction (RRR) and not Absolute Risk Reduction and is opposite that is the Number Needed to Treat (NNT) present a bias about the results obtained. These last two parameters, applied to clinical trials published on leading medical journals, are very important for the readers, to achieve the best clinical decisions to apply in their daily medical practice. (4) (Canadian Medical Journal Association 2004 vol. 171 pp. 353-358) Although randomized controlled trials provide the most valid estimates of the benefit and harm of a treatment, the application of these results to individual patients may be difficult. " In the evaluation of the results of clinical trials, the absolute risk reduction is superior to the relative risk reduction because it incorporates both the baseline risk and the magnitude of the risk reduction. Its reciprocal, the number needed to be treated, expresses the absolute risk reduction in a manner that is easily understood by clinicians, and can be used to describe the harm as well as the benefit of therapy.” (5) (New England Journal of Medicine 1988 vol. 318 pp. 1728-1733). After these considerations, we can understand that the NOA are clinically equivalent to warfarin and that at the moment these drugs are grossly overvalued. Furthermore these drugs have not an antidote available as vitamin K antagonists.  Warfarin, differently from these drugs, can be monitored with the International Normalized Ratio (INR). (see rivaroxaban review, section on “laboratory tests”) It  interferes with many drugs and some foods as we will discuss in the section on “drug and food interactions” because it is metabolized by cytochrome p450 hepatic microsomial enzymes, by CYP2C9 and by CYP3A4, that are involved in the metabolism of many drugs. Now has been developed a new vitamin K antagonist, tecarfarin, that avoid cytochrome P450 (CYP) related metabolism and transport by P-glycoprotein (P-gp) that is a major cause of safety and efficacy problems related to the use of warfarin but also to a less extent, to the use of NOA. For this, tecarfarin does not interfere with other drugs and furthermore can be administered to patients with renal impairment without problems because is not excreted via the kidney.(6) (www.armetheon.com)  This drug is not commercially available at the moment, until will not be done an open label study and until will not be approved by the regulatory agencies.  In patients in therapy with warfarin, not only clinical control, but especially a good laboratory control by the INR is crucial. For this, it is very important to address every patient in therapy with warfarin or other vitamin K antagonists to specialized anticoagulation clinics managed by skilled physicians and skilled laboratory technicians that treat patients, keeping them in a good Time in the Therapeutic Range (TTR).  The most important adverse reaction of warfarin is bleeding, but differently from NOA, we can use Prothrombin Complex Concentrates (PCCs) to reverse the anticoagulant effect of warfarin not only in case of an important bleeding, but also in case of an emergency surgery. Furthermore, differently from NOA again, we can use a simple laboratory test, the INR, to decide if a patient can receive a surgery. In case of an high INR without important bleeding, we can use vitamin K to antagonize the anticoagulant effect of warfarin, although to obtain this therapeutic effect, will require about 24 hours. Another adverse reaction is the interference of warfarin with Osteocalcin and  the GLA matrix that, as we will see in the section on “adverse reactions”, can be responsible for important clinical effect as osteoporosis (7) www.drugs.com/news/warfarin-raises-bone-fracture-risk-1705.html and heart valves calcification respectively. (8) (Clinical Journal of The American Society of Nephrology 2008 vol. 3 pp. 1504-1510)  (9) Thrombosis and Haemostasis 2008 vol.100 (4) pp. 593-603.  In the section on “contraindications”, we will examine all the cases in which it is not possible to use warfarin and so, other therapeutic strategies must be considered. For this, before starting a therapy with warfarin, we must carefully evaluate the bleeding and the thrombotic risk of a patient using some bleeding and thrombotic scores, and especially using our clinical judgement. At the moment, warfarin is one of the most important drugs that saved many lives and many patients from disabilities,  and will still remain an important medical tool for many years.

References :

1 )  Ruff Christian T., Giugliano Robert P., Eugene Braunwald et al., : Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation : A meta-analysis of randomized trials. The Lancet 2013; doi: 10.1016/S0140-6736 (13) 62343-0
2 )  Chatterjee Saurav, Sardar Partha, Biondi-Zoccai Giuseppe et al., : New oral anticoagulants and the risk of intracranial hemorrhage : Traditional and bayesan meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurology 2013; 70, 1486-1490
3 )  Mandrola John : Novel oral anticoagulants vs warfarin : The truth is relative; www.medscape.com/viewarticle/818013: December, 18 2013
4 )  Barratt Alexandra, Wyer Peter C., Hatala Rose et al., : Tips for learners of evidence-based medicine : 1). Relative risk reduction, absolute risk reduction and number needed to treat.  Canadian Medical Journal Association 2004; 171 (4), 353-358
5 )  Laupacis Andreas, Sackett David L., and Roberts Robin S. : An assessment of clinically useful measures of the consequences of treatment.  New England Journal of Medicine 1988; 318, 1728-1733
6 )  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
7 )  Drugs.com (internet). Warfarin raises bone-fracture risk. c2000-2012: www.drugs.com/news/warfarin-raises-bone-fracture-risk-1705.html
8 )  Danziger J. :  Vitamin K-dependent proteins, warfarin, and vascular calcification.  Clinical Journal of The American Society of Nephrology 2008; 3 : 1504-1510
9 )  Schurgers L. J., Cranenburg E. C., Vermeer C. : Matrix Gla-protein : the calcification inhibitor in need of vitamin K.
Thrombosis and Haemostasis 2008; 100 (4) : 593-603

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