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Prof. Márcio Figueiredo
Warfarin's shortcomings regard variations in individual responses and interactions with certain foods and drugs. In atrial fibrillation, the Rely, Rocket-AF and Aristotle studies have proven the efficacy of Dabigatran, Rivaroxaban and Apixaban which have now all been approved for use in stroke prevention and Dabigatran in cardioversion. Rapid onset, a fixed dose, with no need for INR (International Normalized Ratio) monitoring counterbalance the added cost.
During the Great Depression in Wisconsin, a farmer presented at a school of agriculture with a milk can full of blood which would not coagulate. In his truck, he had also brought a dead young cow and some clover hay; he wanted to know what had killed his cow and spoilt his hay. Prof. Karl Paul Link a biochemist, got funding from the Wisconsin Alumni Research Foundation to research sweet clover disease which was known to cause the cattle to bleed to death after ingesting spoilt sweet clover. He identified a substance with anti-clotting properties he named dicoumarol. Although the drug initially found commercial application as a killer of rats and mice in 1941, it was approved in 1954 and among its first recipients was President Dwight Eisenhower, as he recovered from a heart attack in 1955. It has been widely used in heart and vascular medicine ever since (Warfarin is a portmanteau word combining WARF the accronym of Wisconsin Alumni Research Foundation and adin, the ending from word Coumadin) (1,2)Warfarin's efficacy in preventing embolic events in patients with atrial fibrillation (AF) has been proven and its mechanism understood (3,4). However, apart from patient's risk of bleeding when using it, Warfarin has several shortcomings:
These factors render difficult the use of Warfarin to prevent embolic events in patients with AF and therefore anticoagulation is often inadequate in regards to what is recommended (next e-journal for comment on recommendations) (10). Many patients at risk do not benefit from much needed anticoagulation, and remain at risk. Thus, researchers have sought other drugs with improved pharmacodynamic and pharmacokinetic characteristics, yet keeping with the efficacy and hopefully increased levels of safety.
Based on the coagulation cascade - the sequence of biochemical activities that stop bleeding by forming a clot, two possible targets for the development of new oral anticoagulants were: 1) drugs acting as direct thrombin inhibitors (such as Dabigatran) or 2) activated factor X (such as Rivaroxaban and Apixaban). These drugs have been developed and tested in large clinical trials in patients with AF, to prove its efficacy and safety compared with Warfarin.
Direct comparison among the new anticoagulants is not easy to carry out since despite their similarities, these large studies have distinctive designs, and evaluated patients with clinically significant differences. Still, it is possible to establish certain common features in these new drugs.
Warfarin's shortcomings regard variations in individual responses and interactions with certain foods and drugs. In atrial fibrillation, the Rely, Rocket-AF and Aristotle studies have proven the efficacy of Dabigatran, Rivaroxaban and Apixaban which have now all been approved for use in stroke prevention and Dabigatran in cardioversion. Rapid onset, a fixed doe, with no need for INR counterbalance the added cost.
1 - Schofield FW. Damaged sweet clover; the cause of a new disease in cattle simulating haemorrhagic septicemia and blackleg. J Am Vet Med Ass 1924:64: 553–6. 2 - Link KP. The discovery of dicumarol and its sequels. Circulation. 1959 Jan;19(1):97-107. 3 - Adjusted-Dose Warfarin versus Aspirin for Preventing Stroke in Patients with Atrial Fibrillation.Hart RG, Pearce LA, Aguilar MI. Ann Intern Med 2007; 146: 857–674 - Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.Arch Intern Med. 1994 Jul 11;154(13):1449-57.5-Factors affecting the maintenance dose of warfarin. James AH, Britt RP, Raskino CL, Thompson SG. J Clin Pathol 1992; 45:704–7066-Effect of ageing upon warfarin dose requirements: a longitudinal study.Wynne HA, Kamali F, Edwards C, Long A, Kelly P. Age Ageing 1996; 25: 429–4317-Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Garcia D, Regan S, Crowther M, Hughes RA, Hylek EM. Chest 2005; 127: 2049–20568-Interactions of warfarin with drugs and food.Wells PS, Holbrook AM, Crowther NR, Hirsh J. Ann Intern Med 1994; 121: 676-6839-Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th ed.)Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, et al. Chest 2008; 133:160S–198S10-Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation.Waldo AL, Becker RC, Tapson VF, Colgan KJ, for the NABOR Steering Committee. J Am Coll Cardiol 2005; 46: 1729–3611-Dabigatran versus Warfarin in patients with atrial fibrillation.Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med 2009; 361: 1139-5112 - Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversionNagarakanti R, et al. Circulation. 2011 Jan 18;123(2):131-6. Epub 2011 Jan 3.13-Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. Patel MR, Mahaffey KW, Garg J, et al. N Engl J Med 2011; 365: 883-9114- Apixaban versus warfarin in patients with atrial fibrillation.Granger CB, Alexander JH, McMurray JJV, et al. N Engl J Med 2011; 365: 981-9215-2012 focused update of the ESC guidelines for the management of atrial fibrillation: An update of the 20 120 ESC guidelines for the management of atrial fibrillation.Camm AJ, Lip GY, De Caterina R, et al. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33: 2719-4716-Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillationShah SV, Gage BF. Circulation 2011; 123: 2562–257017-Cost–Effectiveness of Rivaroxaban compared to warfarin for stroke prevention in atrial fibrillationLee S, Anglade MW, Pham D, et al. Am J Cardiol 2012; 110: 845-51 18-Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Faxon DP, Eikelboom JW, Berger PB, Holmes DR, Bhatt DL, Moliterno DJ, Becker RC, Angiolillo DJ. Thromb Haemost 2011; 106: 572–584
Prof. Márcio FigueiredoResponsible for the Cardiac Electrophysiology LaboratoryProfessor, Cardiology Dept., State University of Campinas, São Paulo, BrazilMember of the European Heart Rhythm Association Author's disclosures: None declared.
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