Anticoagulants are the substances used to treat and prevent diseases caused by blood clotting and thrombus formation, in particular for myocardial and pulmonary coronary thrombosis, thrombotic and embolic strokes, thrombophlebitis. Anticoagulants are used to prevent coronary and cerebral atherosclerosis, rheumatic mitral valve diseases. In surgery, anticoagulants are used to prevent the formation of thrombus during operations and in the postoperative period.
Atrial fibrillation is the most common cardiac arrhythmia. It is estimated that more than 5.8 million Americans and 6 million people in Europe suffer from atrial fibrillation. The risk of atrial fibrillation development is estimated at about 25 percent for individuals in the age of 40 years and older. One of the most serious medical problems for people with atrial fibrillation is the risk of stroke, which is five times higher than in people who do not have atrial fibrillation. 15 percent of all strokes in the USA are associated with atrial fibrillation. In addition, strokes caused by atrial fibrillation are more severe than strokes for other reasons. In patients who did not receive anticoagulant therapy, mortality due to strokes associated with atrial fibrillation is 24% for 30 days and 50% for one year. The administration of warfarin reduces the risk of thromboembolic complications by 61%, while the administration of acetylsalicylic acid (ASA) - only by 22%
The mechanism of action is divided into several groups: vitamin K antagonists, heparins, direct thrombin inhibitors and direct factor Xa inhibitors.
Vitamin K antagonists, among which the most well-known is Warfarin, have introduced the convenience of oral use (in the form of tablets) compared to heparins that are used as injections, but have a very narrow dosing spectrum, interact with many drugs and food products and, consequently, require constant monitoring of blood homeostasis. This property makes the drug uncomfortable for use and expensive for the budget.
The effect of drugs based on factor Xa is most preferable, because factor Xa protein is involved only in the process of blood coagulation and its inhibition causes the least amount of adverse effects. Modern anticoagulants should meet the high-efficacy requirements of preventing blood clotting, low toxicity and low risk of adverse effects, a mainly low risk of bleeding.
The latter requirement presents a serious obstacle since the flip side of the blood clotting prevention lies in an increased risk of bleeding. One of approaches to solution of this problem can be the search for molecules of high affinity and selectivity to proteins involved in the clotting that, in turn, would reduce the used concentration of active substance and consequently the risk of bleeding. A serious problem in selection of the anti-coagulant molecule is also the requirement to develop a drug for oral administration.
The list of companies with various success developing oral anticoagulants, direct thrombin or factor Xa inhibitors since the mid-2000s includes the following: Boehringer-Ingelheim (Dabigatran); Johnson&Johnson / Bayer (Rivaroxaban); Daiichi Sankyo (Edoxaban); Takeda (TAK-442); Astellas (YM150); Eli Lilly (LY517717); Portola Pharmaceuticals (Betrixaban); Sanofi-Aventis (Otamixaban); TransTech (TTP889); Pfizer / Bristol-Myers Squibb (Apixaban); AstraZeneca (Ximelagatran); GlaxoSmithKline (GW813893). Analysts estimate the market of such drugs to USD 15 billion a year. This and the fact that large pharma companies continue to search for and develop anticoagulants confirms that there is a demand for more effective and safe drugs of new generation.
Despite the emergence of new classes and the presence of serious adverse effects, Warfarin remains the first choice drug as an anticoagulant for most indications.