Company product description

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.

1. Pradaxa® = Dabigatran (Boehringer Ingelheim): in 2008. The FDA has authorized ordering of Pradaxa to prevent deep vein thrombosis and pulmonary embolism after knee and hip replacement surgeries , and in October 2010 - ordering in case of atrial fibrillation. On sale. In December 2011, the FDA initiated an investigation with reference of lethal cases after bleeding caused by the use of Dabigatran. As a result, it was shown that there is no advantage of using Dabigatran over Warfarin. Sales of Dabigatran due to these news fell 2 times from the value of USD 1.66 billion in 2013 worldwide. As a result of the agreement, on May 28, 2014, Boehringer Ingelheim agreed to pay the plaintiffs USD 650 million for plaints related to serious adverse effects caused by the use of Dabigatran.
2. Xarelto® = Rivaroxaban (Bayer and Johnson & Johnson): in 2008. The FDA has authorized ordering of Xarelto to prevent deep vein thrombosis and pulmonary embolism after knee and hip replacement surgeries, and in November 2010 - ordering in case of atrial fibrillation. On sale. The recent FDA delay in registration of Rivaroxaban in the USA on indications of stroke prevention in atrial fibrillation, caused by concern about the drug safety. In September 2013, the FDA was concerned about the drug safety because of more than 1,000 cases of adverse effects recording. As a result, Xarelto was found to have more than twice excess of the risk of bleeding compared to Warfarin. Currently, collecting of plaint notes for cases of spontaneous uncontrolled internal bleeding associated with adverse effects in patients taking Rivaroxaban is in the process.
3. Eliquis® = Apixaban (Pfizer and Bristol-Myers Squibb): It was approved by the FDA in December 2012 on indications of thrombosis prevention in case of atrial fibrillation. The market entry of Apixaban has been delayed since 2008, when the FDA asked the developers for additional tests of the Apixaban efficacy compared to low-molecular-weight heparin. Currently, Apixaban is considered the safest.
4. Lixiana® = Edoxaban (Daiichi Sankyo): was approved by the FDA in January 2014 on indications of prevention of deep vein thrombosis and pulmonary embolism after knee and hipreplacement surgeries, as well as indications of thrombus formation prevention in case of atrial fibrillation.

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.