When Blood Clots Form
Thrombosis prophylaxis prevents dangerous embolisms
Immobilization – for example having to lie down for longs period of time – slows down the blood flow. This increases the risk of thrombosis, i.e. undesired clotting of the blood. Of particular concern is the fact that many cases of thrombosis often go completely unnoticed by the people affected. However, because the resulting blood clots (thrombi) can lead to dangerous embolisms (for example in the lungs), their formation should be prevented.
Prevention can be achieved with anticoagulants. For example, people who are bedridden after an operation can expect the nurse to appear at their bedside at least once a day to give them an injection. As a rule, she will inject a heparin preparation into the subcutis. From there the active substance enters the bloodstream and prevents the formation of thrombi. It is an effective prophylaxis, but not everyone finds regular injections pleasant or convenient. Heparins cannot be taken orally because they are destroyed in the stomach. In addition, the fact the heparin has to be injected limits its use outside hospitals.
Although there are anticoagulants, known as vitamin K antagonists, that can be taken in tablet form, the effective dose can vary widely from patient to patient. Regular blood counts are therefore necessary to test the coagulation level.
Thrombosis can be fatal
There is great demand for preventive anticoagulants. About 6.5 million people a year worldwide are affected by a venous thromboembolism (blocked vein) caused by thrombosis. It is thought to be one of the most common causes of death. If a blood clot enters a lung, there is a danger of pulmonary embolism, which kills 300,00 people every year in the USA alone.
Risk groups include people with a high risk of stroke or heart attack, as well as all people whose mobility is restricted - as in the case, for example, of patients who have undergone orthopedic surgery, or people with cancer, cardiac insufficiency or acute respiratory diseases
What causes thrombosis?
Blood coagulation is a complex process in which a number of substances, known as coagulation factors, play a role. Factor Xa (= ten a) is a key substance in this process. It ensures that the enzyme thrombin, and in a second step fibrin, is generated. It is the fibrin fibers, together with the blood platelets, that actually form the thrombus. This process is vital, because as a rule it is such thrombi that close wounds. But under unfavorable conditions, e.g. immobility, "plugs" can also form in uninjured blood vessels; in such cases, we speak of thrombosis.
How anticoagulants have worked up to now
Anticoagulants prevent this danger by impacting on the coagulation process at different stages. Heparins affect the body's own protein anti-thrombin. In this way they accelerate the deactivation of various activated coagulation factors and thus disturb the formation of fibrin.
Vitamin K antagonists suppress the production of several substances including factor X, prothombin or factor II (the preliminary stage of thrombin), as well as signal substances that play a role in injuries.
Both classes of substance have important disadvantages: the many and complex effects of the vitamin K antagonists make it difficult to find the ideal dosage. And heparins can only be injected
New hope for the future in tablet form
In this context, the new active substance Rivaroxaban may offer patients new hope. It directly impacts on the activated factor X, i.e. factor Xa, which regulates the formation of thrombin – and thus ultimately coagulation, too. Because of this selective interference in the coagulation cascade, factor Xa inhibitors are considered easy to dose.
The active substance Rivaroxaban is currently under development and has been designed to be taken in tablet form. According to study results available so far in the prevention of venous thromboembolism, patients take the tablet once a day, enabling convenient administration in both the hospital and at home. The results suggest that routine monitoring of coagulation, as is required in the case of vitamin K antagonists, will not be necessary. In the studies that have been conducted to date, Rivaroxaban has shown a low propensity for interactions with a wide range of drugs that are frequently administered together with anticoagulants.
First Phase III study results positive
Clinical development is already well advanced. It is being carried out together with Johnson & Johnson Pharmaceutical Research & Development. Studies are being conducted on the prevention of venous thrombosis after orthopedic surgery, such as hip-joint and knee operations. The initial results of a Phase III study were presented in early July 2007 at the 21st congress of the "International Society on Thrombosis and Haemostasis" in Geneva. In this study, Rivaroxaban proved to be more effective than the heparin active substance Enoxaparin. In patients who had had knee-joint-replacement surgery, the risk of proximal deep vein thrombosis, pulmonary embolism, and indeed death as a result of these venous thromboembolism, was 49 percent lower in patients who had been given Rivaroxaban than in the case of Enoxaparin. The incidence of major venous thromboembolisms was reduced by as much as 62 percent compared to Enoxaparin.
The first application for market approval for the prevention of venous thromboembolism after major orthopedic surgery is planned for the end of 2007 in Europe, and 2008 in the USA.
Comprehensive development program for further indications
Apart from the prevention of venous thromboembolisms following orthopedic operations, the clinical development of Rivaroxaban includes three further indications, some of which are also in Phase III. They include the treatment of venous thrombosis, stroke prevention in cases of atrial fibrillation, and acute coronary syndrome (ACS), i.e. severe circulatory problems in the coronary vessels.
A total of more than 40,000 patients are expected to take part in studies with Rivaroxaban.
Advice for patients
Every body reacts differently to medicines. Therefore it is impossible to tell which medicine works best for you. Please consult your physician.