Our mission is to become a worldwide reference for education in the field for all professionals involved in the process to dissemintate knowledge & skills of Acute Cardiovascular Care
Our mission is to promote excellence in clinical diagnosis, research, technical development, and education in cardiovascular imaging in Europe.
Our mission: To promote excellence in research, practice, education and policy in cardiovascular health, primary and secondary prevention.
Our goal is to reduce the burden in cardiovascular disease in Europe through percutaneous cardiovascular interventions.
Our Mission is "to improve the quality of life of the population by reducing the impact of cardiac rhythm disturbances and reduce sudden cardiac death"
To improve quality of life and logevity, through better prevention, diagnosis and treatment of heart failure, including the establishment of networks for its management, education and research.
Working Groups goals is to stimulate and disseminate scientific knowledge in different fields of cardiology.
ESC Councils goal is to share knowledge among medical professionals practising in specific cardiology domains.
OUR MISSION: TO REDUCE THE BURDEN OF CARDIOVASCULAR DISEASE
Prof. Steen Dalby Kristensen,
Dr. Giulia Renda
Prof. Raffaele De Caterina,
VKAs remain at this time, with all their problems, the standard of care in patients with AF at medium-high risk of thromboembolic events, but the cardiologist needs to be aware of the explosive pharmacology literature being accrued with new oral anticoagulants, as most of these will likely enter the clinical arena in the near future substituting VKAs in many of their current indications.
Although warfarin and similar coumarin derivatives (vitamin K antagonists, VKAs) have clearly the greatest efficacy, among treatments commonly available (mostly aspirin), in preventing stroke in atrial fibrillation
The marked variability in the dose-response relationship of VKAs makes it unusually difficult for the patient to remain within the ideal international normalised ratio (INR) range. The dose-response relationship of VKAs is influenced by many factors, including:
These factors are common, so that even within the controlled setting of a clinical trial it has not been possible to stay within the therapeutic window more than 50% of the time in most trials(3). This creates the necessity of unpleasant, frequent and assiduous monitoring of the INR in every patient treated with VKAs in order to reduce the risk of serious bleedings on the one hand, and of undertreatment on the other.
In summary, therapy with VKAs is complex, potentially dangerous and unpleasant, and this has resulted in considerable difficulty in convincing physicians and patients to adhere to current practice guidelines, with a resulting undertreatment in a considerable proportion of patients at risk(4). This is an ample justification for the need for safer, more convenient alternatives to coumarin derivatives for stroke prevention.
The combination of clopidogrel plus aspirin was recently compared with oral anticoagulants for prevention of vascular events associated with atrial fibrillation in the ACTIVE-W trial(5). This trial showed that oral anticoagulant therapy with VKAs is a better treatment than clopidogrel plus aspirin in general for patients with atrial fibrillation. This is particularly true in patients previously exposed to oral anticoagulation therapy with VKAs, while for patients new to these drugs, the benefit of VKA therapy relative to clopidogrel plus aspirin are not well defined.
At the current time, therefore, VKAs remain, with all their problems, the standard of care in patients with AF at medium-high risk of thromboembolic events(1).
CLASSIFICATIONS OF ANTICOAGULANTS AND NEW DRUGS IN THE CLINICAL ARENA
Anticoagulants, now produced in large numbers by pharmaceutical companies, can be classified in several ways(6). One is related to a combination of the mechanism of action and their way of administration (oral or parenteral, Table 1).
The “new entries” in the arena, theoretically suitable for the long-term thromboembolic prophylaxis in atrial fibrillation, fall in 3 main categories:
Factor Xa inhibitors act indirectly or directly. Heparin and low-molecular weight heparins indirectly inhibit FXa, among other targets, potentiating the anticoagulant action of antithrombin (antithrombin III). However their action is completely non-selective in the case of unfractionated heparin, and only partially selective for low molecular weight heparins. New indirect inhibitors, fondaparinux and idraparinux, are synthetic analogs of the unique pentasaccharide sequence that mediates the interaction of heparin with antithrombin(7).
Idraparinux is a derivate of fondaparinux. It has 100% bioavailability via the subcutaneous route, is excreted mainly in the urine, has a linear, dose-dependent pharmacokinetic profile, reaches peak concentration in 1–3 hours and has a plasma half-life of 130 hours, allowing a once-weekly administration and making it a candidate drug for long-term prophylaxis of thromboembolism in atrial fibrillation. The drug has no significant binding to other blood, plasma or endothelial proteins(6). Biotinylated idraparinux is a biotinylated derivative of idraparinux, with the same pharmacodynamic and pharmacokinetic properties of the parent molecule, recently developed to offer the advantage of a rapid neutralization by an antidote through the injection of avidin, exploiting the extremely high-affinity avidin-biotin binding.
The oral direct thrombin inhibitors (oral DTI) so far evaluated in phase III studies, ximelagatran and dabigatran etexilate, are synthetic low molecular weight peptidomimetics that bind directly and reversibly to the catalytic site of the thrombin molecule(6). They are administered orally as prodrugs, which are rapidly metabolised to the active compound; ximelagatran is converted to melagatran in several organs, including liver, lungs, intestines and kidneys, whereas dabigatran etexilate is rapidly and completely converted to dabigatran primarily by serum esterase-catalyzed hydrolysis. Pharmacokinetic data for dabigatran etexilate in healthy volunteers show peak plasma levels within 2-3 hours after oral administration and a half-life in healthy subjects of 12-14 h in patients for dabigatran. Both are eliminated primarily by the kidney. Their therapeutic window is fairly wide, and they have therefore been tested in fixed doses.
Ximelagatran had been licensed in Europe in 2004 for venous thromboprophylaxis in high-risk orthopedic patients. Two phase III trials (SPORTIF III and V) have compared ximelagatran 36 mg twice daily with warfarin (targeted to an INR of 2.0-3.0) for the prevention of thromboembolic events in high-risk patients with non-valvular atrial fibrillation. Overall ximelagratran was associated with a 16% relative risk reduction in the composite outcome measure of all strokes (ischemic or hemorrhagic), systemic embolic events, major bleeding and death. However, in the long term use ximelagatran was associated with transient elevations of liver function tests (alanine amino transferase(ALAT)³3 times upper normal limits) in around 8% of patients. At the beginning of 2006, the company producing the drug therefore decided to withdraw it from the market and terminate its development. The withdrawal was triggered by new patient safety data with an adverse event report of serious liver injury in a clinical trial.
Phase III trials have been reported with dabigatran (RE-MODEL, RE-NOVATE trials) showing efficacy equivalent to that of enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile(8). On March 2008 the European Medicines Agency (EMEA) therefore approved the use of dabigatran etexilate for the prevention of venous thromboembolic events after total hip replacement and total knee replacement surgery.
The oral direct thrombin inhibitor AZD0837 is a prodrug, which is metabolised to the active thrombin inhibitor via an intermediate form. Based on encouraging results from the first phase IIa study, further development of AZD0837 is continuing, with the decision to develop this product through an extended release formulation for prophylaxis of thromboembolic events.
A number of oral FXa inhibitors have also entered clinical development. These agents have a molecular weight of approximately 500 Da, are direct inhibitors of FXa, as they do not require a plasma cofactor for their action, and are selective for FXa, as their Ki is at least 5,000 times lower than that for any other serine protease. The direct inhibitors of FXa are inhibitors of the catalytic site of this important coagulation factor. Clinical data are currently available for at least five oral inhibitors of FXa: razaxaban, rivaroxaban (BAY 59-7939), apixaban (BMS-562247-01, YM 150, and DU 176-b. In general, these agents have shown a reasonably large therapeutic window. Rivaroxaban has also successfully completed some phase III trials in DVT prophylaxis(9) and it is admitted for approval in Europe for the indication VTE-prevention in patient undergoing major orthopedic surgery. Phase III trials with apixaban are ongoing.
ONGOING CLINICAL TRIALS IN ATRIAL FIBRILLATION
The results obtained form the first studies with these new anticoagulants suggested that several of these, not requiring coagulation monitoring, have the potential to replace VKAs for prevention of stroke or systemic embolism in atrial fibrillation. The main characteristics of ongoing Phase III clinical trials with new anticoagulants in patients with atrial fibrillation are comparatively reported in Table 2.
Table 1. A classification of currently available anticoagulants reflecting their route of administration
Table 2. Ongoing clinical trials with new anticoagulants in patients with atrial fibrillation
The past twenty years have led to a considerable improvement in the antithrombotic prophylaxis of atrial fibrillation, through a proper stratification of the thromboembolic risk, the establishment of the proper ranges of anticoagulation with VKAs, and the demonstration of its superiority over treatment with single antiplatelet agents in high-risk patients. We are now at the verge of therapeutic revolution, that will likely overcome VKA therapy with better tolerable and manageable drugs. The cardiologist needs to be aware of the explosive pharmacology literature being accrued with these new drugs, as most of these will likely enter the clinical arena in the near future.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
Prof. R. De Caterina, Dr. G. Renda, Institute of Cardiology and Center of Excellence on Aging, “G. d’Annunzio” University – Chieti, Italy Prof *S.Dalby-Kristensen,Skejby University Hospital Aarhus, Denmark.
*Past-Chairmen of the ESC Working Group on Thrombosis.
Prof. Raffaele De Caterina
Institute of Cardiology and University Cardiology Division
Ospedale Clinicizzato SS. Annunziata
Via dei Vestini
66013 Chieti – Italy