New oral anticoagulants: just a new therapeutic option or a real breakthrough?

Abstract

The number of anticoagulant agents currently available for clinical use is relatively limited. This is immediately clear when the number of the available anticoagulants is matched up to that of antimicrobial or the anti-inflammatory agents or the drugs used to treat arterial hypertension. Despite their reduced number, treatment with the available anticoagulant agents has been associated with an outstanding improvement of clinical care. Unfractionated heparin, several low-molecular weight heparins and fondaparinux reduce by more than 60% the rate of venous thromboembolism in patients undergoing major orthopedic or cancer surgery and in high-risk medical patients. Vitamin K antagonists reduce by more than 90% the risk of recurrence in patients with deep vein thrombosis or pulmonary embolism and by about 60% the risk of stroke in patients with atrial fibrillation. Bivalirudin, a parenteral thrombin inhibitor, has been shown to be effective and safe in patients with acute coronary syndromes who had a stent implanted. Given these achievements, it could be easy to assume that the currently available agents, if properly used, are able to meet most of the clinical needs in the antithrombotic therapy. However, the currently available agents have several limitations. Unfractionated or lowmolecular weight heparin, fondaparinux or bivalirudin require parenteral administration and are cumbersome to be used in the so-called ‘‘chronic indications’’, that is to say, those requiring a prolonged administration. The oral vitamin K antagonists are associated with a remarkable individual variability in the dose‐response and therefore require relatively frequent laboratory monitoring for dose adjustment. It makes clinical sense to anticipate that an oral agent at least as effective and safe as the vitamin K antagonists (but possibly more) to be given at fixed doses without laboratory monitoring would be a real breakthrough in the current clinical practice. Indeed, prophylaxis of postoperative thromboembolism in high-risk patients could be easily extended, long-term treatment of venous thromboembolism and prophylaxis of stroke in patients with atrial fibrillation could be made less cumbersome. In patients with atrial fibrillation treatment would be made available for that 50% of patients to whom anticoagulant treatment is denied for the impracticality of the vitamin K antagonists. In the last 10 years a number of new oral agents have entered the procedures of the clinical evaluation. The clinical development of most of these agents did not go beyond the phase II (dose-finding) studies, but some among the survivors of such a tremendous selection process reached or are about to reach the clinical use. The clinical development of an antithrombotic agent follows a secure pathway which a critical mind could also see as a sort of imagination-free stereotype. Indeed, almost all the new agents are first tested in the prevention of venous thromboembolism in major orthopedic surgery and, only after they have been shown to be effective and safe in this indication, are further evaluated in the treatment of venous thromboembolism and in the prevention of stroke in patients with atrial fibrillation. Prevention of venous thromboembolism in major orthopedic surgery is the preferred initial step for Phase II and Phase III studies as it is associated with a high and predictable event rate, a reliable measurability of the study outcome (deep vein thrombosis as assessed by venography) and a relatively careful assessment of agent-related bleeding. Once the clinical development has been completed, the