Anticoagulants. Old and new.

Anticoagulants are effective in the prevention and treatment of a variety of arterial and venous thrombotic disorders but are associated with an increased risk of serious bleeding complications. Based on well documented studies of patients using vitamin K antagonists the incidence of major bleeding is 0.5%/year and the incidence of intracranial bleeding is 0.2%/year, however, in real life practice this incidence may be even higher. Risk factors for bleeding are the intensity of anticoagulation, the management strategy to keep the anticoagulant effect in the desired range, and patient characteristics. Recently, a new generation of anticoagulants have been developed and is currently evaluated in clinical trials. Initial results show a similar or superior efficacy over conventional anticoagulant agents with a good safety profile. In case of serious bleeding complications in a patient who uses vitamin K antagonists, this anticoagulant treatment can be quickly reversed by administration of vitamin K or coagulation factor concentrates. For the newer anticoagulants, quick reversal strategies are more cumbersome, although some interventions, including prothrombin complex concentrates, show promising results in initial experimental studies.

Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists.

BACKGROUND: Rivaroxaban is a new oral anticoagulant (NOAC) that can be prescribed in a fixed dose, making regular monitoring and dose adjustments unnecessary. It has been proven to be safe and effective in comparison with enoxaparin/vitamin K antagonists (LMWH/VKA) for the (extended) treatment of venous thromboembolism in the EINSTEIN studies. Nevertheless, there is a need for information regarding the clinical impact of (major) bleeding events with NOACs such as rivaroxaban. OBJECTIVES: A post-hoc analysis was performed to compare the severity of clinical presentation and subsequent clinical course of major bleeding with rivaroxaban vs. LMWH/VKA. METHODS: Two investigators performed a blinded classification of major bleeding using a priori defined criteria. During the EINSTEIN studies, data concerning the clinical course and measures applied were prospectively collected for each major bleed. RESULTS: Treatment with LMWH/VKA caused more major bleeding events (1.7%) than rivaroxaban (1.0%; hazard ratio, 0.54; 95% confidence interval [CI], 0.37-0.79). Major bleeding events during rivaroxaban therapy had a milder presentation (23% were adjudicated to the worst categories vs. 38% for LMWH/VKA; hazard ratio or HR, 0.35; 95% CI, 0.17-0.74; P = 0.0062). The clinical course was severe in 25% of all major bleeding events associated with rivaroxaban, compared with 33% of LMWH/VKA-associated bleeds (HR, 0.46; 95% CI, 0.22-0.96; P = 0.040). CONCLUSIONS: Rivaroxaban-associated major bleeding events occurred less frequently, had a milder presentation and appeared to take a less severe clinical course compared with major bleeding with LMWH/VKA.

Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents.

The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In the case of severe bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, it may be useful to reverse anticoagulant treatment. Conventional anticoagulants such as vitamin K antagonists may be neutralized by administration of vitamin K or prothrombin complex concentrates, whereas heparin and heparin derivatives can be counteracted by protamine sulphate. The anti-hemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors as well as new antiplatelet agents have been introduced and these drugs show promising results in clinical studies. A limitation of these new agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although experimental studies show hopeful results for some of these agents.

Periprocedural reversal and bridging of anticoagulant treatment.

Anticoagulants are effective agents in reducing the risk of thromboembolism but the most important adverse effect of these agents is the occurrence of bleeding. Bleeding complications may occur spontaneously but the risk of bleeding is particularly increased in case of trauma or around invasive procedures. If patients being treated with anticoagulants need to undergo an invasive intervention, physicians need to consider whether to interrupt the use of this medication or to allow its use to be continued. Suspending the use of anticoagulants increases the risk of thrombosis, whereas continued use may cause bleeding complications. To shorten the period in which anticoagulant treatment is interrupted, bridging strategies have been advocated. No evidence-based scientific research has been carried out regarding best practice for the perioperative use of anticoagulants. The periprocedural anticoagulation policy in patients should be individualised based on the risk of a thromboembolic complication (which can be estimated with available scoring systems) offset against the bleeding risk associated with the intervention.

How to prevent, treat, and overcome current clinical challenges of VTE.

Venous thromboembolism (VTE) is most commonly initially treated with low molecular weight heparin (LMWH), fondaparinux, or unfractionated heparin, in combination with vitamin-K antagonists (VKA) for long-term treatment. VKA have some drawbacks, however, which has led to the development of new anticoagulants. Most of these new drugs can be administered orally, and have been investigated in several phase III clinical trials. The benefits of these anticoagulants include their stable therapeutic effect, reduced interactions with other medication and food, and, therefore, the reduced need for regular monitoring. The duration of anticoagulant treatment for VTE is usually 3-12 months, but depends on the balance between the risks of recurrent thrombosis, major bleeding, and the patient's preference. Clinical decision rules to assess the risk of recurrence to tailor the duration of anticoagulant treatment are being investigated. The beneficial aspects of novel anticoagulants may prolong the duration of treatment. VTE treatment should be adjusted in special patient groups, such as in cases of malignancy, renal failure, pregnancy, or obesity. In this review, the current and future aspects of the treatment of VTE are explored.

Bleeding in patients using new anticoagulants or antiplatelet agents: risk factors and management.

The most important adverse effect of antithrombotic treatment is the occurrence of bleeding. In case of serious or even life-threatening bleeding in a patient who uses anticoagulant agents or when patient on anticoagulants needs to undergo an urgent invasive procedure, anticoagulant treatment can be reversed by various specific strategies. Heparin and heparin derivatives can be counteracted by protamine sulphate, whereas the anticoagulant effect of vitamin K antagonists may be neutralised by administration of vitamin K or prothrombin complex concentrates. The antihaemostatic effect of aspirin and other antiplatelet strategies can be corrected by the administration of platelet concentrate and/or desmopressin, if needed. Recently, a new generation of anticoagulants with a greater specificity towards activated coagulation factors has been introduced and most of these agents are currently being evaluated in clinical studies, showing promising results. The new-generation anticoagulants include specific inhibitors of factor IIa or factor Xa (including pentasaccharides) and antiplatelet agents belonging to the class of thienopyridine derivatives. A limitation of the new class of anti-IIa and anti-Xa agents may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs, although in some cases the administration of recombinant factor VIIa may be an option.