Pulmonary embolism (PE) and deep vein thrombosis (DVT) are considered to be two manifestations of the same condition: venous thromboembolism (VTE) – which has an incidence of 1–3 per 1000 of the general population per year, and is the third most common cardiovascular disorder in industrialised countries. With the aging of the current population, the incidence is expected to increase further [1,2]. Anticoagulant treatment in patients with VTE is highly effective, as it reduces the incidence of recurrent disease from about 25% to about 3% during the first 6–12 months of therapy . Since 1960, treatment with oral vitamin K antagonists (VKA) has been the mainstay of long-term anticoagulation therapy for haemodynamicly stable patients with VTE, for both prevention of thrombus extension, and recurrence of the disease . There are well-known disadvantages with the use of VKA. Although VKA administration can usually be started immediately after diagnosis, the slow onset and offset of action often requires bridging with parental or subcutaneous anticoagulant drugs, which challenges outpatient treatment . The initial treatment with low molecular weight heparin (LMWH), fondaparinux or unfractionated heparin (UFH) can only be stopped after the international normalised ratio (INR) remains above 2.0 for at least 24 h , which usually takes 5–10 days [5,6]. LMWH or fondaparinux are usually preferred to intravenous UFH because they rarely require monitoring and are both associated with fewer recurrent thrombotic events, and less major bleeding . However, dose adjustments for severe renal impairment and extreme obesity are not standardised for LMWH, and there is no antidote unlike for UFH, which can be directly reversed with protamine sulphate. A rare but serious complication of UFH, LMWH, and in extreme rare situations of fondaparinux, is heparin-induced thrombocytopenia (HIT) [8,9]. Besides the need for additional bridging, other drawbacks of VKA therapy include the interactions with other drugs and food, and the narrow therapeutic window, which leads to a great inter-individual variability in dose-response rate. Consequently, the risk of either under- or overtreatment is high and, therefore, routine monitoring and dose adjustments are necessary . Patients taking VKA spend at least one-third of the time outside the therapeutic INR range . Therefore, the development of new anticoagulants in the last decade was welcome. In contrast to VKA, these new drugs, (in-)direct factor Xa and thrombin inhibitors, have less disadvantages as they all have predictable pharmacological profiles (Table 1) [12,13]. Currently, many clinical trials with new anticoagulants have been published or are on-going. Factor Xa inhibitors that are most advanced in clinical development are rivaroxaban, apixaban, idrabiotaparinux and edoxaban, whereas Dabigatran is the most advanced thrombin inhibitor [12,13]. Critically, there is a lack of information on the appropriate antidote, and on reliable monitoring for special circumstances, such as in case of a major bleeding or when an urgent invasive procedure is required .
Initial anticoagulant treatment is different for patients with massive PE with haemodynamic instability and a high mortality risk. Systemic thrombolysis is recommended as first-line treatment, because of the short-term resolution of emboli and the beneficial hemodynamic effect of thrombolysis [4,15–17]. However, the available evidence on the benefit of thrombolytic therapy in patients with massive PE is modest, let alone in patients with right ventricular dysfunction and a normal blood pressure (submassive PE). Embolectomy (surgically, by aspiration of the clot, or by angioplasty) is indicated in patients with PE and arterial hypotension in whom thrombolysis has failed or is contraindicated . However, a randomised clinical trial to compare the efficacy of the surgical and the catheter-based techniques has not been performed .
If anticoagulant or thrombolytic therapy is contraindicated, VTE can also be treated with an inferior vena cava (IVC) filter. Patients with an IVC filter are recommended to receive a conventional course of anticoagulant therapy once the risk of bleeding is diminished [4,18]. No randomised trials or prospective cohort studies have been performed to evaluate IVC filters as monotherapy of VTE, without concurrent anticoagulation. Consequently, the use of IVC filters is restricted to patients with VTE who have a temporary contraindication to anticoagulant treatment .
In this state of the art review, the results from large clinical trials with new anticoagulants will be outlined. Additionally, the optimal duration of anticoagulant treatment of VTE will be discussed; with a focus on special patient groups, such as cancer, renal failure, obesity and antiphospholipid syndrome, as well as the use of anticoagulant treatment in pregnant women.