It was hypothesized that the four‐factor prothrombin complex concentrate (4F‐PCC) Kcentra 25 unit/kg would reverse impairment of thrombin generation in healthy volunteers dosed with apixaban to steady state. In this randomized, two‐period crossover, assessor‐blinded trial, 12 healthy subjects received 5 mg apixaban every 12 h. Three h after the fifth dose, four‐factor prothrombin complex concentrate (4F‐PCC) 25 unit/kg or saline were infused. Serial blood samples were assessed for thrombin generation using PPP‐reagent and PPP‐reagent low, anti‐Xa, PT, and PTT assays. Geometric mean ratio was calculated at 30 min postinfusion, and at 24, 48, and 72 h. Peak thrombin generation was 76% higher at 30 min postinfusion with 4F‐PCC (p = 0.025). The difference declined to 24% at 24 h and resolved by 48 h. Other thrombin generation parameters were also partially normalized. There was no difference between 4F‐PCC and saline in anti‐Xa assessment at 30 min or later time points.

Betrixaban, the fifth novel oral anticoagulant in line for the Food and Drug Administration (FDA) approval, possesses some unique pharmacokinetic characteristics in comparison with the currently available novel anticoagulants, including limited renal excretion, minimal metabolism through the cytochrome p450 system and a long half-life. This pharmacokinetic profile may allow greater flexibility for use in patients with poor renal function, offer the convenience of once daily dosing, and exhibit less drug interactions. Betrixaban is currently being evaluated for prophylaxis against venous thromboembolic disease (VTED) and the prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation, its role in the management of acute VTED and acute coronary syndromes is yet to be defined based on clinical data and evaluation. Of interest, a factor Xa decoy, PRT4445, is currently under evaluation in conjunction with betrixaban, and may be a universal reversal agent for all anticoagulants with anti-Xa activity. Currently, there are no specific reversal agents for the novel anticoagulants. The availability of an effective reversal agent would be very attractive for the management of associated bleeding, bleeding due to trauma, or the need for emergent surgery.

The new oral anticoagulants may prove to be one of the most significant innovations in clinical practice in the past 60 years. Apixaban and rivaroxaban are specific inhibitors of Factor Xa while dabigatran inhibits Factor IIa. The predictable pharmacological profile of these new agents will allow physicians to use these drugs without the need for routine coagulation monitoring which is the mainstay of warfarin therapy. In addition, these new agents have not been shown to have any food interactions and limited drug-drug interactions due to their minimal metabolism through the CYP450 system. This unique pharmacokinetic profile may usher in for clinicians a new era of managing thromboembolic disorders. In this paper, the pharmacology of these new oral anticoagulants are reviewed along with the major clinical trials in venous thromboembolism prevention in total hip and knee replacement orthopedic surgery, the treatment of venous thromboembolic disorders and stroke prevention in atrial fibrillation.

Computerized systems are associated with substantial improvements in the prescribing of appropriate prophylaxis and reductions in VTE events, particularly in medical patients. More robust systems can be established with computer-based rather than paper-based CDSS. A drawback of computerized systems is that some hospitals may not have adequate information technology system resources.