Non-vitamin K antagonist oral anticoagulants in cardiovascular disease management: evidence and unanswered questions

Abstract

Summary What is known and objective Anticoagulation is important in the management of cardiovascular disorders; however, traditional anticoagulants such as heparins and vitamin K antagonists (VKAs) have limitations, including parenteral administration with the former and the need for coagulation monitoring and dose adjustments with the latter. Three non‐VKA oral anticoagulants (OACs), dabigatran, rivaroxaban and apixaban, are available for the prevention of stroke in patients with atrial fibrillation (AF) and may change clinical practice. This article reviews current knowledge and important unanswered questions on the use of these agents in patients with cardiovascular disease. Methods A literature search was performed using PubMed and the search terms dabigatran, rivaroxaban, apixaban, AF and acute coronary syndrome (ACS). Peer‐reviewed, published clinical trials, review articles, relevant treatment guidelines and prescribing information documents were identified and reviewed for relevance. Results and discussion Dabigatran is an oral direct thrombin inhibitor; rivaroxaban and apixaban are oral direct Factor Xa inhibitors. These agents have a quicker onset and offset of action, more predictable pharmacokinetic and pharmacodynamic profiles, and fewer drug–drug interactions than VKAs, allowing use of fixed doses. For the prevention of stroke in patients with AF, the non‐VKA OACs were either non‐inferior or superior to warfarin with similar or improved bleeding profiles, particularly with respect to reductions in intracranial haemorrhage. In patients with ACS receiving dual antiplatelet therapy, the addition of rivaroxaban significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke without increasing fatal bleeding, but led to higher rates of major bleeding. Dose reductions with non‐VKA OACs are mandated in certain circumstances in patients with AF, such as moderate renal impairment. Contraindications include creatinine clearance <15 mL/min (<30 mL/min for dabigatran in Europe and Canada) and moderate or severe hepatic impairment, but patients can be transitioned to other anticoagulants if appropriate. It is unknown which non‐VKA OAC is optimal for stroke prevention in patients with AF, although factors such as co‐medications (e.g. dabigatran may be preferred if a patient is taking a co‐medication that is a strong cytochrome P450 3A4 inhibitor) and renal function (rivaroxaban and apixaban depend less on renal clearance than dabigatran) will be important for individual patients. Addition of rivaroxaban to antiplatelet therapy for prevention of recurrent events in patients with recent ACS is approved in Europe for patients at the highest risk (with elevated cardiac biomarkers) and must take into account the increased risk of major bleeding. Although routine coagulation monitoring is not required, an understanding of which assays are appropriate for each non‐VKA OAC and how they are affected is important. In a bleeding emergency, non‐specific prohaemostatic agents are suggested ...

Safety and efficacy of direct oral anticoagulants compared to warfarin for extended treatment of venous thromboembolism -a systematic review and meta-analysis

“…Firstly, the studies that investigated the safety and efficacy of DOACs included a small proportion of patients of older age > 75, patients with extreme bodyweight and excluded patients with severe renal impairment and severe liver failure [8,[14][15][16][17]23]. There have been raised concerns about the use of DOACs in patients with renal impairment due to their pharmacokinetic profile and a possible accumulation, which could lead to an increased risk of bleeding in patients with renal impairment [23][24][25][26]. It is known that the use of VKAs in patients with renal impairment increases the risk of bleeding and thus it is not only a concern regarding DOACs [27].…”

Determination of Apixaban Levels in Human Plasma by a High-Throughput Liquid Chromatographic Tandem Mass Spectrometry Assay / Determinarea rapidă a apixabanului în plasma umană prin cromatografie de lichide de înaltă performanță cuplată cu spectrometrie de masă în tandem

“…It represents a new oral anticoagulant molecule, and it received the authorization for European use in 2011, being approved in prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation, for treatment of deep venous thrombosis, pulmonary embolism and for the prevention of recurrence of DVT and PE after elective hip or knee replacement surgery [3]. The available evidence provided by the pre-approval studies (AVER-ROES, ADVANCE, ARISTOTLE, AMPLIFY) and various analysis of emerging clinical experience suggest that apixaban is non-inferior to existing standard anti-thrombotic therapies and that it has improved safety, expressed as reduced hemorrhagic risk [4][5][6].…”

“…Moreover, it involves the administration of standard, indication-dependent, twice daily doses; it has a rapid onset of action (in 3 to 4 hours after oral intake maximum concentration Cmax is achieved) and decline of the anticoagulant effect (after intravenous administration a half-life of approximately 12 hours), with considerable fewer clinically significant drug interactions [3,5,11].…”

“…On the other hand, apixaban overdose does not have an antidote and various algorithms for managing hemorrhage have been suggested to this end, using nonspecific reversal agents [14]. Assays to measure drug levels would also be necessary in various clinical situations as those involving unavoidable co-prescription with interacting drugs or those which need differentiation between therapy inefficacy and poor adherence [2,5,11]. Moreover, unplanned surgery or postoperative periods would benefit from precise evaluations of hemorrhagic risk, as apixaban plasma concentrations proved to be linearly correlated to its anti-Xa activity, over a wide dose range of apixaban (0.5 -50 mg), for both patients and healthy subjects [3].…”

HNO-Chirurgie bei Patienten unter oraler Antikoagulation und Plättchenhemmer-Therapie

“…Die Substanz wird in der Thromboseprophylaxe 1 × täglich und in der Thrombembolieprophylaxe 2 × täglich verordnet. Dosierungen von 75, 110 und 150 mg stehen zur Verfügung.Rivaroxaban: Rivaroxaban (Xarelto ® ) ist ein Faktor-Xa-Antagonist und ist zugelassen für die Prophylaxe von Schlaganfällen und systemischen Embolien bei nichtvalvulärem Vorhoffl immern, für die Behandlung von tiefen Venenthrombosen (TVT) sowie Prophylaxe rezidivierender TVT und Lungenembolien nach akuten TVT, wie auch zur Thromboseprophylaxe bei orthopädischen Eingriff en[ 9 ] . Die Inhibition von Faktor Xa hemmt die Thrombinbildung.…”