Novel oral anticoagulants and the 73rd anniversary of historical warfarin

International guidelines have recommended the use of NOACs in line with their established safety, efficacy and compliance [29], [30], [31]. The safety of NOAC is supported by real world post-marketing surveillance registry studies, such as the Danish registry where bleeding and MI were not attributed to dabigatran [32]. In addition, reports from the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA™-AF) which emphasizes the under clinical utility of NOACs, have recently emerged. Dabigatran was coined as the most prescribed NOAC in the Phase II registry [33], [34]. The GLORIA™-AF was the largest, global observational study to date on the use of anticoagulants in patients with AF. The early reported findings were based on treatment trends in 3415 AF patients who entered the GLORIA™-AF registry from November 2011 to February 2014. The GLORIA™-AF results demonstrated that 21.9% of patients with occasional AF and a CHADS2-VASC score of 2 or higher were either undertreated with aspirin or given no anticoagulant treatment at all, compared to 12.4% and 11.2% of those diagnosed with persistent or permanent AF, respectively [33]. Current AF guidelines call for patients to receive oral anticoagulant therapy based on their risk of stroke, rather than their type of AF [34], [35]. Furthermore, given the availability of NOACs, guidelines state that the use of antiplatelet therapies (such as aspirin) for stroke prevention in AF should be limited to the few patients who refuse any form of oral anticoagulant, as the evidence for effective stroke prevention from Apixaban versus acetylsalicylic acid (ASA) is weak, with a potential for harm [35]. NOAC is the standard therapy in significantly reducing the risk of stroke and systemic embolism in AF patients. Physicians have diverse factors to consider when selecting a NOAC option for antithrombotic treatment in AF patients. Revealing factors such as risk stratification for bleeding, therapeutic monitoring, and renal status may serve in bridging the treatment gap. NOAC limitations There was no treatment evidence for NOACs in patients with valvular AF (valves/devices). There are other NOAC limitations, such as not having a reversal agent in the event of bleeding. Currently, however, antidote trials for each specific NOAC reversal are underway (Phase II and III trials); and these include idarucizumab for dabigatran (RE-VERSE AD trial), andexanet for apixaban-alfa (ANNEXA™, Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of factor XA Inhibitors trial) [36]. There is no FDA-approved NOAC antidote for clinical use in case of medical emergencies. Despite the fact that no routine laboratory monitoring is required for general outpatient follow-up, some laboratory assays such as ECT and aPTT are available for emergency situations in which patients are suffering from life-threatening bleeding. Activated charcoal can be used to decrease the absorption of dabigatran [37], and prothrombin complex concentrates (PCC) have been shown to completely reverse the anticoagulant effect of rivaroxaban in healthy subjects [38]. However, a recent randomized, double-blind, placebo controlled trial of 145 healthy volunteers demonstrated that idarucizumab, a humanized antibody that binds dabigatran with high affinity, could result in immediate and sustained reversal of the anticoagulant effect [39], [40]. The study reported that idarucizumab is well tolerated without adverse events and completely reverses prolonged clotting time within five minutes of administration. This was the sole specific antidote for one of the NOACs; however, further research is required to demonstrate its clinical utility. In order to be implicated in clinical practice, the following points need to be considered: 1. Clinical use according to patient need: life-threatening hemorrhage, trauma, procedure with anticipated risk for major bleeding. 2. Careful risk assessment will be needed as the risk for bleeding outweighs the benefit of thrombo-prophylaxis. 3. Attention to fundamentals of hemostasis and supportive measures. 4. Will the availability of NOAC antidotes drive the uptake of NOACs? The future of NOACs Some gaps need to be addressed in order for clinicians to select a NOAC and/or convert and switch from warfarin to a NOAC. These gaps have to be highlighted by expert opinions from the gained meta-analysis, registries and from global experiences who can summarize them for clinicians without bias or conflict of interest. This may help solve the various controversies and disparities in the clinical utility of NOACs. The research conducted by clinicians working in day-to-day clinical practice will be of extreme value as their views and that of their patients (treatment satisfaction) will provide deeper insights into the authentic clinical utility of NOACs. Researchers are encouraged to focus on patient satisfaction and quality of life aspects of these NOACs. The emerging betrixaban novel once-daily factor Xa inhibitor has been shown in a small phase II study to competitively bind to factor Xa and to inhibit its activity. The EXPLORE-Xa study was designed to evaluate the safety and tolerability of betrixaban compared to warfarin in patients with AF who are receiving or are eligible for VKA. This phase II study of betrixaban, at doses of 40–80 mg per day, indicated that it was well tolerated in AF patients at risk for stroke, with a risk of bleeding that was similar to, or lower than, that of well-managed warfarin. The most important fact about this drug is its hepatic elimination, which may provide preferences over other NOACs in patients with renal impairment of <30 mL/min [41].