Novel anticoagulants will likely replace need for vitamin K antagonists
BY MADHUKAR S. PATEL, M.D., AND ELLIOT L. CHAIKOF, M.D.
The discovery of oral anticoagulants began in 1924, when Schofield linked the death of grazing cattle from internal hemorrhage to the consumption of spoiled sweet clover hay.1 It was not until 1941, however, while trying to understand this observation, that Campbell & Link were able to identify the dicoumarol anticoagulant, which formed as a result of the spoiling process.2 Ultimately, after noting that vitamin K led to reversal of the dicoumarol effect, synthesis of the first class of oral anticoagulants, known as vitamin K antagonists (VKAs), began.
Despite the numerous challenges associated with managing patients using this class of anticoagulants, VKAs have become the mainstay of oral anticoagulation therapy for the past 70 years. Over the past 5 years, however, new oral anticoagulants (NOACs) have emerged and are changing clinical practice.
Mechanistically, these medications are targeted therapies and work as either direct thrombin inhibitors (dabigatran etexilate) or direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). Given their favorable pharmacologic design, NOACs have the potential to replace VKAs as they not only have an encouraging safety profile, but also are therapeutically equivalent or even superior to VKAs when used in certain patient populations.
The targeted drug design of NOACs provides many pharmacologic advantages. Compared to VKAs, NOACs have a notably more predictable pharmacologic profile and relatively wide therapeutic window, which allows for fixed dosing, a rapid onset and offset, and fewer drug interactions.3 These characteristics eliminate the need for the routine dose monitoring and serial dose adjustments frequently associated with VKAs.
NOACs less commonly require bridging therapy with parenteral unfractionated heparin or low-molecular-weight heparins (LMWH) while awaiting therapeutic drug levels, as these levels are reached sooner and more predictably than with VKAs.4 As with any medication, however, appropriate consideration should to be given to specific patient populations such as those who are older or have significant comorbidities that may influence drug effect and clearance. Lastly, it should be mentioned that the pharmacologic benefits of NOACs apply not only from a patient perspective, but also from a health care systems standpoint, as their use may provide an opportunity to deliver more cost-effective care.
Specifically, economic models using available clinical trial data for stroke prevention in nonvalvular atrial fibrillation have shown that NOACs (apixaban, dabigatran, and rivaroxaban) are cost-effective alternatives when compared to warfarin.5 Although the results from such economic analyses are limited by the modeling assumptions they rely upon, these findings suggest that at least initially, cost should not be used as a prohibitive reason for adopting these new therapeutics.
The decision to institute oral anticoagulation therapy depends on each patient’s individualized bleeding risk to benefit of ischemia prevention ratio. A major determinant of this ratio is the clinical indication for which anticoagulation is begun. Numerous phase III clinical trials have been conducted comparing the use of NOACs to VKAs or placebos for the management of nonvalvular atrial fibrillation and venous thromboembolism, and as adjunctive therapy for patients with acute coronary syndrome.6
Meta-analyses of randomized trials have shown the most significant benefit to be in patients with nonvalvular atrial fibrillation, where NOACs yield significant reductions in stroke, intracranial hemorrhage, and all-cause mortality compared to warfarin, while displaying variable effects with regard to gastrointestinal bleeding.6,7 In patients with VTE, NOACs have been found to have efficacy similar to that of VKAs with regard to the prevention of VTE or VTE-related death, and have been noted to have a better safety profile.6
Lastly, when studied as an adjunctive agent to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs have been associated with an increased bleeding risk without a significant decrease in thrombosis risk.6 Taken together, these data suggest that the primary indication for instituting NOAC therapy should be considered strongly when deciding upon which class of anticoagulant to use.
Since the introduction of NOACs, there has been concern over the lack of specific antidotes to therapy, especially when administered in patients with impaired clearance, a high likelihood of need for an urgent or emergent procedure, or those presenting with life threatening bleeding complications.
Most recently, however, interim analysis from clinical trial data has shown complete reversal of the direct thrombin inhibitor dabigatran with the humanized monoclonal antibody idarucizumab within minutes of administration in greater than 88% of patients studied.8 Similarly, agents such as a PER977 are currently under phase II clinical trials as they have been shown to form noncovalent hydrogen bonds and charge-charge interactions with oral factor Xa inhibitors as well as oral thrombin inhibitors leading to their reversal.9