New Oral Anticoagulants: Great Promise for Therapeutic Advance but Great Knowledge Gaps Remain to Be Filled

For almost 60 years, warfarin has been the only available oral anticoagulant for the management of venous, arterial, and cardiac thrombosis and for prophylaxis against thromboembolism. However, warfarin is characterized by complex food and drug interactions leading to variable anticoagulation, less than optimally predictable dosing, and the consequent need for relatively frequent, costly, and inconvenient blood testing to monitor the drug's activity. Therefore, more ‘user friendly' anticoagulants have long been sought. Three new oral anticoagulants (NOACs), i.e. dabigatran, rivaroxaban and apixaban, all acting on different elements of the coagulation cascade than warfarin, have recently been approved for marketing by the US Food and Drug Administration (FDA). None is likely to prove ‘ideal' and none is as fully characterized as warfarin in terms of efficacy, safety, and dose-response relation. Nonetheless, these agents all manifest theoretical and apparent clinical advantages compared with warfarin and have opened an exciting new chapter in the effort to prevent pathological clotting and its sequelae. Two additional NOACs, i.e. edoxaban [1] and betrixaban [2], both direct factor Xa inhibitors like riveroxaban and apixaban, are well into development, and may also be available for clinical use within the next few years. The ideal anticoagulant should be capable of oral administration, should be in a form that makes administration/dosing simple for the patient, should manifest a rapid onset of action and a relatively rapid loss of activity after cessation of administration, should require limited monitoring, should be unaffected by pharmacological or food interactions, should have a wide therapeutic index, and should be affordable so as to preclude financial hardship when used indefinitely. In addition and very importantly, an effective antidote should be available in case of an overdose or unexpectedly excessive activity. As a group, the NOACs meet some of these needs far better than warfarin. As a result, the use of oral anticoagulants is currently of great interest, as the applicability of this therapy for various medical problems is reconsidered. However, some deficiencies in the characteristics of the NOACs as anticoagulants have become apparent and, in addition, gaps in our knowledge of the new drugs currently prevent their optimal application. For example, one of the most highly praised characteristics of the NOACs is the lack of requirement for monitoring of activity, leading to easier use and lower maintenance costs in comparison with warfarin. However, it is important to consider that lack of a convenient method for monitoring the therapeutic effect may preclude identification of the occasional individual who may be genetically incapable of the expected response to a NOAC and, in addition, renders the prescriber incapable of objectively assessing adherence to the prescribed regimen. The relative importance of the benefits and possible deficiencies of lack of monitoring will need clarification as research in this field continues, while development of a convenient monitoring system may prove desirable.This article will briefly review the unique pharmacology of each of the NOACs, as well as available evidence suggesting particular applicability in certain settings compared with warfarin. Most importantly, we will emphasize deficiencies in the applicability of the current NOACs and gaps in our knowledge that must be filled by additional research if the full potential of NOACs is to be understood and realized. Dabigatran etexilate mesylate (Pradaxa) was the first NOAC approved by the FDA for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). Dabigatran etexilate mesylate is a prodrug which, when metabolized to dabigatran by cleavage of two side chains, is a direct thrombin inhibitor (fig. 1) with high affinity and specificity for the active site of thrombin. Thus, it prevents the conversion of fibrinogen to fibrin, inhibiting clot formation [3]. Rivaroxaban, the second FDA-approved NOAC, is a highly selective inhibitor of factor Xa. Since factor Xa is located at the junction of the intrinsic and the extrinsic coagulation pathways, its inhibition interrupts both pathways of the blood coagulation cascade that produces thrombin from prothrombin and the development of thrombi. Its effect is reversible. Apixaban, the third and most recently approved NOAC, also directly inhibits factor Xa. Table 1 describes the pharmacokinetics of all three medications and compares them with those of warfarin. It is readily apparent that, in comparison with warfarin, the NOACs, as a group, have substantially shorter times to peak blood concentrations and half-lives and, in general, have far fewer potentially deleterious drug-drug interactions. However, to date, antidotes to reverse excessive effects (bleeding) have not yet been developed for any of these drugs though active efforts are ongoing in this area [3]. Two of the three require twice daily dosing, an inconvenience compared with warfarin.Dabigatran was compared to warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial [4]. In that study, 18,113 patients with AF and at least one other thromboembolic risk factor were randomized to fixed doses of dabigatran (110 or 150 mg twice daily) or warfarin titrated to a conventionally therapeutic international normalized ratio (INR). Low-dose dabigatran was noninferior to warfarin but the higher dose of dabigatran was superior to warfarin in reducing the primary composite outcome of stroke or systemic embolism. Bleeding events were significantly lower with low-dose dabigatran than with warfarin, but when the higher dose of dabigatran was administered bleeding events were indistinguishable from those with warfarin. Both doses were superior to warfarin in reducing hemorrhagic stroke but were not distinguishable in terms of effects on mortality. Indeed, the relative paucity of hemorrhagic stroke has been noted with all NOACs, though the basis for this apparent benefit remains speculative, as discussed below. Rivaroxaban was compared to warfarin in the Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) [5]. In 14,264 patients with nonvalvular AF who had other factors associated with moderate-to-high risk for stroke, either a fixed dose of rivaroxaban or INR-based dose-adjusted warfarin was administered in a randomized fashion. Rivaroxaban was noninferior to warfarin in the prevention of subsequent stroke or systemic embolism. Major bleeding and clinically relevant nonmajor bleeding did not differ significantly between the two study groups. Intracranial and fatal bleeding occurred more frequently in the warfarin group and bleeding from gastrointestinal sites occurred more frequently in the rivaroxaban group, as did bleeding that led to transfusion. Cerebral ‘tissue factor' is known to modulate hemostasis in the cerebral vessels. The reason for reduced intracerebral bleeding with NOACs is not clear but it has been speculated that NOACs do not affect the complex of tissue factor and factor VIIa that promotes normal intracerebral clotting, whereas warfarin decreases the activity of this complex. The first large randomized study of apixaban for nonvalvular AF was the Apixaban versus Acetylsalicylic Acid to Prevent Stroke (AVERROES) trial [6,7]. The study population comprised 5,599 patients with nonvalvular AF who were not candidates for vitamin K antagonist therapy because of previous intolerance or other ineligibility. Patients were randomized to receive either acetylsalicylic acid (81-324 mg/day) or apixaban. The AVERROES trial was terminated early by the data and safety monitoring committee when the interim efficacy analysis showed that apixaban was better than acetylsalicylic acid for the reduction of stroke and systemic embolism. Apixaban was associated with a lower rate of ischemic stroke and fewer hemorrhagic strokes than aspirin, though there was no statistically significant difference in mortality rates. Importantly, there was also no difference in major bleeding, though apixaban was associated with a significantly greater frequency of minor bleeding. Though this trial demonstrated the superiority of apixaban to aspirin, the potential adjunctive benefit of aspirin to NOACs remains an important issue requiring assessment. It is now known that platelets, presumably activated, are well distributed in and contribute in several ways to the formation and propagation of venous as well as arterial thrombi. Activated platelets also produce many factors that potentiate clot lysis. The Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial was conducted to compare apixaban and warfarin for stroke prevention in patients with nonvalvular intermediate- to high-risk AF [8,9]. This trial randomized 18,201 patients to either fixed-dose apixaban or INR-based warfarin. After a median follow-up of 1.8 years, patients in the apixaban group had a lower incidence of stroke or systemic embolism than the warfarin group. Apixaban also reduced all-cause mortality and cardiovascular mortality. In addition, apixaban was associated with fewer major bleeding events than warfarin.Hence, all three NOACs have been effective in preventing systemic thromboembolism in patients with nonvalvular AF. However, in this area, important gaps in our current knowledge remain which need to be filled with additional research. For example, no trial has directly compared one NOAC to any other. As a result, there is no rigorous evidence from which to infer superiority of one over another for the indication of stroke or embolism prevention in nonvalvular AF and no data to enable the clinician to match specific patients to one NOAC over another for this indication. Nonetheless, apixaban is the only medication of the three which has shown a mortality benefit over warfarin in any study population, though patient selection differed for ARISTOTLE compared to that for the other NOAC trials, precluding a firm comparison. Perhaps more importantly, no data as yet relate the use of any NOAC on the basis of the CHADS2 and/or CHA2DS2-VASc scores. The application of these scores is based on the expected effects of warfarin and of aspirin. With NOACs, algorithms for incorporating risk scores into treatment decisions may differ from the warfarin-based standard. In other words, we lack data to determine the risk:benefit relation of the new antithrombotic therapies for the individual patient.Dabigatran was originally studied for the prevention of deep vein thrombosis (DVT) after orthopedic surgery and was effective [10,11]. Initially, dabigatran was compared to enoxaparin for thromboprophylaxis after total hip arthroplasty in RE-NOVATE II (Oral Dabigatran versus Enoxaparin for Thromboprophylaxis after Primary Total Hip Arthroplasty) [10]. Dabigatran (220 mg once daily, starting with a half dose 1-4 h after surgery) for 28-35 days was effective as well as acceptably safe compared to enoxaparin (40 mg once daily, starting the evening before surgery). The primary efficacy outcome including a composite of total venous thromboembolism (VTE) and death from all causes occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group (p < 0.0001). Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group (p = 0.03). Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p = 0.40). The incidence of adverse events during treatment, including liver enzyme elevations and cardiac events, was similar between the groups. In parallel, dabigatran was noninferior to enoxaparin in thrombophylaxis in total knee surgery in the RE-MODEL (Thromboembolism Prevention after Knee Surgery) trial [11]. In this study, patients undergoing total knee replacement received dabigatran 150-220 mg once daily, starting with a half dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily, starting with a half dose 1-4 h after surgery. Patients were followed for 3 months. The primary efficacy outcome, VTE or mortality during treatment, occurred in 37.7% (193 of 512) of the enoxaparin group versus 36.4% (183 of 503) of the dabigatran etexilate 220 mg group. Both dabigatran doses were noninferior to enoxaparin based on the prespecified noninferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3 vs. 1.5 and 1.3%, respectively). No significant differences in the incidences of liver enzyme elevation or acute coronary events were observed during treatment or follow-up. In contrast to RE-MODEL, the RE-MOBILIZE (Oral Thrombin Inhibitor Dabigatran Etexilate vs. North American Enoxaparin Regimen for Prevention of Venous Thromboembolism after Knee Arthroplasty Surgery) trial [12] which compared dabigatran (150 or 220 mg once daily, given 6-12 h after surgery) to enoxaparin (30 mg subcutaneous twice daily after surgery) found dabigatran to be inferior to enoxaparin. In this study, drug administration stopped at contrast venography 12-15 days after surgery. The incidence of VTE was higher with dabigatran (34 and 31% for dabigatran 150 and 220 mg, respectively) compared to enoxaparin (25%). Bleeding rates were similar, and no drug-related hepatic illness was recognized. The discrepancy in results between the two trials may be attributable to the delayed administration of dabigatran and more intense or prolonged administration of enoxaparin. However, dabigatran is effective in the treatment of acute VTE. The RE-COVER (Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism) trial compared dabigatran (150 mg twice daily) with warfarin (dose adjusted to achieve an INR of 2.0-3.0) for the treatment of acute VTE and found these regimens to be equivalent in terms of the incidence of recurrent symptomatic VTE and related deaths after 6 months of treatment [13,14]. Most recently, Schulman et al. [15] reported data from the Extended Use of Dabigatran, Warfarin or Placebo in Venous Thromboembolism (RE-MEDY and RE-SONATE) trials. The active-control study was designated RE-MEDY, and the placebo-control study was designated RE-SONATE. Both studies had a randomized, double-blind design and enrolled patients who had completed at least 3 months of treatment for VTE. The primary efficacy outcome was recurrent symptomatic and objectively verified VTE or death associated with VTE (or unexplained death in the placebo-control study). In RE-SONATE, dabigatran 150 b.i.d. was compared with placebo for 6 months after 6-18 months of standard anticoagulation with warfarin for DVT. Dabigatran reduced recurrent by though bleeding events were significantly higher with dabigatran than with no difference was observed versus placebo in terms of major bleeding. The follow-up showed that dabigatran reduced recurrent by compared to In active-control dabigatran was statistically significantly inferior to warfarin in reducing recurrent VTE vs. 1.3%, = Major bleeding rates were similar but the incidence of acute coronary was higher in the dabigatran group compared to the warfarin group vs. = The comprised three studies that compared rivaroxaban and enoxaparin plus a vitamin K antagonist for the treatment of symptomatic prevention of recurrent VTE in patients with acute symptomatic and acute symptomatic embolism prevention of recurrent venous blood with rivaroxaban was studied in in patients who had completed 6 or months of treatment with rivaroxaban or a vitamin K The studies showed that, like dabigatran and apixaban, as the be used both in treatment and prevention of the studies were by other evidence of the of The of in Major the of and patients undergoing total hip arthroplasty or total knee arthroplasty The rivaroxaban regimens were significantly more effective than different enoxaparin regimens at reducing the composite of symptomatic and and all-cause mortality. of major bleeding did not differ significantly between rivaroxaban and enoxaparin was compared with enoxaparin to prevent venous thrombosis in patients in the and for the Prevention of VTE in Patients Rivaroxaban with In that rivaroxaban was associated with a reduction in the risk of compared with in patients with However, bleeding rates were significantly with rivaroxaban major randomized trials have apixaban with enoxaparin for the prevention of VTE. 1 versus Anticoagulation with and in Patients Total Knee Surgery) patients total knee replacement surgery. 3 patients total hip replacement surgery. 1 did not meet the prespecified for noninferiority but and 3 showed that apixaban was statistically significantly superior to enoxaparin in terms of the primary composite of all VTE and death from any The Apixaban to from trial showed that days of treatment with apixaban mg twice daily no significant compared to days of treatment with enoxaparin 40 mg daily for the prevention of VTE in patients for medical who were at risk for but major bleeding was more with apixaban after the of Embolism and with trial enrolled patients with acute or who were randomized to apixaban mg twice daily for 1 followed by mg twice daily for 6 months compared to enoxaparin plus warfarin. were not yet available at the of a randomized patients who had completed 6-12 months of anticoagulation for VTE to low-dose apixaban mg = apixaban mg = or placebo = for an additional of follow-up. Apixaban in an reduction in recurrent VTE or death when either or was used but no difference in bleeding events between apixaban and placebo when the dose of the NOAC was used Therapy to in to Therapy in Subjects with Acute in was a randomized trial more than patients with two doses of rivaroxaban with placebo on a of standard therapy showed that rivaroxaban cardiovascular and stroke patients with with Apixaban for Prevention of Acute 1 apixaban, at doses of mg daily, in patients who had and who were Treatment with apixaban in in bleeding events and a fewer ischemic both ischemic events and bleeding events, the optimal dose to be mg was showed that, compared with apixaban was associated with a significant in the risk of bleeding, a significant effect on the incidence of recurrent ischemic events In of the of the reason for a with apixaban, also a Factor Xa is not No major trial has dabigatran in patients with the FDA a that dabigatran is in patients with The was based on cessation of the trial II to the and of Oral Etexilate in Patients after in which dabigatran more including and compared to warfarin. results the in dose-response with NOACs compared with doses of dabigatran were far higher than those used in nonvalvular AF and yet were greater with dabigatran than with warfarin in this The basis for this discrepancy is as is the dabigatran dose that be acceptably effective in bleeding None of the NOACs is currently for thromboembolic prophylaxis in the of to the basis of the dose-response relation of NOACs in the of certain is important to if that be to prevent pathological thrombosis in the of of the three NOACs have several of the of an ideal Dabigatran, and apixaban have a relatively rapid onset of be administered and, warfarin, do not require monitoring for in because of drug-drug and interactions. effective antithrombotic doses for the studied bleeding rates are lower with all three medications when compared to warfarin. the three NOACs, rivaroxaban may in more adherence to prescribed regimens because of its relatively long compared with the other daily than the twice daily with dabigatran and apixaban. three NOACs replacement in the other great with the need for of the NOAC with warfarin for some while the vitamin K antagonist which days during which the patient be the of dabigatran versus warfarin was and costs were in the study In this study, dabigatran was superior to warfarin in terms of and the ratio in another study, the higher of dabigatran was by in INR monitoring and a lower of clinical events than with warfarin Though NOACs are very for several for which have been anticoagulation for some is expected to be However, the effects and of therapy with NOACs are not yet the benefits and of warfarin for have been from of patients over 60 years. NOACs have been studied in a population of patients with nonvalvular in and for VTE prophylaxis or the efficacy of these medications in AF and atrial has not yet been demonstrated and, as the data from the of the dose-response characteristics of dabigatran in the of a the need for additional research before of this drug to this important area be rivaroxaban and apixaban in AF or for is not yet Bleeding rates are lower with NOACs than with effective doses of warfarin. However, in contrast to warfarin, if a patient has a bleeding no antidote so far to reverse the effects of NOACs, though several are development Anticoagulation with warfarin be with vitamin K and, for rapid with have been reported with rivaroxaban when the drug is in the of anticoagulation, though this may be a of of the shorter acting drug when administration of warfarin, with its relatively delayed onset of is rigorous for evidence of a must be with research. Nonetheless, as with drug the of between different including those for or subcutaneous administration, will the efficacy and safety of anticoagulation for patients in or for events surgery) require of anticoagulation for This must be In addition, more is to enable to bleeding risk optimally in individual i.e. risk factors specific to additional is in the use of NOACs for patients at a high risk for bleeding, as patients with relatively is available to the use of NOACs in patients of an data the potential for particular though more data this may not be a and those with most adverse effect of dabigatran is the of which is The next most side effect is bleeding. The most adverse effect with the other two NOACs is bleeding. The of other adverse effects are similar for all three hepatic and and for NOACs are in Dabigatran was the first NOAC approved by the FDA for the prevention of stroke and systemic thromboembolism in AF. This occurred in Rivaroxaban was approved by the FDA in for prophylaxis of VTE in patients undergoing hip and knee In the FDA approved rivaroxaban for the prevention of thromboembolism in AF. the FDA approved rivaroxaban for the treatment of VTE including and and for prophylaxis against The approved apixaban in for the prevention of VTE. Most recently, in the FDA approved apixaban for the prevention of thromboembolism in AF or be expected in the are warfarin in the management of venous and systemic thromboembolism and for the management of when with standard However, additional data are to determine there is a efficacy NOACs for any specific clinical indication. Warfarin remains the anticoagulant of in for which no data for NOACs, and for patients who the new The of NOACs is the of many to anticoagulation in for which NOACs are However, in this early of our knowledge and in application of the new drugs is with to approved more data are