Novel oral anticoagulants for acute coronary syndrome

Acute coronary syndrome

Acute coronary syndrome (ACS) is the diagnosis given to several cardiovascular conditions including unstable angina (UA), ST-elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI) [Mozaffarian et al. 2016]. Male patients of advanced age with a family history of coronary artery disease are at a higher risk of experiencing ACS [Timmins, 2015]. In 2010, approximately 600,000 patients annually were discharged from hospitals due to ACS [Mozaffarian et al. 2016]. The overall incidence of patients with ACS or myocardial infarction (MI) due to STEMI has been declining within the last few years [Mozaffarian et al. 2016].

While the clinical presentation of NSTEMI and UA may differ, the pathophysiology is similar, allowing for the umbrella term non-ST-elevation-ACS (NSTE-ACS) in the US guidelines [Amsterdam et al. 2014]. The primary pathogenesis of ACS is due to the development of atherosclerotic plaques and the consequences of the subsequent rupture of unstable plaques in the myocardium [Dobesh and Oestreich, 2013]. The ruptured atherosclerotic plaque not only reduces coronary blood flow but also causes platelet activation as a result of injury to the blood vessel [Dobesh and Oestreich, 2013]. Following platelet activation, the rupture of the atherosclerotic plaque triggers the activation of the coagulation pathway, which further leads to thrombin production [De Caterina and Goto, 2016]. Some plaques that are firmly rooted in the vessel wall may fully occlude the vessel, which results in STEMI, and necessitates immediate reperfusion therapy [Amsterdam et al. 2014; Dobesh and Oestreich, 2013; De Caterina et al. 2016]. Alternately, some plaques become mobile in the bloodstream and may cause ischemia or decreased oxygen supply to the myocardium due to partial obstruction of the blood vessel [Dobesh and Oestreich, 2013].

MI occurs when there is evidence of myocardial necrosis or ischemia. Diagnosis is primarily made by evaluating specific cardiac biomarkers, electrocardiographic (ECG) findings, and imaging, or by pathology. Cardiac troponin I or T in the blood are the preferred biomarkers used to detect MIs. In acute MI, a positive diagnosis is made by an increase in cardiac biomarkers (>99^th percentile of the upper reference limit) such as cardiac troponins (I or T) or the myocardial b fraction of creatinine kinase (CKMB) plus one or more of the following: the development of ST changes or new left-bundle branch block, development of Q waves, imaging indicative of new myocardial necrosis, or identification of intracoronary thrombus by angiography or autopsy. MIs are subdivided into different classifications based on clinical presentation, disease progression, and pathology [Thygesen et al. 2012].

Anticoagulation in acute coronary syndrome

Initial management of ACS involves the use of oxygen, nitrates, calcium channel blockers, beta adrenergic blockers, analgesic therapy, cholesterol management, and antiplatelet agents [Amsterdam et al. 2014]. Antiplatelet agents are used to counteract the increase in platelet activation that occurs during ACS. The American Heart Association and American College of Cardiology NSTE-ACS Guidelines recommend dual antiplatelet therapy (DAPT) with the use of aspirin, if tolerated, and a P2Y₁₂-receptor inhibitor such as clopidogrel, prasugrel, or ticagrelor for up to 12 months in patients for whom NSTE-ACS is definite or likely, whether they receive ischemia guided therapy or early invasive strategies [Amsterdam et al. 2014]. Additionally, due to the resulting platelet-rich thrombus and the prothrombotic state, the use of anticoagulants, such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs) and antithrombotic agents, are also indicated in the management of ACS [Mozaffarian et al. 2016; De Caterina et al. 2016; De Caterina and Goto, 2016]. The majority of anticoagulants indicated for the management of ACS are available in parenteral formulations, which are ideal for the acute setting but not optimal for long-term use [Dobesh and Oestreich, 2013; De Caterina et al. 2016]. Following the initial ACS event, thrombin remains elevated and patients are at an increased risk for recurrence of ACS [Carreras and Mega, 2015].

Vitamin K antagonists, such as warfarin, exert their anticoagulant activity by interfering with the conversion of vitamin K and vitamin K epoxide through inhibition of vitamin K epoxide reductase [Hirsch et al. 1998]. This results in the inhibition of vitamin K-dependent coagulation factors including prothrombin, factor VII, factor IX, factor X, protein S and protein C. Because the anticoagulant activity of warfarin is based on the inhibition of vitamin K-dependent factors, frequent therapeutic monitoring is required to achieve optimal anticoagulation levels. In addition, the onset of warfarin effect is not immediate; the onset of anticoagulant effect may not occur for 2–7 days, depending on the dose administered. For this reason, patients should be given parenteral anticoagulants, such as heparin, to bridge the anticoagulant effect until warfarin is therapeutic [Hirsch et al. 1998]. Warfarin is the only oral anticoagulant indicated for use in the treatment of ACS in the US. The use of warfarin is restricted to patients with an indication for triple therapy (warfarin plus aspirin and a P2Y₁₂-receptor inhibitor), such as those with atrial fibrillation, mechanical valve or deep venous thromboembolism (VTE). The current guidelines recommend treatment for the shortest duration possible to decrease the risk of bleeding in those requiring triple therapy [Amsterdam et al. 2014]. Frequent monitoring, increased drug interactions, food–drug interactions, and increased risk of bleeding when combined with DAPT further limit the use of warfarin in ACS. The development of novel oral anticoagulants (NOACs) addresses some of the limitations of warfarin and may have a potential role in the management of ACS. The purpose of this review is to discuss the role of NOACs such as rivaroxaban and apixaban in the management and prevention of ACS.

Novel oral anticoagulants

Selective factor Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban are used in the US under the brand names Xarelto, Eliquis and Savaysa, respectively [Bayer Pharma AG, 2015; Bristol-Myers Squibb Company, 2012; Daiichi Sankyo Co., 2015]. These factor Xa inhibitors do not require the use of a cofactor, such as antithrombin III, for their inhibition of the coagulation process. All of these agents have been FDA approved for use in the prevention of ischemic strokes for patients with nonvalvular atrial fibrillation and for the treatment of VTEs and pulmonary embolism. However, only apixaban and rivaroxaban have indications for VTE prophylaxis for patients posthip- or knee-replacement surgery. The most significant adverse events associated with factor Xa inhibitors are bleeding events [Bayer Pharma AG, 2015; Bristol-Myers Squibb Company, 2012; Daiichi Sankyo Co., 2015].

Dabigatran, marketed in the US as Pradaxa, is the only oral direct thrombin inhibitor currently available [Boehringer Ingelheim Pharmaceuticals, Inc., 2010]. Dabigatran works by binding to thrombin and preventing the thrombin-mediated conversion of fibrinogen to fibrin, which is an important step in the clotting cascade and the development of thromboembolisms. Like the factor Xa inhibitors, dabigatran is indicated for the prevention of strokes in patients with nonvalvular atrial fibrillation, treatment of VTEs, and for prophylaxis of VTEs in patients undergoing hip-replacement surgery. Bleeding events are also the major adverse events associated with dabigatran, however gastric-like symptoms are common events seen with dabigatran, unlike the other novel agents [Boehringer Ingelheim Pharmaceuticals, Inc., 2010].

Warfarin’s major advantage over factor Xa inhibitors has been the use of an established reversal agent. Dabigatran is the first of the novel agents to have an available reversal drug, idaruxizuman (Praxibind), which was approved in the US in 2015 [Boehringer Ingelheim Pharmaceuticals, Inc., 2015]. Currently, andexanet alfa is being reviewed by the FDA to reverse the effects of factor Xa inhibitors, based on results from a trial of its use in rivaroxaban- and apixaban-treated patients [Siegal et al. 2015]. Research into the role of NOACs in ACS is supported by the success of the approved NOACs for their current indications and the potential to reverse these agents after a bleeding event.

Rivaroxaban

The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With or Without Thienopyridine Therapy in Subjects With ACS-Thrombolysis In MI 46 (ATLAS ACS-TIMI 46) study was a randomized, double-blind, placebo-controlled, phase II, dose-escalation trial were 3491 participants were randomly assigned to rivaroxaban 5, 10, 15, or 20 mg once daily or placebo [Mega et al. 2009]. The study population was further stratified, based on whether the participant was on aspirin only, or DAPT, prior to randomization. The primary safety endpoint was clinically significant bleeding; whereas the primary efficacy endpoint was time-to-the-first episode of death, MI, stroke, or severe, recurrent ischemia requiring revascularization [Mega et al. 2009]. The absolute rates of clinically significant bleeding occurred less in the stratum of patients that were on aspirin only; however, there were fewer patients in this stratum compared with the stratum of patients on DAPT. There was an overall observed dose-dependent increase in bleeding risk among the rivaroxaban treatment arms compared with placebo, with reported hazard ratios of 2.21 for the 5 mg dose, 3.35 for the 10 mg dose, 3.60 for the 15 mg dose, and 5.06 for the 20 mg dose (p < 0.0001). The data showed a trend towards benefit of rivaroxaban over placebo for the primary efficacy endpoint; although, statistical significance was not reached during the study (p = 0.10) [Mega et al. 2009].

Although potential efficacy was seen, the dose-dependent trend in increased bleeding risk with rivaroxaban in the ATLAS ACS-TIMI 46 trial led to the study of safety and efficacy with two lower doses of rivaroxaban in the phase III ATLAS ACS 2-TIMI 51 clinical trial. In this double-blind, placebo-controlled, phase III study, 15,526 subjects, already managed on aspirin with or without a thienopyridine (clopidogrel or ticlopidine), were randomly assigned to rivaroxaban, dosed at 2.5 mg twice daily or 5 mg twice-daily, or placebo [Mega et al. 2012]. Baseline characteristics showed that >90% of the study population was on standard DAPT. The primary efficacy endpoint was the composite of death from cardiovascular causes, MI or stroke. Whereas the primary safety endpoint was thrombolysis in myocardial infarction (TIMI) major bleeding, not related to coronary artery bypass grafting [Mega et al. 2012]. The combined doses of rivaroxaban significantly reduced the primary efficacy endpoint as compared with placebo, with a combined rate of 8.9% in the rivaroxaban arm compared with a rate of 10.7% in the placebo arm (p = 0.008). Contrary to the positive results for the primary efficacy endpoint, there was a significantly higher rate of the primary safety endpoint in the rivaroxaban arm. TIMI major bleeding rates were 2.1% in the rivaroxaban study arm compared with 0.6% in the placebo arm (p < 0.001) [Mega et al. 2012]. This trend in increased bleeding risk among the rivaroxaban study participants was also observed when evaluating TIMI minor bleeding, TIMI bleeding requiring medical attention, and intracranial hemorrhage (p = 0.003, p < 0.001, and p = 0.009, respectively). However, there were no statistically significant differences in fatal bleeds between the rivaroxaban and placebo arms [Mega et al. 2012].

In a prespecified secondary analysis of the ATLAS ACS 2 TIMI 51 trial, a subset of stabilized STEMI patients were evaluated to determine if early initiation of rivaroxaban would be of benefit in reducing cardiovascular death, MI, or stroke in this specific group of patients [Mega et al. 2013a]. Approximately half of the original trial’s study population presented with a STEMI for a subgroup study population of 7817. Results from this analysis revealed a benefit in rivaroxaban over placebo at reducing the primary efficacy endpoint of composite cardiovascular death, MI, or stroke 8.4% versus 10.6% (p = 0.019). Importantly, this significant difference between rivaroxaban and placebo emerged early on in the study, where patients are at a higher risk of post-STEMI events, 1.7% versus 2.3% within the first 30 days of treatment (p = 0.042) [Mega et al. 2013a]. As observed in the primary study, the rivaroxaban arms had significant increases in TIMI major bleeding and intracranial hemorrhage compared with placebo (p < 0.001 and p = 0.015, respectively), without an observed significant increase in fatal bleeds (p = 0.51) [Mega et al. 2013a].

An additional subgroup analysis of the ATLAS ACS 2 TIMI 51 study evaluated the use of rivaroxaban in patients with previous stents as well as those who may have undergone percutaneous coronary intervention (PCI) as part of the index event [Gibson et al. 2013]. DAPT is the standard of therapy for patients following PCI to reduce stent thrombosis and occlusion. Twice daily rivaroxaban 2.5 mg, in addition to DAPT, further reduced the incidence of Academic Research Consortium (ARC)-defined definite or probable stent thrombosis and mortality when compared with placebo (p = 0.023 and p = 0.039, respectively) [Gibson et al. 2013].

Throughout the ATLAS ACS 2 TIMI 51 study and subgroup analyses, most of the data were reported as composite doses of rivaroxaban compared with placebo [Mega et al. 2012]. When the individual 2.5 and 5 mg doses were compared with each other, substantial differences in the safety profiles were identified [Mega et al. 2013b]. There were lower rates of fatal bleeding and TIMI major or minor bleeding in the 2.5 mg arm compared with the 5 mg arm (p = 0.044 and p = 0.021, respectively). This difference in bleeding rates was observed without a significant difference between the doses for the primary efficacy endpoint (p = 0.89) [Mega et al. 2013b]. The data are promising for the 2.5 mg dose of rivaroxaban for use in ACS; however, limitations may exist if patients have indications beyond ACS that would warrant the full dose of rivaroxaban, such as patients with atrial fibrillation or VTE [Mega et al. 2013b].

Based on several clinical trials, the recommendation to use NOACs in ACS has been restricted, due to the increased risk of bleeding events when adding these agents to standard of care with DAPT without an observed impact on cardiovascular events. The exception to this was seen in the ATLAS ACS 2-TIMI 51 trial, where low-dose rivaroxaban added to DAPT had positive benefits in the reduction of death and recurrent cardiovascular events, despite the observed increases in bleeding [Mega et al. 2012]. New research, spurred by this and other previous studies and observations, is underway to evaluate removing aspirin from the conventional ASC treatment and replacing it with a factor Xa inhibitor, rivaroxaban [Povsic et al. 2016]. The rationale is that directly inhibiting thrombin will result in a more direct inhibition of platelet activation, which relies on thrombin. Rat models demonstrated that the combination of rivaroxaban with clopidogrel was more effective in reducing thrombus than either agent alone, with DAPT, or a combination of rivaroxaban with aspirin. This efficacy was achieved while maintaining lower bleeding rates than with DAPT or triple therapy. Additionally, it is proposed that rivaroxaban may work in synergy with ticagrelor in the inhibition of platelet aggregation, suggesting that this combination may reduce ischemic events through both anticoagulation and inhibition of platelet activation [Povsic et al. 2016].

Apixaban

Apixaban, a selective factor Xa inhibitor, was approved in the US under the brand name Eliquis in 2012 [Bristol-Myers Squibb Company, 2012]. The development of a reversal agent, andexanet alfa, which has positive data when studied in older apixaban-treated patients, may increase the interest in apixaban for its current indications and in ACS [Siegal et al. 2015]. The usage of apixaban for ACS was first explored in the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial [APPRAISE steering committee and investigators, 2009]. Authors of this international, multicenter trial measured four doses of apixaban (2.5 mg twice daily, 10 mg daily, 10 mg twice daily, 20 mg daily) versus placebo in over 1700 STEMI or NSTE-ACS patients administered within 7 days of the acute event. Treatment with apixaban was given for 26 weeks, along with standard post-ACS treatment such as aspirin, which was given in all patients, and clopidogrel, which was given at the discretion of the patient’s physician. The two higher doses of apixaban (10 mg twice daily and 20 mg daily) were stopped early, due to increased bleeding events. The remaining doses also showed dose-dependent increases in bleeding and failed to show a statistically significant difference in the primary outcome of composite cardiovascular death, MI, severe recurrent ischemia, or ischemic stroke (2.5 mg, p = 0.21; 10 mg, p = 0.07) [APPRAISE Steering Committee and Investigators, 2009].

Subsequent apixaban trials, the APPRAISE-2 and APPRAISE-J, were not able to show a major benefit of apixaban for ACS [Alexander et al. 2011; Ogawa et al. 2013]. The APPRAISE-2, which was a phase III multicenter study, tested apixaban 5 mg twice daily versus placebo in over 7000 patients after an ACS event. This trial was stopped early due to an increase in bleeding observed in the apixaban arm (hazard ratio 2.59; 95% CI 1.50–4.46, p = 0.001) while having a nonsignificant decrease in the primary outcome of composite cardiovascular death, MI, or ischemic stroke (hazard ratio 0.95; 95% CI 0.80–1.11, p = 0.50) [Alexander et al. 2011]. The APPRAISE-J trial was designed to analyze the safety of apixaban in 151 Japanese ACS patients [Ogawa et al. 2013]. This trial was not powered for efficacy events and resulted in only a trend towards more bleeding events in apixaban-treated patients (p values not provided). Ultimately, APPRAISE-J was stopped early, based on the data from the APPRAISE-2 trial [Ogawa et al. 2013].

Emerging agents

Edoxaban, a factor Xa inhibitor marketed under the name Savaysa in the US, was FDA approved in 2015 [Daiichi Sankyo Co., 2015]. The mechanism for its use in ACS is the same as rivaroxaban and apixaban; however, there are no published trials for this indication [Daiichi Sankyo Co., 2015]. Dabigatran, the only oral direct thrombin inhibitor currently on the market, has one trial in ACS patients. Results from the RE-DEEM study, a double-blind, placebo-controlled, dose-escalation, phase II clinical trial comparing dabigatran 50 mg, 75 mg, 110 mg, and 150 mg with placebo when added to DAPT post ACS, were similar to the results of the apixaban and rivaroxaban clinical trials [Oldgren et al. 2011]. Subjects in the dabigatran 110 mg and 150 mg arms had a substantial increase in the primary outcome of major or clinically relevant minor bleeding compared with placebo (p < 0.001) [Oldgren et al. 2011]. The patients at the higher dabigatran doses also had a lower composite of cardiovascular death, nonfatal MI, or nonhemorrhagic stroke; although, this was not set to be evaluated as a primary study outcome [Oldgren et al. 2011].

Other oral factor Xa inhibitors with clinical trials for ACS include darexaban (YM150) and letaxaban (TAK-442). Darexaban is represented in the RUBY-1 trial that examined its use in 1279 high risk NSTE-ACS or STEMI patients compared with placebo [Steg et al. 2011]. The primary endpoint was the incidence of major and clinically relevant nonmajor bleeding events based on the International Society on Thrombosis and Hemostasis (ISTH) definition, with secondary outcomes such as TIMI major bleeding and all-cause mortality. Darexaban had significantly more bleeding in a dose-response relationship than placebo (p = 0.009 for trend) and the bleeding rates were similar, whether receiving once daily or twice daily doses. The study was not powered for efficacy; however, the secondary efficacy endpoints were comparable between darexaban and placebo [Steg et al. 2011]. The AXIOM trial for letaxaban had an analogous phase II, placebo-controlled design [Goldstein et al. 2014]. AXIOM was a dose-ranging study of 2753 patients who were hospitalized following an ACS event. The primary endpoint of TIMI major bleeding was comparable in letaxaban versus placebo (p = 0.47), however the combined TIMI major and minor bleeding was significantly more in letaxaban (2.1% versus 0.9%, p = 0.025). Again, this trial was not powered for efficacy and there was no major difference between letaxaban and placebo [Goldstein et al. 2014]. It is unclear whether future studies will be performed to pursue this as an ACS indication for darexaban or letaxaban.

Differing from the NOACs that have been studied in ACS, there is a new intravenous agent in development that has early studies in ACS. Otamixaban, another factor Xa inhibitor, was studied in a phase II and phase III trial for treatment of patients with ACS, the SEPIA-ACS1 TIMI 42 and the TAO trial, respectively [Sabatine et al. 2009; Steg et al. 2013]. The SEPIA-ACS1 TIMI 42 trial was a dose-ranging study of five doses of otamixaban infusion versus heparin in combination with eptifibatide (a glycoprotein IIb/IIIa inhibitor) administered during PCI in 3241 patients [Sabatine et al. 2009]. The method of providing bolus doses followed by various continuous infusions was similar to the regimens used in a previous study of otamixaban in patients’ schedules for nonurgent PCI, known as the SEPIA-PCI trial [Cohen et al. 2007]. The primary outcome was a composite of all-cause death, MI, severe, recurrent MI requiring urgent revascularization, or bailout use of a glycoprotein IIb/IIIa inhibitor within 7 days of treatment. The primary safety outcome was TIMI major or minor bleeding within 7 days. Otamixaban failed to show a significant difference in the primary efficacy endpoint (p = 0.34) among all treatment groups compared with heparin. There was an observed dose-response increase in bleeding for the otamixaban groups compared with the heparin combination (p = 0.0001 for trend) [Sabatine et al. 2009]. The bleeding results differed from the SEPIA-PCI trial, which had no difference in TIMI major, minor, or minimal bleeding between otamixaban groups compared with heparin, with the exception of the lowest dose, which had lower bleeding (p = 0.018) [Cohen et al. 2007]. The phase III TAO trial evaluated the use of otamixaban for 13,229 patients in the subset of ACS with NSTE-ACS versus heparin used with eptifibatide [Steg et al. 2013]. The primary efficacy outcome was all-cause death or new MI within 7 days of the intervention. Otamixaban failed to show superiority to heparin for the primary outcome (p = 0.93) and had more TIMI major or minor bleeding compared with heparin (p < 0.001) [Steg et al. 2013].

Conclusion

Due to the known increase in thrombin production during ACS, there is a potential role for targeting thrombin specifically for secondary prevention [Giri and Jennings, 2015]. NOACs’ future in ACS is unclear, due to the amplified risk of bleeding in the aforementioned trials, lack of consensus for a target dose for each agent, and the need for more evidence of efficacy. Rivaroxaban has arisen as the most promising agent and has gained approval for ACS by the European Medicinal Agency (EMA) for its 2.5 mg twice-daily dose based on ATLAS-2 [Bayer Pharma AG, 2015]. Additionally, the 2016 European Society of Cardiology (ESC) guidelines list rivaroxaban as an option for patients after the acute phase of ACS, who are receiving aspirin and clopidogrel [Roffi et al. 2016]. The two newest antiplatelet agents, prasugrel and ticagrelor, have had positive results when compared with clopidogre,l at reducing the rates of cardiovascular death, nonfatal MI, and nonfatal stroke in the landmark trials, TRITON-TIMI 38 and PLATO respectively [Montalescot et al. 2009; Wallentin et al. 2009]. There were some differences in bleeding events with each of these agents compared with clopidogrel; in particular, an increased risk of bleeding following coronary artery bypass grafting with prasugrel and an increased risk of fatal intracranial bleeding with ticagrelor [Montalescot et al. 2009; Wallentin et al. 2009]. Extra caution should be taken when considering using the NOACs with prasugrel or ticagrelor, due the potential increased risk for bleeding and the lack of clinical outcome data with this combination. Currently, the US has not approved any NOACs for ACS treatment and these agents are not recommended in the STEMI or NSTE-ACS guidelines [Amsterdam et al. 2014; O’Gara et al. 2013]. Rivaroxaban and apixaban have ongoing studies related to ACS patients, which may aid in clarifying the role of NOACs.