New Anticoagulants in Ischemic Heart Disease
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- Rajan, L. & Moliterno, D.J. Curr Cardiol Rep (2012) 14: 450. doi:10.1007/s11886-012-0270-1
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Historically, the use of oral anticoagulants in acute coronary syndromes (ACS) has been controversial. Several prospective trials have shown that vitamin K antagonists (VKAs), such as warfarin or dicoumarol, reduce recurrent ischemic events but with a concomitant increased risk of bleeding. Other trial data have shown a neutral or net negative effect. Regardless, these prior observations are not readily transposable to contemporary practice where many ACS patients receive dual antiplatelet therapy and undergo cardiac catheterization and percutaneous coronary intervention. Because recurrent ischemic events continue to occur following index ACS presentation despite evidence-based practice and knowing the limitations of current oral anticoagulation strategies with VKA, the endeavor continues to find a more effective anticoagulant with predictable, dose-proportional pharmacokinetics, and minimal interactions with food and drugs. We review novel, emerging classes of anticoagulants that focus on specific targets in the coagulation cascade with the aim of improving long-term net clinical outcomes.
KeywordsAcute coronary syndromesNew oral anticoagulantsDirect thrombin inhibitorsFactor Xa inhibitorsAptamersIschemic heart disease
The recurrence of ischemic events following an acute coronary syndrome (ACS) despite an early invasive strategy combined with intravenous anticoagulants, use of glycoprotein IIb/IIIa inhibitors, dual antiplatelet regimens, and best evidence-based medical therapy for secondary prevention exposes a gap in our ability to reconcile successful immediate results with more durable long-term outcomes [1–3]. Oral anticoagulation with the vitamin K antagonist (VKA) warfarin added to conventional antiplatelet therapy has been shown to reduce ischemic events but at the cost of increased bleeding risks [4–6]. Patients being treated for ACS who have coexistent atrial fibrillation or mechanical valve prosthesis are similarly exposed to this treatment dilemma . Bleeding is not only a complication of antithrombotic therapy but may also have a causal relationship to cardiovascular risk, which may persist up to a year following the initial ACS presentation [8–10].
New oral anticoagulants in ACS
Aptamers REG1 (IV)
ATLAS ACS 2-TIMI 51 phase III [16•]
SEPIA-ACS TIMI 42 phase II 
RADAR phase IIb [28•]
REDEEM phase II 
Heparin+eptifibatide (all patients on DAPT)
Heparin (all patients on DAPT)
Placebo (all patients on ASA+thienopyridine)
Primary: CV death, MI, stroke 8.9 % vs 10.7 % placebo (P = 0.008)
Primary: Death, MI, urgent revascularization, bailout with GP IIb/IIa inhibitor
Secondary: Ischemic events, level of IXa inhibition, anticoagulant activity, duration of hospitalization, feasibility of early sheath removal
Secondary: All-cause mortality MI, stroke 9.2 % vs. 11.0 % placebo (P = 0.006)
40 % reduction in primary composite end point
4.4 % vs 7.3 % placebo
3.8 % to 3.6 % vs 6.2 % placebo
Major: 2.1 % vs 0.6 % Placebo (P < 0.001)
TIMI major or minor bleeding not related to CABG
Primary outcomes: ACUITY major or minor bleeding through 30 days
Primary end point: ISTH major bleeding or clinically relevant minor bleeding
Intracranial hemorrhage 0.6 % vs 0.2 % placebo (P = 0.009)
Nonsignificant increase 3.1 % to 3.4 % vs 2.7 %
18.2 %, 11.9 %, 8.5 % and 7.0 % with 25 %, 50 %, 75 % and 100 % reversal, respectively, vs 10.9 % placebo
3.5 %, 4.3 %, 7.9 %, and 7.8 % in the 50-,75-,110-, and 150- mg dosages, respectively, vs 2.4 % placebo
Fatal bleeding 0.3 % vs 0.2 % placebo (P = 0.660)
Factor Xa has long been regarded as a high-value therapeutic target integral to the coagulation cascade since it is the unification point of the intrinsic and extrinsic pathways. Rivaroxaban is a potent oral anticoagulant that directly and selectively inhibits factor Xa (Table 1). It has a high oral bioavailability with a half-life of 5 to 9 h, and undergoes biliary-fecal and renal clearance. It demonstrates stable, dose-dependent, predictable pharmacokinetics with a fast onset-offset of action. It has minimal food and drug interactions [12–14].
ATLAS ACS-TIMI 46 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46) was a phase II dose-determination trial. In this multinational, double-blind, dose-escalation study, 3,491 patients with a recent ACS were enrolled, and rivaroxaban was tested in doses ranging from 5 to 20 mg daily compared with placebo .
The primary safety end point was clinically significant bleeding (Thrombolysis In Myocardial Infarction [TIMI] major, TIMI minor, or requiring medical attention); the primary efficacy end point was death, myocardial infarction (MI), stroke, or severe recurrent ischemia requiring revascularization within 6 months. The composite end point of death, MI, or stroke was reduced with the lowest hazard ratios seen at the lowest twice-daily doses. Rates of the primary efficacy end point were 5.6 % (126/2331) for rivaroxaban versus 7.0 % (79/1160) for placebo (HR [hazard ratio] 0.79; 0.60–1.05; P = 0.10). There was a direct dose-dependent correlation to clinically significant bleeding (HR, 2.21; 95 % CI, 1.25–3.91) for 5 mg, 3.35 (2.31–4.87) for 10 mg, 3.60 (2.32–5.58) for 15 mg, and 5.06 (3.45–7.42) for 20-mg doses (P < 0.0001).
Based on the above observational data, an international, multicenter, double-blind placebo-controlled phase III trial, ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome 2 Thrombolysis in Myocardial Infarction 51), was launched to evaluate twice-daily rivaroxaban at doses of 2.5 and 5 mg as adjunctive therapy in patients with a recent ACS [16•]. In this study, 15,526 patients were randomized within 7 days of an ACS to receive twice-daily doses of either 2.5 or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. Standard medical therapy included aspirin and thienopyridines. The primary efficacy end point was a composite of death from cardiovascular causes, MI, or stroke. The secondary efficacy end point was death from any cause, MI, or stroke . The primary safety end point was TIMI major bleeding not related to coronary artery bypass grafting (CABG). Patients with a history of intracranial hemorrhage, ischemic stroke or transient ischemic attack, gastrointestinal bleed within the last 12 months, and renal impairment (creatinine clearance <30 mL/min) were excluded.
Rivaroxaban reduced the primary efficacy end point by 16 % compared with placebo, with respective rates of 8.9 % and 10.7 % (HR, 0.84; 95 % CI, 0.74–0.96; P = 0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1 % vs 10.7 %; P = 0.02) and the twice-daily 5-mg dose (8.8 % vs 10.7 %; P = 0.03). Rivaroxaban also reduced the secondary composite efficacy end point of death from any cause, MI, or stroke (9.2 % vs 11.0 %; HR, 0.84; 95 % CI, 0.74–0.95; P = 0.006). In addition, rivaroxaban reduced the risk of stent thrombosis (definite, probable, or possible) (2.3 % vs 2.9 %; HR, 0.69; 95 % CI, 0.51–0.93; P = 0.02) . It is arguable that the reduction in stent thrombosis may have contributed to the composite benefit. The lower dose of twice-daily 2.5-mg rivaroxaban resulted in a mortality benefit with a reduction in rates of death from cardiovascular causes (2.7 % vs 4.1 %; P = 0.002) and from any cause (2.9 % vs 4.5 %; P = 0.002). Interestingly, a survival benefit was not observed with the twice-daily 5-mg dose.
Compared with placebo, rivaroxaban increased the rates of major bleeding not related to bypass surgery (2.1 % vs 0.6 %; P < 0.001) and intracranial hemorrhage (0.6 % vs 0.2 %; P = 0.009), without a significant increase in fatal bleeding (0.3 % vs 0.2 %; P = 0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1 % vs 0.4 %; P = 0.04). It is plausible that the increased rate of bleeding seen with the higher doses of rivaroxaban negatively impacted the survival benefit compared to the lower-dose protocol. Furthermore, temporary cessation of antithrombotic therapy in cases of bleeding may have also driven the loss of efficacy.
Apixaban is a direct, selective, orally active, noncompetitive factor Xa inhibitor that is reversible [18, 19]. The APPRAISE (Apixaban for Prevention of Acute Ischemic Safety Events) trial was a phase II, double-blind, placebo-controlled study that investigated a range of doses of apixaban compared with placebo over 26 weeks in patients who had suffered a recent ACS and received standard evidence-based therapy for stabilization . A total of 1,715 patients were randomized to placebo for 6 months with four doses of apixaban, ranging from 2.5 mg twice daily to 20 mg daily. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, MI, severe recurrent ischemia, or ischemic stroke.
The independent Data and Safety Monitoring Committee recommended that the two higher-dose apixaban arms be discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (HR, 1.78; 95 % CI, 0.91–3.48; P = 0.09) and 10 mg once daily (HR, 2.45; 95 % CI, 1.31–4.61; P = 0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding.
Apixaban 2.5 mg twice daily (HR, 0.73; 95 % CI, 0.44–1.19; P = 0.21) and 10 mg once daily (HR, 0.61; 95 % CI, 0.35–1.04, P = 0.07) resulted in numerically lower rates of ischemic events, although not reaching statistical significance. There was also increased bleeding and reduced efficacy among patients receiving DAPT (76 % of patients were receiving clopidogrel) compared to those taking aspirin alone.
APPRAISE 2 was a phase III randomized, double-blind, placebo-controlled trial comparing apixaban at a dose of 5 mg twice daily with placebo and standard antiplatelet therapy among patients with a recent ACS and at least two additional risk factors for recurrent ischemic events . The median follow-up on 7,392 patients was 241 days; the primary outcome of cardiovascular death, MI, or ischemic stroke occurred in 7.5 % of patients assigned to apixaban and in 7.9 % of patients in the placebo arm (HR with apixaban, 0.95; 95 % CI, 0.80–1.11; P = 0.51). TIMI major bleeding occurred in 1.3 % of patients who received at least one dose of apixaban compared to 0.5 % of patients who received at least one dose of placebo (HR with apixaban, 2.59; 95 % CI, 1.50–4.46; P = 0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. Due to safety concerns resulting from increased major bleeding events without a corresponding reduction in recurrent ischemic events, the trial was prematurely discontinued.
RUBY-1 (a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban [YM150] following ACS) was a phase II dose-determining trial. In this international, multicenter, double-blind, prospective, randomized, parallel-group study, 1,279 patients with a recent ACS received 1 of 6 darexaban regimens ranging from 10 mg to 60 mg daily for 6 months or placebo, together with DAPT . The primary study end point was the incidence of major or clinically relevant nonmajor bleeding events. The main efficacy outcome was a composite of death, stroke, MI, systemic thromboembolism, and severe recurrent ischemia. At 6 months, bleeding rates were numerically higher in all darexaban arms versus placebo (pooled HR, 2.28; 95 % CI, 1.13–4.60; P = 0.022). There was the suggestion of a dose–response relationship as bleeding risks increased with escalating dosages (3.1 % for placebo vs 6.8 %, 5.6 %, 7.5 %, 5.6 %, 11.3 %, and 7.3 % for 5 mg twice daily, 10 mg once daily, 15 mg twice daily, 30 mg once daily, 30 mg twice daily, or 60 mg once daily of darexaban, respectively.)
The disappointing results were further underscored by a lack of an efficacy signal and failure to achieve a meaningful decrease in ischemic events (5.6 % for all doses combined vs 4.4 % for placebo), although the study was not adequately powered to assess efficacy. As a result of the above findings, further development of the drug has been halted.
This is an intravenously administered, direct, reversible factor Xa inhibitor with near-immediate onset of action and a short half-life, offering rapid on-off anticoagulant activity. It is also mainly cleared unchanged via the hepatobiliary system, thereby requiring no dose modification in renal insufficiency.
SEPIA-PCI (Randomized, Double-Blind, Dose-Ranging Study of Otamixaban, a Novel, Parenteral, Short-Acting Direct Factor Xa Inhibitor, in Percutaneous Coronary Intervention) was a dose-finding, double-blind, phase II trial where otamixaban (using five incremental weight-adjusted regimens) was compared to unfractionated heparin (UFH) in 947 patients before elective percutaneous coronary intervention (PCI) . Most patients received DAPT for the duration of the study. The primary end points were change in prothrombin fragments 1+2 (F1+2) and anti-factor Xa activity. The main secondary end points were TIMI bleeding at day 3 or hospital discharge and 30-day ischemic events.
Otamixaban reduced the prothrombin fragments F1+2 significantly more than UFH at the highest dose regimen (−0.3 vs −0.2 ng/mL, P = 0.008), and anti-factor Xa levels rose incrementally from 65 to 691 ng/mL with ascending otamixaban doses. No significant difference in the incidence of TIMI bleeding was observed between the otamixaban and UFH groups. TIMI major or minor bleeding occurred in 2.0 %, 1.9 %, 3.8 %, 3.9 %, and 2.6 % of patients receiving otamixaban doses 1 to 5, respectively, and in 3.8 % of patients receiving UFH.
The triple composite end point of ischemic events occurred in 5.8 %, 7.1 %, 3.8 %, 2.5 %, and 5.1 % of patients receiving otamixaban doses 1 to 5, respectively, and in 5.6 % of patients receiving UFH. There was no clear dose–response relationship in the incidence of ischemic events with doses 1 to 5, respectively, nor was there any significant difference in the rate of ischemic events between the otamixaban and UFH groups. This study was not designed or powered for “hard” clinical end points but laid the groundwork for the next phase II study of patients with ACS.
The SEPIA-ACS TIMI 42 (Otamixaban for the Treatment of Patients with Non-ST-elevation Acute Coronary Syndromes) was a double-blind, international, multicenter trial that randomized 3,241 patients to 1 of 5 maintenance doses of otamixaban (all given with a 0.08-mg/kg bolus) or to a control of UFH plus eptifibatide in patients with non-ST elevation MI (NSTEMI) ACS (Table 1). These doses reflected the intermediate dose range of otamixaban (0.12 and 0.16 mg/kg/h) in the preceding SEPIA-PCI trial, which showed lower ischemic end points and similar bleeding rates compared with heparin among patients undergoing non-urgent PCI. Nearly all patients were on DAPT with clopidogrel [24•].
The primary efficacy end point was a composite of death, MI, urgent revascularization, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days. The primary safety end point was TIMI major or minor bleeding not related to bypass surgery. Treatment with otamixaban at intermediate doses of 0.105 or 0.140 mg/kg/h compared with UFH plus eptifibatide was associated with a 40.0 % reduction in death or ischemic complications, 3.8 % to 3.6 % versus 6.2 % (relative ratio [RR], 0.61; 95 % CI, 0.36–1.02 and RR, 0.58; 95 % CI, 0.34–0.97, respectively), as well as a nonsignificant excesses of TIMI major or minor bleeding not related to CABG up to 7 days (3.1 % to 3.4 % vs 2.7 %). These differences in the composite end point were driven by reductions of 45 % (RR, 0.52; 95 % CI, 0.28–0.98 and RR, 0.56; 95 % CI, 0.30–1.03, respectively) in death or MI in the otamixaban group.
A phase III trial (NCT01076764) is now in progress comparing otamixaban to heparin plus eptifibatide in 10,930 patients with unstable angina or NSTEMI undergoing an early invasive strategy. The primary efficacy composite end point is all-cause death and MI from randomization to day 7. The primary safety end point is TIMI significant bleeding (composite of TIMI major and minor). The trial is expected to be completed in June 2012.
Factor IXa Inhibitors: Aptamers
Protein-binding oligonucleotides (aptamers) are single-stranded nucleic acids that inhibit a selected target protein or small molecule’s function by folding into a specific three-dimensional structure that permits high-affinity binding [25, 26]. Complementary oligonucleotides that alter aptamer conformation and actively reverse anticoagulant activity complete the system. REG1 is an anticoagulation system that consists of a therapeutic RNA aptamer, pegnivacogin, which is a specific factor IXa inhibitor, and anivamersen, its complimentary 15-nucleotide controlling agent. It carries the advantage of being specific, immediate, and titratable .
RADAR (A Study Assessing the REG1 Anticoagulation System Compared Heparin in Subjects with Acute Coronary Syndrome) is a phase IIb trial (Table 1) that has three main objectives. The trial sought to confirm that a dose of 1 mg/kg of pegnivacogin resulted in near-complete inhibition of factor IXa in patients with ACS, as well as to determine the safety of a range of doses of its reversal agent, anivamersen, after cardiac catheterization. Third, the efficacy of anticoagulation with pegnivacogin in patients with ACS undergoing PCI was to be evaluated [28•].
The primary outcome is a composite of major and minor bleeding through 30 days using a modified ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) bleeding scale. Secondary outcomes include ischemic events (death, nonfatal MI, recurrent ischemia in target vessel distribution, or urgent target lesion revascularization), level of factor IXa inhibition as measured by effect on measures of coagulation, duration of hospitalization, feasibility of early sheath removal, and clinical and laboratory markers of anticoagulant activity. In the pharmacokinetic/pharmacodynamic substudy, an intravenous bolus of 1 mg/kg of pegnivacogin resulted in consistent plasma concentrations with prolongation of activated partial thromboplastin time and virtually complete inhibition of factor IX activity in a cohort of patients with ACS undergoing cardiac catheterization .
Six hundred forty patients with ACS undergoing cardiac catheterization within 24 h of the index event were randomized to receive pegnivacogin 1 mg/kg or heparin; 388 of these patients went on to have PCI. Nearly all patients were on DAPT. Following cardiac catheterization, the group receiving pegnivacogin was further randomized to escalating doses of anivamersen to attain 25 %, 50 %, 75 %, and 100 % reversal followed by immediate sheath removal, while the heparin group had their sheaths removed within 6 h per standard of care.
The results were presented at the Transcatheter Cardiovascular Therapeutics meeting in November 2011. In the PCI cohort, the overall composite ischemic event rates (death, MI, recurrent ischemia, and urgent target vessel revascularization) were 4.4 % for the REG1 group and 7.3 % for the heparin group. The ACUITY major bleeding rates were comparable to heparin (18.2 %, 11.9 %, 8.5 %, and 7.0 % for the pegnivacogin group receiving 25 %, 50 %, 75 %, and 100 % reversal, respectively, vs 10.9 % for the heparin group).
The efficacy of REG1 in PCI appears favorable with numerically lower rates of ischemic events. Higher reversal corresponded to better safety with less bleeding events. This paves the way for REG1 to be further evaluated in adequately powered clinical trials.
Other active control models of aptamers directed against coagulation proteins like fVIIa–tissue factor complex, fIXa, fXa, and thrombin together with their reversal agents or antidotes are in the early stages of development [16•].
Direct Thrombin (Factor IIa) Inhibitors
Thrombin has a dual role in thrombogenesis. It is a principal factor in the coagulation cascade, facilitating the conversion of fibrinogen to fibrin in the generation of thrombus. It is also a potent factor in platelet activation during vascular endothelial injury and plaque rupture .
Ximelagatran was the first rollout of a novel oral anticoagulant and is a direct thrombin inhibitor that is rapidly metabolized to melagatran, its active form predominantly cleared by the kidneys . It has stable absorption and pharmacokinetics allowing for fixed dosing and has a rapid onset of action. It does not require surveillance of drug levels and has no significant drug interactions. It has a short plasma elimination half-life of 4 h, allowing a fairly rapid offset in the event of unexpected hemorrhage or emergent surgery.
ESTEEM (Efficacy and Safety of the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Recent Myocardial Damage) was a phase II, placebo-controlled, double-blind, international, multicenter, dose-determining study  of 1,883 patients with an ACS who were randomized within 14 days to 1 of 4 doses of ximelagatran (24, 36, 48, or 60 mg twice daily) or placebo for 6 months. All patients were on aspirin 160 mg daily. The primary efficacy outcome was the occurrence of all-cause death, nonfatal MI, and severe recurrent ischemia.
There was a 24 % relative risk reduction in the primary composite end point for the combined ximelagatran groups versus placebo (16.3 % vs 12.7 %; HR, 0.76; 95 % CI, 0.59–0.98; P = 0.036). While there was no dose response in relation to efficacy, it was apparent in the side effects of bleeding and elevated alanine transaminase concentrations. The cumulative risk of total bleeding (major and minor) was higher in those on ximelagatran than in those on placebo (22.0 % vs 13.0 %, respectively). Major bleeding rates were 1 % for the placebo group versus 2 % for the combined ximelagatran group.
Ultimately, the risks of hepatotoxicity and elevated liver enzymes that persisted even after the drug was terminated led to rejection by the US Food and Drug Administration and its withdrawal from the market . There were initial concerns that the hepatotoxicity was a class effect, but further studies on newer anticoagulants have not detected this signal.
Dabigatran etexilate was the first oral direct thrombin inhibitor approved for the indication of thromboembolism prophylaxis in patients with nonvalvular atrial fibrillation . Dabigatran is a potent, competitive, reversible, direct thrombin inhibitor that inhibits free thrombin, fibrin-bound thrombin, and thrombin-induced platelet aggregation .
The REDEEM (Randomized Dabigatran Etexilate Dose Finding Study in Patients with Acute Coronary Syndromes Post Index Event with Additional Risk Factors for Cardiovascular Complications Also Receiving Aspirin and Clopidogrel) trial was reported at the American Heart Association’s 2009 Scientific Sessions . This is a phase II, multicenter, dose-finding trial that randomized 1878 ACS patients within 14 days of an acute MI to placebo or 1 of 4 dabigatran dose regimens (50, 75, 110, or 150 mg) given twice daily and followed up for 6 months. Patients were already on DAPT with aspirin and clopidogrel and had at least one other risk factor prior to the index event (including prior MI in 29.0 %, heart failure in 12.0 %, and diabetes in 31.0 %). The primary end point was major bleeding (International Society of Thrombosis and Haemostasis criteria) or clinically relevant minor bleeding (Table 1).
The primary outcome was dose-dependent (P for trend <0.001), with the difference driven by rates in the two highest groups (2.4 % in the placebo group vs 3.5 %, 4.3 %, 7.9 %, and 7.8 % in the 50-, 75-, 110-, and 150-mg dosages, respectively). The rates of major bleeding alone were 0.5 % for placebo versus 0.8 %, 0.3 %, 2.0 %, and 1.2 % in the low- to high-dosage groups, respectively. Further evaluation will be required in a larger-scale phase III study that is adequately powered for clinical outcomes.
New oral anticoagulants and the evolving antithrombotic paradigm
• Stable pharmacodynamics and pharmacokinetics
• Increased bleeding risks
• Fixed dosing regimens
• No data comparing efficacy and safety with new antiplatelet agents like ticagrelor and prasugrel
• Minimal drug or food interactions
• No data on patients with concomitant atrial fibrillation, prosthetic heart valves, elderly, and renal impairment
• Fast on-off action
• Cost-benefit and risk-benefit issues
• Mortality benefit seen in low-dose rivaroxaban in combination with DAPT in ACS
• Polypharmacy–third antithrombotic therapy complicates patient adherence to multiple drug regimens
As more drugs compete for a place in the ideal anticoagulation regimen, the question remains whether polypharmacy therapy translates into better real-world outcomes. Likewise, as health care costs escalate, we will have to grapple with issues of cost-benefit and risk-benefit ratios. Nevertheless, there is room for cautious optimism, and the initial promise of drugs like rivaroxaban offer us strong encouragement into a future where a new generation of anticoagulants are tasked with improving the long-term outcomes of patients after their index cardiovascular event.
No potential conflicts of interest relevant to this article were reported.