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Anticoagulation in Acute Coronary Syndrome

Review of Major Therapeutic Advances

Pop, Calin, MD, PhD1,2,*; Matei, Claudia, MD, PhD1; Petris, Antoniu, MD, PhD3

doi: 10.1097/MJT.0000000000000913
Systematic Reviews
Free
SDC

Background: In patients with acute coronary syndrome (ACS), a persistent hypercoagulable state has been demonstrated and antithrombin therapy in addition to platelet inhibition has been proposed.

Areas of Uncertainty: Vitamin K antagonists (VKAs) were used as oral anticoagulant (OAC) therapy and produced mixed results whereas trials are still ongoing with non-vitamin K OACs (NOACs).

Data Sources: A literature search regarding benefits and risks of different OAC therapies in ACS was conducted through MEDLINE and EMBASE (last 20 years until September 2018).

Therapeutic Advances: Patients receiving dual antiplatelet therapy (DAPT) in combination with NOAC are to be considered at high bleeding risk. Rivaroxaban 2.5 mg BID in triple therapy with DAPT, rivaroxaban 15 mg, or dabigatran 110/150 mg BID in dual therapy with P2Y12 inhibitor (mainly clopidogrel) is safer in terms of bleeding risk than triple therapy with VKA plus DAPT. The reduction in ischemic events by NOACs was most promising when added to single antiplatelet therapy. Ongoing trials with apixaban and edoxaban could clarify whether dual therapy NOACs with P2Y12 inhibitor sufficiently protect against stent thrombosis or myocardial infarction and are safer in terms of bleeding risk than a dual therapy with a VKA and clopidogrel. In the absence of randomized trials, it is unknown whether dual therapy with NOAC and aspirin could be an alternative to NOAC and a P2Y12 inhibitor. Thus, the overall benefit of adding NOAC to antiplatelet treatment after ACS in patients without clear indication for long-term OAC is still unknown.

Conclusions: Different OACs have been tested as antithrombotic therapy after ACS in combination with single or DAPT and led to a modest reduction in ischemic events. Further studies evaluating NOACs in combination with single antiplatelet therapy or shorter duration of triple antithrombotic therapy are warranted.

1Emergency Clinical County Hospital of Baia Mare, Romania;

2“Vasile Goldis” University, Faculty of Medicine Arad, Romania; and

3Cardiology Clinic, “St. Spiridon” County Emergency Hospital, University of Medicine and Pharmacy “Grigore T. Popa” Iaşi, Romania.

Address for correspondence: Associate Professor, Emergency Clinical Hospital of Baia Mare, G. Cosbuc St no 31, Baia Mare 430200, Romania. E-mail: medicbm@yahoo.com

The authors have no conflicts of interest to declare.

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BACKGROUND

The most emergent manifestations of cardiovascular disease are the acute coronary syndromes (ACSs).1 The key event in the development of ACS is the thrombotic occlusion of a coronary artery as a result of the rupture of an atherosclerotic plaque, which triggers thrombosis through the activation of the hemostatic system.2,3 Besides the well-established role of platelets, there is substantial evidence suggesting the involvement of the coagulation system in the pathogenesis of ACS.1,2 Despite revascularization and optimal medical therapy (including newer P2Y12 receptor inhibitors), in patients with ACS, a persistent hypercoagulable state has also been demonstrated even after clinical stabilization; these patients remain at risk for recurrent vascular events.1,2 Thrombin levels are elevated for at least 6 months after the initial event for patients with ACS.1 This suggests a potential opportunity to lower the risk of recurrent ischemic cardiovascular events through direct thrombin or factor Xa inhibition.2–4

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AREAS OF UNCERTAINTY

In ACS, once plaque rupture has occurred, the potential for reperfusion is maximized by the initiation of antiplatelet and anticoagulant medications. By interrupting both platelet activation and the coagulation cascade, the goal is to prevent fibrin/platelet clot formation and cross-linking. Traditionally, anticoagulant therapy has targeted the intrinsic pathway of the coagulation cascade including unfractionated heparin (UFH) and low-molecular weight heparin (LMWH). Factor Xa is central in the coagulation cascade because it is involved in the initiation, amplification, and propagation phases of clot formation.5 Exposure to the tissue factor, after plaque rupture or erosion, activates factor Xa, which catalyzes the conversion of prothrombin to active thrombin.5 On a molar basis, factor Xa is more thrombogenic than thrombin (factor IIa) and is important for cellular proliferation and the inflammatory pathway.4,5 For synergy in preventing thrombus formation and inflammation, antithrombin therapy in addition to platelet inhibition has been proposed.1,4,5

In the 1940s, intravenous (IV) UFH was used for the treatment of patients with acute myocardial infarction (AMI). At that time, vitamin K antagonists (VKAs) were used as oral anticoagulant (OAC) therapy and were the only oral agents in use for several decades. Warfarin, a representing drug of the VKA class, inhibits multiple enzymes in the coagulation cascade including factor II (prothrombin), factor VII, factor IX, factor X, protein C, and protein S.7 Oral VKAs have been shown to prevent recurrent ischemic events after ACS, both as monotherapy and in combination with aspirin, but are cumbersome to use because of multiple interactions with food and drugs, the need for frequent laboratory monitoring, and the risk of bleeding.6,7 In addition, warfarin manifests a relatively long time–action relationship, complicating dosing.7 Warfarin has produced mixed results in patients with ACS. In some trials, it was shown to reduce cardiac ischemic events, but in others, no difference was observed when it was compared with aspirin alone. Thus, the search has continued for an anticoagulant with more predictable pharmacokinetics that perhaps provides a convenient fixed-dose administration option. Non-vitamin K OACs (NOACs), such as factor Xa inhibitors, have been evaluated as treatment options for ACS.7 NOACs have been tested as antithrombotic therapy after ACS in combination with single antiplatelet therapy or dual antiplatelet therapy (DAPT).

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DATA SOURCES

A literature search was conducted through MEDLINE and EMBASE (last 20 years until the first week of September 2018) using the search terms: ACS, parenteral anticoagulation, oral anticoagulation, bleeding risk, thrombosis, safety, and efficacy. Clinicaltrials.gov was consulted for a comprehensive list of ongoing and completed studies. Additional studies were identified through bibliographical citations.

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THERAPEUTIC ADVANCES IN PARENTERAL AND ORAL ANTICOAGULATION

Parenteral anticoagulation in ACS

Four agents are commonly used in ACS: UFH, LMWH (enoxaparin), fondaparinux (indirect agents), and bivalirudin (direct inhibitor of thrombin). IV UFH is indicated in all scenarios of ACS, alone or in combination with glycoprotein IIb/IIIa inhibitors, and should be administered when the diagnosis is made.8–10 In the course of ACS, the short-term use of parenteral anticoagulants have reduced the incidence of thrombotic events.3 Routine postprocedural anticoagulant therapy is not indicated after primary percutaneous coronary intervention (PCI), except when there is a separate indication of either full-dose anticoagulation [due, for instance, to atrial fibrillation (AF), mechanical valves, or left ventricle thrombus] or prophylactic doses for the prevention of venous thromboembolism in patients requiring prolonged bed rest.5–10

Enoxaparin, a LMWH used in patients with myocardial infarction (MI) who have been treated using fibrinolysis, proved to be more effective than UFH and was associated with a lower rate of rethrombosis but with an increase in minor bleeding complications and greater treatment costs.11 An IV bolus of enoxaparin 0.5 mg/kg was compared with UFH in randomized open-label AMIs were treated with primary angioplasty and IV enoxaparin or UFH to lower ischemic and bleeding events in a short- and long-term follow-up (ATOLL) trial including 910 patients with ST-segment elevation myocardial infarction (STEMI).12 The primary composite endpoint of 30-day death, MI, procedural failure, or major bleeding was not significantly reduced by enoxaparin, but there was a reduction in the composite main secondary endpoint of death, recurrent MI or ACS, or urgent revascularization.12 Importantly, there was no evidence of increased bleeding after the use of enoxaparin over UFH. In the per-protocol analysis of the ATOLL trial, IV enoxaparin was superior to UFH in reducing the primary endpoint, ischemic endpoints, mortality, and major bleeding.12 In a meta-analysis of 23 PCI trials (30, 966 patients, 33% primary PCI), enoxaparin was associated with a significant reduction in death as compared with UHF.13,14

UFH and LMWH are both factor IIa and factor Xa inhibitors. Fondaparinux inhibits factor Xa by potentiating antithrombin III. A significant reduction in both bleeding risk and mortality was observed, with no statistically significant difference in cardiovascular events between patients with non-ST segment elevation MI (NSTEMI) who were treated with fondaparinux as compared with enoxaparin.15,16 Patients with STEMI who were treated with fondaparinux had a significant decrease in cardiovascular events and mortality without an increase in bleeding complications in comparison with those treated with UFH. This benefit was not found in patients undergoing PCI. Thus, fondaparinux may be a useful option in patients who do not undergo reperfusion therapy.15 The use of fondaparinux in the context of primary PCI was associated with potential harm in the Organization for the Assessment of Strategies for Ischemic Syndromes 6 trial and is not recommended16 (Table 1).

Table 1

Table 1

Bivalirudin provides effective anticoagulation during PCI with reduced bleeding complications as compared with other options for both stable angina and patients with low-risk ACS.17 A meta-analysis of 5 dedicated randomized controlled trials compared bivalirudin with UFH with or without the planned use of GP IIb/IIIa inhibitors in patients with STEMI and showed no mortality advantages with bivalirudin but a reduction in the risk of major bleeding at the cost of an increased risk of acute stent thrombosis.18 The HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in AMI) trial showed markedly reduced bleeding complications and significantly reduced cardiac mortality in patients randomized to bivalirudin therapy with benefits that were maintained for up to 3 years after the initial procedure (bivalirudin group vs. UFH plus glycoprotein IIb/IIIa inhibitor group).19 In the MATRIX (bivalirudin or UFH in patients with ACSs managed invasively with and without ST elevation) trial that included 7213 patients with ACS (56% with STEMI), bivalirudin did not reduce the incidence of the primary endpoint (composite of death, MI, or stroke) as compared with UFH.20 A post hoc analysis suggested that prolonging bivalirudin with a full dose after PCI was associated with the lowest risk of ischemic and bleeding events, which is in accordance with the current label of the drug. Based on these data, bivalirudin should be considered in STEMI, especially in patients with a high bleeding risk.19,21 Bivalirudin is also recommended for patients with heparin-induced thrombocytopenia.9,21

The main limitation of all these anticoagulant agents is the need for parenteral administration, which makes their use impractical after hospital discharge. In patients receiving conservative treatment or fibrinolytic therapy, all agents can be used except for bivalirudin, which has not been well studied in these settings–Tables 1 and 2.

Table 2

Table 2

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Oral thrombin inhibitors in ACS

The first experiment with ximelagatran, an oral direct thrombin inhibitor that was later withdrawn from the market because of liver toxicity, showed numerically higher major bleeding and a reduction in the composite of death, MI, and stroke when added to aspirin for 6 months after an ACS22 (Table 3).

Table 3-a

Table 3-a

Table 3-b

Table 3-b

Dabigatran is the only oral direct thrombin inhibitor available for clinical use. Dabigatran etexilate is an oral prodrug that is rapidly converted by a serum esterase to dabigatran (a potent, direct, competitive inhibitor of thrombin). The efficacy and safety of dabigatran in patients with ACS were investigated in the phase II, dose-ranging randomized dabigatran etexilate dose finding study in patients with ACSs after index event with additional risk factors for cardiovascular complications; also receiving aspirin and clopidogrel trial.23 A total of 1861 patients with recent STEMI or NSTEMI, receiving treatment with DAPT, aspirin, and clopidogrel or another thienopyridine, were randomly assigned with different doses of dabigatran (dabigatran 50, 75, 110, and 150 mg BID) or a placebo. The index event had to be documented using elevated values of cardiac biomarkers together with ischemic symptoms or electrocardiographic changes. In addition, participants were required to have at least one risk factor for subsequent cardiovascular complications: age 65 years or above, diabetes mellitus (DM), previous MI, left bundle branch block, congestive heart failure requiring treatment, left ventricular ejection fraction ≤40%, peripheral arterial disease, moderate renal insufficiency (creatinine clearance ≥ 30–60 mL/min), or no revascularization in the index event. The rate of major or clinically relevant minor bleeding was 7.8%–7.9% with the 2 highest doses of dabigatran, an approximately 4-fold increase as compared with the placebo. Dabigatran was not associated with any ischemic benefit. It significantly reduced coagulation activity, such as D-dimer concentration23 (Table 3).

The open-label RE-DUAL PCI (Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting) trial randomly assigned more than 2700 patients with AF who underwent PCI to a regimen of warfarin plus a P2Y12 receptor inhibitor (clopidogrel or ticagrelor), and aspirin for 1 to 3 months or to a regimen of dabigatran (110 or 150 mg twice daily) plus a P2Y12 inhibitor. Therapy was continued for at least 6 months; after 1 year, the P2Y12 receptor blocker could be stopped or switched to aspirin at the discretion of the investigator. About 50 percent of patients presented with ACS. The primary endpoint of a major or clinically relevant nonmajor bleeding event occurred less often in the 110 and 150 mg dabigatran dual therapy groups. The incidence of a composite secondary efficacy endpoint (thromboembolic events, death, or unplanned revascularization) was similar in the 2 dual therapy groups combined as compared with the triple therapy group24 (Table 4).

Table 4-a

Table 4-a

Table 4-b

Table 4-b

Table 4-c

Table 4-c

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Oral Factor Xa inhibitors in ACS

Factor Xa inhibitors directly inhibit the enzyme-catalyzing generation of thrombin. Four of these agents, apixaban, darexaban, rivaroxaban and letaxaban, have been assessed in phase II studies in ACS.2,25

Rivaroxaban is an oral, selective, direct-acting factor Xa inhibitor that leads to the inactivation of free, fibrin-bound Xa, and factor Xa within the prothrombinase complex. Rivaroxaban has a half-life of 5–9 hours and is eliminated through the renal (66%) and fecal/biliary systems (28%). The inhibition of factor Xa persists for up to 24 hours after administration of a drug dose. Rivaroxaban is not recommended for cirrhotic patients with concomitant coagulopathy and end-stage renal failure (creatine clearance of <15 mL/min), and the dose needs to be adjusted in patients with advanced renal insufficiency (creatine clearance of 15–29 mL/min).2,4 The safety and efficacy of rivaroxaban in patients with ACS (1–7 days after the index event) were explored in a dose-escalation phase II randomized controlled trial of 3491 patients–ATLAS ACS-TIMI 46 study (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin with or without Thienopyridine Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46)25 (Table 3). The trial had 2 strata: stratum 1—monotherapy of aspirin; stratum 2—patients were enrolled and were given a placebo or different doses (5–20 mg) of rivaroxaban (2.5, 5, 7.5, 10 mg BID, 5, 10, 15, and 20 mg QD) for a 6-month period. Rivaroxaban showed a dose-dependent increase in clinically significant bleeding with a nonsignificant reduction in the primary efficacy endpoint (death, MI, stroke, or severe recurrent ischemia requiring revascularization). The secondary efficacy endpoint (death, MI, or stroke) was significantly decreased with rivaroxaban. A dose of 2.5 mg BID was the only regimen that did not show a statistically significant increase in bleeding risk.25 On the basis of the findings of this trial, the low-dose regimens (ie, 2.5 and 5 mg twice daily) were selected for further evaluation in a further randomized double-blind, multicenter, phase III trial, ATLAS ACS 2-TIMI 51.26 For this trial, 15,526 patients with ACS were enrolled within 7 days after the index event. Randomization was done on a 1:1:1 basis to receive either rivaroxaban (2.5 or 5 mg twice a day) or a placebo within each stratum (ie, acetylsalicylic acid vs. DAPT). The primary efficacy endpoint was a composite of cardiovascular death, MI, or stroke. The secondary efficacy endpoint was death from any cause, MI, or stroke. Thrombolysis in myocardial infarction (TIMI) major bleeding, not related to bypass surgery, was designated as the primary safety endpoint. Rivaroxaban reduced the primary efficacy endpoints in comparison to the placebo with rates of 9.1 versus 10.7% for 2.5 mg (P = 0.02) and 8.8 versus 10.7% for 5 mg (P = 0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the 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), a survival benefit that was not seen with the twice-daily 5-mg dose. Overall, a 16% relative risk reduction was observed in the primary efficacy composite with rivaroxaban (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.74–0.96; P = 0.008). The results also showed a significant decrease in secondary efficacy endpoints among patients who received rivaroxaban with rates of 9.2% and 11.0%, respectively (HR, 0.84; 95% CI, 0.74–0.95; P = 0.006). Rivaroxaban lowered the rate of stent thrombosis significantly (definite, probable, or possible), as compared with the placebo with rates of 2.3% and 2.9%, respectively (HR, 0.69; 95% CI, 0.51–0.93; P = 0.02). Although there was no increase in the rate of fatal bleeding, the incidence of TIMI major bleeding was higher among those who received rivaroxaban as compared with the placebo with rates of 2.1% and 0.6%, respectively (HR, 3.96; 95% CI, 2.46–6.38; P < 0.001), a finding that was also significant for the 2.5-mg and 5-mg doses of rivaroxaban (P < 0.001 for both comparisons). The rate of intracranial hemorrhage in the rivaroxaban group also increased significantly as compared with the placebo, 0.6% versus 0.2%, P = 0.009. The low dose of rivaroxaban (2.5 mg twice daily) was associated with a lower risk of bleeding events, including TIMI major bleeding, intracranial hemorrhage, and bleeding requiring medical attention, as compared with the 5-mg dose3 (Table 4). Making a direct comparison, the 2 treatment arms differed significantly in terms of the risk of cardiovascular death (both ischemic and hemorrhagic events) and total mortality with lower rates being seen with the 2.5-mg dose. In the analysis that directly compared the 2 doses of rivaroxaban, the incidence of overall fatal cardiovascular events was significantly greater with the 5-mg dose than with the 2.5-mg dose whereas the difference in fatal MIs trended toward significance.3,27 Given the survival benefit presented in the ATLAS ACS 2-TIMI 51 trial, the 2.5 mg BID regimen of rivaroxaban with aspirin alone or with DAPT obtained regulatory approval from the European Medicines Agency for secondary prevention in patients with ACS with elevated cardiac biomarkers.2 On the other hand, rivaroxaban has not been approved by the Food and Drug Administration for ACS indication because of concerns regarding missing data in the pivotal trial.3 The addition of low-dose rivaroxaban (2.5 mg BID for 1 year) is now considered within the European Society of Cardiology guidelines on NSTEMI and STEMI.8,9 In particular, in patients with NSTEMI without a history of previous stroke/TIA and at a high ischemic risk as well as a low bleeding risk who are receiving aspirin and clopidogrel, low-dose rivaroxaban (2.5 mg BID) may be considered after discontinuation of parenteral anticoagulation (class IIb, level of evidence B); in selected patients with STEMI who are receiving aspirin and clopidogrel, low-dose rivaroxaban (2.5 mg BID) may be considered if the patient has a low bleeding risk (class IIb, level of evidence B).

The bleeding risk of low-dose rivaroxaban (in addition to a P2Y12 receptor inhibitor) without aspirin was evaluated in phase II of the GEMINI-ACS-1 (A study to compare the safety of rivaroxaban vs. acetylsalicylic acid in addition to either clopidogrel or ticagrelor therapy in participants with acute coronary syndrome-1) trial.28 A total of 3037 patients with ACS were randomly assigned to 2.5 mg BID rivaroxaban versus 100 mg aspirin (1:1 ratio) in addition to a P2Y12 receptor inhibitor in a double-blind fashion. The choice of the P2Y12 receptor inhibitor (ticagrelor or clopidogrel) was not randomized and was left at the discretion of the investigator. The results of this phase II trial indicate that low-dose rivaroxaban (2.5 mg BID) does not result in higher bleeding as compared with aspirin (100 mg daily) in patients already on a P2Y12 inhibitor, post-ACS. There was a significant increase in bleeding with ticagrelor as compared with clopidogrel. Ischemic endpoints were also similar, but the trial was not powered to assess these independently. The GEMINI-ACS-1 trial suggests that stopping aspirin and adding low-dose rivaroxaban to a P2Y12 inhibitor has a similar bleeding profile to DAPT, but the ischemic benefit will need to be tested in a larger phase III trial.

The PIONEER AF-PCI (Open-label, Randomized, Controlled, Multicenter Study Exploring 2 Treatment Strategies of Rivaroxaban and a Dose-adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention) trial randomly assigned more than 2100 stented patients with nonvalvular AF to one of 3 antithrombotic regimens in a 1:1:1 ratio: low-dose rivaroxaban (15 mg daily) plus a P2Y12 inhibitor for 12 months; very low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months; or standard therapy with a dose-adjusted VKA plus DAPT for 1, 6, or 12 months. The index events were NSTEMI at 18%, STEMI at 12%, and unstable angina at 21%. The primary safety outcome was clinically significant bleeding or bleeding requiring medical attention or laboratory evaluation. The primary safety outcome occurred less often in 2 groups receiving rivaroxaban. The rates of death from cardiovascular causes, MI, or stroke were similar in 3 groups. The trial was not powered for ischemic events. Among participants with AF who underwent PCI with stenting, administration of either low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months or very low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a VKA plus DAPT for 1, 6, or 12 months.29 This trial adds to the growing body of literature suggesting a role for low-dose rivaroxaban in patients post-ACS (Table 4).

Apixaban is a selective direct-acting FXa inhibitor that affects both free and prothrombinase-bound FXa. The half-life of apixaban is approximately 12 hours, and it is eliminated through multiple pathways including hepatic metabolism, renal clearance, and biliary secretion.27 APPRAISE (Apixaban for Prevention of Acute Ischemic and Safety Events), a randomized, double-blind, multicenter, phase II study, evaluated apixaban in doses from 2.5 mg twice a day to 20 mg once a day. Within 7 days after the ACS event, 1715 patients were enrolled. The primary endpoint was major bleeding and clinically relevant nonmajor bleeding according to the International Society of Thrombosis and Haemostasis definitions. Overall, the addition of apixaban to patients with ACS treated with DAPT was associated with dose-related increase in bleeding events with a modest benefit in the form of a reduction of ischemic events30 (Table 3).

The phase III Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial investigated a 5 mg BID dose of apixaban (2.5 mg twice daily if creatinine clearance was ≤40 mL/min) in addition to DAPT after an ACS event. Among the baseline characteristics of study participants, 59% of patients were ≥65 years old, 47.8% of patients had DM, 10.0% of patients had a prior stroke, and 28.9% of patients had impaired renal function. TIMI major bleeding (primary safety outcome) occurred in 1.3% and 0.5% of patients in the apixaban and placebo groups, respectively. Apixaban was also associated with an increase in fatal bleeding events and intracranial bleeding as compared with the placebo: 2.7% versus 1.1%, P < 0.001. There was no reduction in ischemic events with the primary efficacy outcome, defined as a composite of cardiovascular death, MI, or ischemic stroke: 7.5% versus 7.9%, HR 0.95, 95% CI, 0.80–1.11, P = 0.51. After the recruitment of 7392 participants, the APPRAISE-2 trial terminated prematurely because of increased bleeding without clinical benefits31,32 (Table 3).

The result of the 2 phase III trials, ATLAS ACS 2-TIMI 51 and APPRAISE-2 are discordant. One probable reason may be attributed to the characteristics of the study population. The study participants of APPRAISE-2 were older and had more comorbidities (more DM and renal dysfunction). Patients with a history of stroke were excluded in ATLAS ACS 2-TIMI 51 trial but were enrolled in the APPRAISE-2 trial. The higher risk profile of patients enrolled in the APPRAISE-2 trial is also supported by the higher ischemic event rate. Another possible reason is the level of anticoagulant effects. The APPRAISE-2 trial tested 5 mg BID of apixaban, which is the same dose used for stroke prevention in patients with AF. In ATLAS ACS 2-TIMI 51, there was a survival benefit with the 2.5 mg BID daily dose, which is one-quarter of the total daily dose of rivaroxaban used in AF. Therefore, a high anticoagulant effect (doses used in AF) when added to DAPT in patients with ACS may not provide benefits because of the high risk of bleeding complications.2,33

A still ongoing clinical, phase 3b AUGUSTUS study open-label trial will evaluate the safety of apixaban versus a VKA and aspirin versus aspirin placebo in patients with AF and ACS or PCI (An Open-label, 2 × 2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban versus Vitamin K Antagonist and Aspirin versus Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention [ClinicalTrials.gov Identifier: NCT02415400]). This study can answer whether dual therapy strategies combining a NOAC with clopidogrel are safer in terms of bleeding risk than a dual therapy with a VKA and clopidogrel.

Darexaban is an oral, direct factor Xa inhibitor. The active metabolite, darexaban glucuronide, is responsible for the anticoagulant effect. The tolerability and safety of darexaban (YM150) for secondary prevention in patients with ACS was tested in the phase II, 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) trial (Table 3). In this trial, a total of 1279 patients with recent ACS (STEMI/NSTEMI) were enrolled and randomly assigned to different doses of darexaban (5, 10, 15, 30, 30, and 60 mg QD) or a placebo. The primary outcome, major bleeding, was increased in a dose-dependent manner in the darexaban group as compared with the placebo. There was no decrease in the incidence of adverse cardiovascular events with darexaban as compared with the placebo. After the RUBY-1 trial, the development of darexaban for patients with ACS was stopped2,34 (Table 3).

Letaxaban (TAK-442). The safety and tolerability of letaxaban were tested in the AXIOM ACS (Safety and efficacy of TAK-442 in subjects with acute coronary syndromes) trial.35 The AXIOM ACS trial was a dose-ranging, phase II trial that enrolled 2753 patients with ACS. This trial explored a wide range of letaxaban doses (from 10 to 120 mg BID) (Table 3). The rate of TIMI major bleeding, the primary endpoint of this study, was not significantly different between groups. The composite rate of TIMI major and minor bleeding was more frequent with letaxaban. The efficacy endpoint was similar between letaxaban and the placebo. There has not been further testing for patients with ACS with letaxaban (Table 3).

Edoxaban is a direct oral factor Xa inhibitor used for the prevention of ischemic strokes in patients with AF and used for the prevention/treatment of venous thromboembolism.2 In the phase III ENGAGE AF-TIMI 48 trial, edoxaban (60 or 30 mg once/daily) was noninferior to warfarin with respect to the prevention of strokes or systemic embolisms and was associated with significantly lower rates of bleeding and death from cardiovascular causes in patients with AF.36 At the time of this article, there is an ongoing prospective, randomized, parallel-design, open-label, pharmacodynamic study being conducted on patients with coronary artery disease who are on aspirin and clopidogrel to test 2 different edoxaban dosing regimens (60 or 30 mg once/daily) in addition to DAPT and in combination with clopidogrel only (after stopping aspirin)—Effects of Edoxaban on the Cellular and Protein Phase of Coagulation in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy With Aspirin and Clopidogrel (EDOX-APT): A Prospective Randomized Study (ClinicalTrials.gov Identifier: NCT02567461). Another ongoing study with edoxaban and post-ACS patients with stent placements is ENTRUST-AF-PCI: Edoxaban Treatment versus Vitamin K Antagonist in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ClinicalTrials.gov Identifier: NCT02866175).

Although it is preferable to administer parenteral anticoagulation in patients with ACS in well-organized intensive cardiovascular care units, the next frontier and measure of performance in ACS treatment may be to measure doses of prescribed OAC and compare them to doses used in randomized trials that show benefits.37,38

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CONCLUSIONS

In recent years, substantial progress in the prevention, diagnosis, and management of patients with ACS has been accomplished. Despite optimal pharmacological and invasive therapies, the burden of recurrent ischemic events and mortality remains high. The key challenge in terms of how to provide optimal protection against thrombotic events without excessive increases in bleeding risk has remained the same for decades. Navigating the different treatment possibilities remains a daunting task. Within a vast knowledge base and excellent trials, controversy still exists on how to best manage patients presenting with ACS. Although guidelines and assistance exist, ultimately many of these questions are best answered when considering the totality of the patient's presentation. The practicing cardiologist faces numerous uncertainties as they treat patients with ACS. Addition of a NOAC to antiplatelet therapy led to a modest reduction in cardiovascular events but an increase in bleeding, most pronounced in patients receiving DAPT. The reduction in ischemic events by NOACs was most promising when added to single antiplatelet therapy. However, single antiplatelet treatment is rarely used because many patients with ACS are treated with PCIs and stents for which guidelines recommend dual antiplatelet treatment. Further studies evaluating NOACs in combination with effective single antiplatelet therapy or shorter duration of triple antithrombotic therapy are warranted. Alternative strategies with new drugs, both antiplatelet and anticoagulant agents, and new coronary stents will help on the journey to achieve this ultimate goal.

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Keywords:

acute coronary syndrome; parenteral anticoagulation; oral anticoagulation; bleeding risk; thrombosis; safety; efficacy

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