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Keywords:

  • Coagulation/Thrombosis;
  • Ischemic heart disease;
  • Acute coronary syndromes;
  • New anticoagulants

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References

Apixaban is an orally active, selective, direct-acting, reversible inhibitor of factor Xa that is under evaluation for the management of acute coronary syndromes (ACS). This article critically reviews the rationale and evidence for the use of anticoagulants in the long-term management of ACS, preliminary data for apixaban from the phase 2 apixaban for prevention of acute ischemic and safety events (APPRAISE) trial, and the potential future role of apixaban for this indication.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References

The last decade has witnessed the development of orally active, selective inhibitors of individual coagulation factors, particularly those drugs targeting activated factor X (Xa) and thrombin [1]. Designed to overcome the limitations of the oral vitamin K antagonists (VKAs), the new oral anticoagulants have many of the characteristics of an ideal anticoagulant (Table 1) including a predictable dose response, which obviates the need for routine laboratory monitoring, a rapid onset of action, low potential for food and drug interactions, and a low risk of off-target side effects.

Table 1.  Characteristics of an ideal anticoagulant
Pharmacokinetics
Administered orally, once daily, or parenterally
Low potential for food and drug interactions
Predictable dose response and pharmacokinetics
Multiple pathways of elimination (no dose adjustment required with renal or hepatic dysfunction)
Pharmacodynamics and clinical characteristics
Selective inhibitor of coagulation, limiting the potential for off-target side effects
Inhibits both free and clot-bound-activated coagulation factors, potentially improving efficacy
Rapid onset of action
No requirement for routine coagulation monitoring
Highly effective in reducing thromboembolic events
Low bleeding rates
Availability of an effective antagonist for reversal of anticoagulant effect

Parenterally administered anticoagulants (unfractionated and low molecular weight heparins) are effective for the prevention of myocardial infarction and death in patients with acute coronary syndromes (ACS). However, despite contemporary evidence-based care, patients continue to suffer adverse clinical events during the weeks and months after an episode of ACS [2]. In the Global Registry of Acute Coronary Events registry, nearly 40% of the deaths and a third of the myocardial infarctions (MI) occurred between 2 and 6 months after the index episode of ACS [2]. Even with dual antiplatelet therapy, death, MI, or stroke occurs in over 9% of patients 1 year after an ACS [3].

One potential strategy to prevent the risk of recurrent ischemic events is to continue anticoagulation long term. The complexity of parenteral administration of heparins limit their use beyond hospital discharge and a strategy of prolonged administration of low molecular weight heparin compared to placebo has not been shown to be beneficial in patients with ACS [4]. Long-term anticoagulation with a VKA reduces the risk of recurrent ischemic events in patients with ACS, both when given alone and in combination with aspirin [5–7], but is infrequently used because VKAs have a narrow therapeutic index, variable dose-response, numerous food and drug interactions, and a high propensity to bleeding, particularly when used in combination with antiplatelet agents [7]. Because of the favorable properties of the new, orally active anticoagulants and their proven effectiveness compared with warfarin for stroke prevention in patients with atrial fibrillation [8], prolonged oral anticoagulant therapy is theoretically an attractive option for patients with ACS. Three new oral anticoagulants, the factor Xa inhibitors, apixaban, and rivaroxaban, and the direct thrombin inhibitor, dabigatran etexilate, are in advanced stages of evaluation for this indication [9–13] (Table 2). In this article, we review the pharmacological and clinical data for the use of apixaban in ACS.

Table 2.  Pharmacokinetics of the three new orally active anticoagulants under evaluation for the long-term management of patients with ACS
 Apixaban [9,15]Rivaroxaban [10,12]Dabigatran [11,13]
  1. CYP, cytochrome.

  2. aPotent inhibitors of CYP3A4 include azole antifungals, macrolide antibiotics (e.g., clarithromycin), and protease inhibitors (e.g., atanazavir).

  3. bPotent inhibitors of both CYP3A4 and P-glycoprotein include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole) and protease inhibitors, such as ritonavir.

  4. cincludes amiodarone and quinidine.

TargetFactor XaFactor XaThrombin
ProdrugNoNoYes
Bioavailability60%90%6%
DosingTwice dailyTwice dailyTwice daily
t-max (median, h)131.5
t-half (h)8–147–1112–14
Protein binding87%90%35%
Renal excretion25%66%80%
Drug interactionsPotent inhibitors of CYP3A4/5aPotent inhibitors of CYP3A4 and P-glycoproteinbInhibitors of p-glycoproteinc

Pharmacology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References

Apixaban (Bristol-Myers Squibb, New York, NY) is an orally bioavailable, highly selective, direct-acting, reversible inhibitor of factor Xa [14]. The drug is rapidly absorbed after oral dosing with maximum plasma concentration (Cmax) achieved in about 1 h. The plasma half-life of apixaban is 8–14 h, thus enabling twice daily dosing [9]. Approximately, 25% of the drug is excreted unchanged in the urine and a further 25% is excreted unchanged in the feces. The remaining drug is metabolized into inactive compounds, partly by CYP3A4 and CYP3A5 enzymes in the liver [1,9,15]. Apixaban does not induce CYP enzymes but is susceptible to interaction with strong CYP enzyme inhibitors and inducers [1]. The multiple elimination pathways of apixaban suggest that the drug can be used in patients with moderate renal or hepatic dysfunction.

Clinical Data

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References

Preclinical and dose-ranging studies have provided encouraging evidence that apixaban is efficacious over a wide range of doses [16–18]. Two large phase III studies evaluated apixaban 2.5 mg twice daily against subcutaneous enoxaparin for the prevention of venous thromboembolism in patients undergoing total knee replacement [19,20]. Although one of the studies failed to show noninferiority of apixaban when compared to enoxaparin [19], both studies demonstrated that apixaban is an effective drug for the prevention of venous thromboembolism with reduced rates of clinically relevant bleeding. Experience to date with apixaban in patients with arterial thrombosis is limited to one large phase II study in patients with ACS [21].

The APPRAISE Study

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References

Design

The phase II Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial is the only published randomized evaluation of apixaban in patients with ACS [21]. APPRAISE was an international, multicenter, double-blind, placebo-controlled, dose-finding study that was performed in two phases. In the first phase (Phase A), patients were assigned in a 1:1:1 fashion to placebo, apixaban 2.5 mg twice daily, or apixaban 10 mg once daily. After about a quarter of the patients had received study drug for at least 30 days, an independent data monitoring committee reviewed the data and recommended the inclusion of two planned higher doses of apixaban (10 mg twice daily and 20 mg once daily). In the second phase (Phase B), treatment assignment was in the ratio of 3:1:1:2:2 (placebo or apixaban 2.5 mg twice daily, 10 mg once daily, 10 mg twice daily, and 20 mg once daily, respectively). The two higher-dose arms were allocated more patients to obtain more information on bleeding events at these doses.

Patients

Patients were eligible for enrollment if they were within 7 days of presentation with ACS (either ST elevation or non-ST elevation), were clinically stable and had at least one additional risk factor for recurrent ischemic events (such as diabetes mellitus, cerebral or peripheral vascular disease, congestive heart failure, or left ventricular ejection fraction <40%). Patients were excluded if they were planned for catheterization or revascularization, had severe renal insufficiency, or were receiving a strong CYP3A4 inhibitor.

Outcomes

The primary study outcome was the occurrence of major bleeding and clinically relevant nonmajor bleeding, as defined by the International Society of Thrombosis and Hemostasis (ISTH) [22]. A secondary outcome was the composite of cardiovascular death, myocardial infarction (MI), severe recurrent ischemia, or ischemic stroke.

Data Monitoring and Analysis

The sample size of 1800 patients was expected to provide reasonably precise estimates of the primary outcome and was not based on formal power calculations.

Unblinded review of the data was done by the independent data monitoring committee after the completion of Phase A of the study and after 50% and 75% of patients had received the study drug for at least 30 days. Limited safety data were assessed every 2 weeks. Based on a review of the data after 1498 patients had been randomized, the committee recommended the discontinuation of the two higher-dose arms of apixaban because of excess bleeding, particularly among those receiving dual antiplatelet therapy.

Bleeding data were analyzed for all patients who received at least one dose of study drug and included events that occurred up to 2 days after the discontinuation of study drug. Kaplan–Meier curves for the primary outcome for each apixaban arm were compared with that of the placebo arm using a Cox proportional-hazard regression model. The efficacy analyses were by intention-to-treat. Analyses were stratified by baseline clopidogrel use.

Results

The study enrolled moderate-risk patients at a median of 4 days after the index ACS. Enrolled patients received contemporary evidence-based care with nearly all of them receiving aspirin and >75% receiving dual antiplatelet therapy with the combination of aspirin and clopidogrel. Over three-fourths of the patients receiving either placebo, apixaban 2.5 mg twice daily, or 10 mg once daily completed the 26-week treatment period. 8.4% discontinued treatment as a result of an adverse event and the proportion of patients discontinuing study therapy was similar in each group.

The principal findings of the study were as follows:

  • 1
    There was a significant, dose-dependent increase in ISTH major or clinically relevant nonmajor bleeding with apixaban 2.5 mg twice daily (5.7%; 95% CI 3.4–8.9) and 10 mg once daily (7.9%; 95% CI 5.2–11.5) compared with placebo (3%; 95% CI 1.8–4.7). The 10 mg twice daily and 20 mg once daily dose arms of apixaban had substantially higher bleeding rates than the 2.5 mg twice daily and 10 mg once daily doses.
  • 2
    Bleeding event rates in apixaban-treated patients were substantially higher in patients who received the combination of aspirin and clopidogrel than in those who received aspirin alone (Figure 1).
  • 3
    There were no significant differences in the rates of nonfatal or fatal cardiovascular events between apixaban 2.5 mg twice daily, apixaban 10 mg once daily, and placebo (Figure 2). However, the event rates were numerically lower in patients receiving apixaban compared to placebo. Cardiovascular event rates were higher among those not receiving clopidogrel, and the difference between the apixaban and placebo arms was greater among patients taking aspirin alone than among those taking clopidogrel and aspirin.
image

Figure 1. Data from the apixaban for prevention of acute ischemic and safety events study. International society of thrombosis and hemostasis major and clinically relevant nonmajor bleeding events were more frequent with apixaban among patients receiving clopidogrel along with aspirin. The increase in bleeding with apixaban compared to placebo was also greater among patients on dual antiplatelet therapy. However, no statistical tests of significance were reported.. Reproduced with permission from reference [21].

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image

Figure 2. Data from the apixaban for prevention of acute ischemic and safety events study. Kaplan–Meier curves for the efficacy composite of cardiovascular death, myocardial infarction, severe recurrent ischemia, and ischemic stroke. The hazard ratio with apixaban 2.5 mg twice daily was 0.73 (95% CI 0.44 to 1.19; P= 0.21) and with apixaban 10 mg once daily was 0.61 (95% CI 0.35 to 1.04; P= 0.07). Reproduced with permission from reference [21].

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The increase in bleeding with either dose of apixaban compared to placebo was evident immediately after randomization but the difference between the two apixaban doses did not become apparent until after about 8 weeks. There was no excess of liver enzyme elevations with apixaban when compared to placebo.

Apixaban for ACS—the Future

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References

The initial phase II experience with apixaban is promising, but raises several issues that will influence the subsequent evaluation of this agent. The most important of these issues is the impact of concomitant antiplatelet therapy. In APPRAISE, there was an increase in bleeding with apixaban among patients receiving clopidogrel in addition to aspirin compared to those on aspirin alone. Although this was a nonrandomized comparison that is subject to confounding, the effect is biologically plausible and is consistent with the experience from trials of other new oral anticoagulants compared with placebo in patients with ACS. In the phase II ATLAS-TIMI-46 study of rivaroxaban in ACS, patients receiving dual antiplatelet therapy had a 1.5- to 4-fold increase in bleeding with each of the doses of rivaroxaban compared to those on aspirin alone [23]. Preliminary data from the RE-DEEM study with dabigatran has also shown bleeding rates similar to those seen in APPRAISE and ATLAS-TIMI-46 (though most patients in the trial were on dual antiplatelet therapy at the start of the study) [24]. This implies that apixaban (and other new oral anticoagulants) will have a meaningful role in the long-term management of ACS patients treated with dual antiplatelet therapy only if associated with robust improvements in efficacy that offset the increase in bleeding.

The presence of renal dysfunction may further increase bleeding rates in ACS patients treated with anticoagulants; In the ATLAS-TIMI-46 trial, rivaroxaban was associated with a more than 2-fold increase in bleeding in patients with a creatinine clearance <60 mL/min compared with those who had a creatinine clearance ≥60 mL/min [23]. Only about 25% of ingested apixaban is excreted through the kidneys. Therefore, unlike rivaroxaban (about 66% renal excretion) and dabigatran (80% renal excretion), apixaban may require no or only minimal dose adjustments in patients with mild-to-moderate renal dysfunction. The APPRAISE investigators did not report bleeding rates in apixaban-treated patients with renal insufficiency.

A significant proportion of ACS patients are elderly, and safety in these patients will be an important factor in the choice of anticoagulants. Rivaroxaban was associated with a 1.5-fold increase in the risk of bleeding in ACS patients ≥65 years [23] The APPRAISE study did not report rates of bleeding with apixaban in the elderly.

Cardiovascular events appeared to be less frequent among aspirin-treated patients who received apixaban than among those on dual antiplatelet therapy (without apixaban), raising the possibility that the apixaban–aspirin combination may be an effective alternative to dual antiplatelet therapy for ACS patients who do not require percutaneous intervention. This may be an area for future study. On the other hand, with the advent of the newer, more potent replacements for clopidogrel (such as prasugrel), it remains to be seen if the aspirin–apixaban combination will remain a relevant comparator. In any case, it is important to recognize that the optimal antithrombotic regimen (antiplatelet agents plus anticoagulants) may vary over time and the components of the treatment regimen may need to be modified depending upon factors such as patients’ bleeding risk and the need for percutaneous intervention.

In conclusion, apixaban is an orally active, direct inhibitor of factor Xa, with a potent and predictable anticoagulant effect. Its half-life of about 12 h, multiple pathways of excretion and low potential for drug or food interactions, makes it an attractive candidate for long-term anticoagulation in patients with ACS. Despite the promising initial data, it is difficult to predict the utility of apixaban in the management of patients with ACS until reliable large-scale data on efficacy and safety become available. The results from the ongoing phase III study (APPRAISE-2, NCT00831441) will help determine the role of apixaban in the long-term management of patients with ACS.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References

GK has no conflicts of interest. JWE has received honoraria and/or grant support from companies that market new anticoagulants (BMS, Sanofi-Aventis, Bayer, BI) and antiplatelet drugs (Eli-Lilly, Astra Zeneca) mentioned in this review.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Pharmacology
  5. Clinical Data
  6. The APPRAISE Study
  7. Apixaban for ACS—the Future
  8. Disclosures
  9. Conflict of Interest
  10. References
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