AUGUSTUS Demonstrates Favorable Safety Results of Eliquis® Versus Vitamin K Antagonists in Non-Valvular Atrial Fibrillation Patients with Acute Coronary Syndrome and/or Undergoing Percutaneous Coronary InterventionSource: Business Wire
AUGUSTUS is the largest trial in this high-risk patient population requiring both anticoagulant and antiplatelet therapies
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AUGUSTUS, which evaluated 4,614 patients, is an open-label, prospective, randomized clinical trial designed to assess two independent hypotheses:
Whether or not Eliquis 5mg* twice daily is non-inferior or
superior to VKAs for the outcome of major or CRNM bleeding, as defined
International Society on Thrombosis and Haemostasis(ISTH), in patients with NVAF and recent ACS and/or undergoing PCI with planned concomitant antiplatelet therapy (a P2Y12 inhibitor with or without low-dose aspirin).
- Whether or not single antiplatelet therapy with a P2Y12 inhibitor is superior to dual antiplatelet therapy with a P2Y12 inhibitor and low-dose aspirin for the outcome of ISTH major or CRNM bleeding in patients with NVAF and recent ACS and/or undergoing PCI and planned concomitant anticoagulant therapy (either Eliquis 5mg* twice daily or VKA).
*2.5mg twice daily if patients met two or more of the following dose-reduction criteria: age ≥ 80 years, weight ≤ 60 kg or creatinine ≥ 1.5mg/dL (133 micromol/L).
Independent of the Eliquis versus VKA comparison, results also showed that in patients receiving a P2Y12 inhibitor and an anticoagulant, the proportion of patients with major or CRNM bleeding at six months was significantly higher for those receiving aspirin compared to those receiving placebo (16.1% vs. 9.0%, respectively; HR: 1.89, 95% CI: 1.59-2.24; p<0.001).
Please note that Eliquis increases the risk of bleeding compared with placebo and can cause serious, potentially fatal, bleeding. Please see below for Important Safety Information, including information from the APPRAISE-2 clinical trial that was terminated early due to higher rates of bleeding for apixaban compared to placebo in post-ACS patients without an indication for oral anticoagulant.1
“Due to concern for major bleeding, there have been ongoing questions
about treating non-valvular atrial fibrillation patients with acute
coronary syndrome and/or undergoing percutaneous coronary intervention,”
The investigators also analyzed the pre-defined secondary composite outcomes of death or hospitalization and death or ischemic events (including myocardial infarction, stroke, definite or probable stent thrombosis or urgent revascularization). At six months, patients receiving a P2Y12 inhibitor with or without aspirin who were treated with Eliquis had lower rates of death or hospitalization (23.5% vs. 27.4%, respectively; HR: 0.83, 95% CI: 0.74-0.93; p=0.002) and similar rates of death or ischemic events (6.7% vs. 7.1%, respectively; HR: 0.93, 95% CI: 0.75-1.16; p=NS) compared to those assigned to VKA. Patients receiving a P2Y12 inhibitor and an anticoagulant who were treated with aspirin had similar rates of death or hospitalization (26.2% vs. 24.7%, respectively; HR: 1.08, 95% CI: 0.96-1.21; p=NS) and similar rates of death or ischemic events (6.5% vs. 7.3%, respectively; HR: 0.89, 95% CI: 0.71-1.11) compared to those assigned to placebo.
“The AUGUSTUS trial evaluated antithrombotic regimens for the often
difficult-to-treat non-valvular atrial fibrillation patient population
that presents with acute coronary syndrome and/or receives percutaneous
coronary intervention,” said
Atrial fibrillation is the most common arrhythmia in the world, affecting an estimated 33 million people in 2010.2 It is estimated that approximately 20-to-30 percent of people with atrial fibrillation also have concomitant coronary artery disease,3,4 which may result in ACS or require PCI. Additionally, five-to-ten percent of patients who undergo PCI have atrial fibrillation.5,6,7,8 While oral anticoagulants and dual antiplatelet therapy help reduce the risk of stroke and recurrent ischemic events, respectively, the combination leads to an increased risk of bleeding. Therefore, additional research has been needed to help inform antithrombotic regimens available for these high-risk patients.
“Advancing care for patients at risk for stroke due to non-valvular
atrial fibrillation is a key focus of the
AUGUSTUS is an international, multicenter, open-label, randomized
controlled trial with a two-by-two factorial design to compare Eliquis
(apixaban) with vitamin K antagonists (VKAs) and aspirin with placebo in
4,614 patients with non-valvular atrial fibrillation (NVAF) and recent
acute coronary syndrome (ACS) and/or undergoing percutaneous coronary
intervention (PCI), and are receiving a P2Y12 inhibitor for at least six
months. The treatment regimen comparing Eliquis with VKA was
open-label; however, the regimen comparing aspirin with aspirin placebo
was double blind. Patients were evaluated for eligibility during their
ACS and/or PCI hospitalization. 37.3 percent of patients included in the
study had ACS undergoing PCI, 23.9 percent of patients had
medically-managed ACS and 38.8 percent of patients underwent elective
PCI. The primary outcome is the composite of major or clinically
relevant non-major (CRNM) bleeding defined by the
About Atrial Fibrillation
Atrial fibrillation (AF) is the most common type of arrhythmia, or
irregular heartbeat. Nonvalvular atrial fibrillation (NVAF) refers to
cases in which the AF occurs in the absence of rheumatic mitral valve
disease, a prosthetic heart valve, or mitral valve repair. It was
estimated that in 2014, 6.4 million people in the U.S. and in 2010, over
six million individuals in
About Acute Coronary Syndrome
Acute coronary syndrome (ACS) is a term used to describe situations in
which the blood supplied to the heart muscle is suddenly blocked, and
includes myocardial infarction (MI), also known as a heart attack, and
unstable angina (sudden, severe chest pain that typically occurs when a
person is at rest). ACS affects an estimated 1.4 million people in the
U.S. and an estimated 1.38 million people in
About Percutaneous Coronary Intervention
Percutaneous coronary intervention (PCI), also known as coronary
angioplasty, is a procedure used to open blocked or narrowed coronary
arteries. Angioplasty also is used as an emergency procedure during a
heart attack. According to the
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, Eliquis decreases thrombin generation and blood clot formation. Eliquis is approved for multiple indications in the U.S. based on efficacy and safety data from multiple Phase 3 clinical trials. Eliquis is a prescription medicineindicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF); for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE, following initial therapy.
ELIQUIS Important Safety Information
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
use of indwelling epidural catheters
concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
a history of traumatic or repeated epidural or spinal punctures
a history of spinal deformity or spinal surgery
optimal timing between the administration of ELIQUIS and neuraxial procedures
is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.
- Active pathological bleeding
- Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions)
WARNINGS AND PRECAUTIONS
- Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
Bleeding Risk: ELIQUIS increases the risk of bleeding and can
cause serious, potentially fatal, bleeding.
- Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs.
- Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage.
- The anticoagulant effect of apixaban can be expected to persist for at least 24 hours after the last dose (i.e., about two half-lives). An agent to reverse the anti-factor Xa activity of apixaban is available. Please visit www.andexxa.com for more information on availability of a reversal agent.
Spinal/Epidural Anesthesia or Puncture: Patients treated with
ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop
an epidural or spinal hematoma which can result in long-term or
The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours.
Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in ELIQUIS patients.
- Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves and is not recommended in these patients.
- Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy: Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
- The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding.
TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS
- ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
- Combined P-gp and Strong CYP3A4 Inhibitors: Inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) increase exposure to apixaban and increase the risk of bleeding. For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or ritonavir). In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors.
Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS.
- Combined P-gp and Strong CYP3A4 Inducers: Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban.
- Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo.
PREGNANCY CATEGORY B
- There are no adequate and well-controlled studies of ELIQUIS in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus.
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i Alexander JH et al. Apixaban with Antiplatelet Therapy
after Acute Coronary Syndrome.
ii Peterson ED, Pokorney SD. New Treatment Options Fail to Close the Anticoagulation Gap in Atrial Fibrillation.
iii The AFFIRM Investigators. Baseline characteristics of patients with atrial fibrillation: the AFFIRM study.
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v Rubboli A, Colletta, M, Herzfeld J, et al. Periprocedural and medium-term antithrombotic strategies in patients with an indication for long-term anticoagulation undergoing coronary angiography and intervention. Coronary Artery Disease. 2007;18:193-199
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vii Perez-Gomez F, Alegria E, Berjon J, et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study.
viii Lip GY, Huber K, Andreotti, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thrombosis and Haemostasis. 2010;103:13-28
ix Kaatz S., Ahmad D., Spyropoulos AC, et al. Definition of clinically relevant non‐major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non‐surgical patients: communication from the SSC of the ISTH.