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ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).
ELIQUIS is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and to reduce the risk of recurrent DVT and PE following initial therapy.
ELIQUIS is indicated 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.
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Choose ELIQUIS to reduce the risk of stroke/systemic embolism for your patients with NVAF1
ONLY ELIQUIS demonstrated superiority in BOTH stroke/systemic embolism AND major bleeding vs warfarin1
SUPERIOR
PRIMARY EFFICACY ENDPOINT
SUPERIOR
PRIMARY SAFETY ENDPOINT
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.1
- Superiority to warfarin was primarily attributed to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin. Purely ischemic strokes occurred with similar rates on both drugs
- In another clinical trial (AVERROES), ELIQUIS was associated with an increase in major bleeding compared with aspirin that was not statistically significant (1.41%/year vs 0.92%/year, HR=1.54 [95% CI: 0.96–2.45]; P=0.07)
- The most common reason for treatment discontinuation in ARISTOTLE and AVERROES was for bleeding-related adverse reactions; in ARISTOTLE, this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively
*Bleeding events were counted during treatment or within 2 days of stopping study treatment (on-treatment period). Bleeding events in each subcategory were counted once per subject, but subjects may have contributed events to multiple endpoints.
†RRR was calculated as (1-HR) X 100. ARR was calculated as the difference between the event rates.
ARR=absolute risk reduction; CI=confidence interval; HR=hazard ratio; RRR=relative risk reduction.
See subgroup analysis below
ARISTOTLE Study Design
A pivotal, phase III, randomized, double-blind clinical trial designed to compare the effects of ELIQUIS 5 mg twice daily‡ (n=9120) and warfarin (n=9081) (target international normalized ratio [INR] range: 2.0–3.0) in reducing the risk of stroke and systemic embolism (SE) in 18,201 patients with NVAF and ≥1 risk factors for stroke: prior stroke or transient ischemic attack (TIA), prior SE, ≥75 years of age, arterial hypertension requiring treatment, diabetes mellitus, heart failure ≥New York Heart Association (NYHA) Class 2, or decreased left ventricular ejection fraction (LVEF) ≤40%.1-3
Patients were followed for a median of ≈1.7 years. The 2 treatment groups were well balanced with respect to baseline characteristics, including age, stroke risk (CHADS2 score),§ and prior vitamin K antagonist (VKA) experience.2
The primary efficacy endpoint was stroke/systemic embolism, and the primary safety endpoint was major bleeding.1
‡A dose of 2.5 mg twice daily was assigned to patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
§Scale from 0 to 6 to estimate stroke risk; higher scores predict greater risk.
Major bleeding was defined as clinically overt bleeding accompanied by ≥1 of the following1: A decrease in hemoglobin of ≥2 g/dL; transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial,|| intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; and fatal bleeding.
Clinically relevant nonmajor (CRNM) bleeding was defined as clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to2,3: 1. Hospital admission; 2. Physician-guided medical or surgical treatment; or 3. A change in antithrombotic therapy.
||Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as intracranial major bleeding.
- Cardiovascular deaths (1.80%/year vs 2.02%/year, HR=0.89 [95% CI: 0.76–1.04]), particularly stroke deaths (0.42% vs 0.72%), were the greatest contributors to the reduction in all-cause mortality vs warfarin2,4
- The incidence of nonvascular mortality was similar in patients taking ELIQUIS to that in patients taking warfarin (1.14%/year vs 1.22%/year, HR=0.93 [95% CI: 0.77–1.13])2
**RRR was calculated as (1-HR) X 100. ARR was calculated as the difference between the event rates.
ARR=absolute risk reduction; CI=confidence interval; HR=hazard ratio; RRR=relative risk reduction.
COMPONENTS OF MAJOR BLEEDING¶
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.1
- In another clinical trial (AVERROES), ELIQUIS was associated with an increase in major bleeding compared with aspirin that was not statistically significant (1.41%/year vs 0.92%/year, HR=1.54 [95% CI: 0.96–2.45]; P=0.07)1
- The most common reason for treatment discontinuation in ARISTOTLE and AVERROES was bleeding-related adverse reactions; in ARISTOTLE, this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively1
Components of ICH and fatal bleeding
- There were significantly fewer ICH events vs warfarin. Hemorrhagic stroke#: 0.24%/yr (n=38/9088) vs 0.49%/yr (n=74/9052), HR=0.51 (95% CI: 0.34-0.75); other ICH: 0.10%/yr (n=15/9088) vs 0.34%/yr (n=51/9052), HR=0.29 (95% CI: 0.16-0.51)1
- There were significantly fewer fatal bleeding events vs warfarin. Intracranial: 0.03%/yr (n=4/9088) vs 0.20%/yr (n=30/9052), HR=0.13 (95% CI: 0.05-0.37); nonintracranial: 0.04%/yr (n=6/9088) vs 0.05%/yr (n=7/9052), HR=0.84 (95% CI: 0.28-2.15)1
¶Bleeding events were counted during treatment or within 2 days of stopping study treatment (on-treatment period). Bleeding events in each subcategory were counted once per subject, but subjects may have contributed events to multiple endpoints.
#On-treatment analysis based on the safety population, compared to intent-to-treat analysis presented in efficacy population.
CI=confidence interval; CRNM=clinically relevant nonmajor; HR=hazard ratio; ICH=intracranial hemorrhage.
Bleeding definitions
Major bleeding was defined as clinically overt bleeding accompanied by ≥1 of the following1: A decrease in hemoglobin of ≥2 g/dL; transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; and fatal bleeding.
Components of major bleeding in ARISTOTLE1:
- Gastrointestinal (GI) bleeding included upper GI, lower GI, and rectal bleeding
- Intracranial bleed included intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as intracranial major bleeding
- Intraocular bleed is within the corpus of the eye (a conjunctival bleed is not an intraocular bleed)3
- Fatal bleeding is an adjudicated death with the primary cause of death as intracranial bleeding or non-intracranial bleeding during the on-treatment period
CRNM bleeding was defined as clinically overt bleeding that did not satisfy the criteria for major bleeding and that led to2,3: 1. Hospital admission; 2. Physician-guided medical or surgical treatment; or 3. A change in antithrombotic therapy.
ARISTOTLE primary efficacy results across subgroups
| Primary efficacy endpoint: stroke and systemic embolism | |||||||
|---|---|---|---|---|---|---|---|
| In ARISTOTLE, results for the primary efficacy endpoint were generally consistent across most major subgroups, including: |
|
||||||
††Scale from 0 to 6 to estimate stroke risk; higher scores predict greater risk.
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
CI=confidence interval; VKA=vitamin K antagonist.
Generally consistent efficacy across levels of renal function in ARISTOTLE in the reduction of the risk of stroke/systemic embolism1,2
- Patients with a serum creatinine level of >2.5 mg/dL or calculated creatinine clearance of <25 mL/min were excluded from the ARISTOTLE trial2
- In the ARISTOTLE trial, 5319 patients in the ELIQUIS arm had various levels of renal impairment1
Note: The figures above present effects in one of various subgroups, all of which are baseline characteristics and all of which were prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.1 The size of the dot for point estimate (hazard ratio) represents the number of patients across each level of renal function.
††In a pre-specified secondary analysis of ARISTOTLE, the outcome of the trial was evaluated in relation to renal function.
CI=confidence interval; HR=hazard ratio.
CI=confidence interval.
ARISTOTLE primary safety results across subgroups
| Primary safety endpoint: major bleeding1,2 | |||||||
|---|---|---|---|---|---|---|---|
| In ARISTOTLE, results for the primary safety endpoint of major bleeding were generally consistent across most major subgroups, including: |
|
||||||
Patients with diabetes who were treated with ELIQUIS bled more than patients without diabetes (3.0%/year vs 1.9%/year, respectively). Major bleeds were observed in ELIQUIS and warfarin patients with diabetes at a rate of 3.0%/year and 3.1%/year, respectively.
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.1
‡‡Scale from 0 to 6 to estimate stroke risk; higher scores predict greater risk.
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics and all of which were prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
CI=confidence interval; VKA=vitamin K antagonist.
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding.1
- Patients with a serum creatinine level of >2.5 mg/dL or calculated creatinine clearance of <25 mL/min were excluded from the ARISTOTLE trial2
- In the ARISTOTLE trial, 5319 patients in the ELIQUIS arm had various levels of renal impairment1
Note: The figures above present effects in various subgroups, all of which are baseline characteristics and all of which were prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. The size of the dot for point estimate (hazard ratio) represents the number of patients across each level of renal function.
§§In a prespecified secondary analysis of ARISTOTLE, the outcome of the trial was evaluated in relation to renal function.
CI=confidence interval; HR=hazard ratio.
CI=confidence interval.
ARISTOTLE: a pivotal, phase III, randomized, double-blind clinical trial of >18,000 patients with NVAF1-3*
Primary objective: Determine whether ELIQUIS (n=9120) was effective (noninferior to warfarin, n=9081) in reducing the risk of stroke (ischemic or hemorrhagic) or systemic embolism (SE).
- Primary efficacy endpoint: Stroke/systemic embolism
- Primary safety endpoint: Major bleeding
- Secondary efficacy endpoint: All-cause mortality
*Key inclusion criteria: NVAF and ≥1 risk factors for stroke: prior stroke, transient ischemic attack (TIA), or SE; ≥75 years of age; arterial hypertension requiring treatment; diabetes mellitus; heart failure ≥New York Heart Association (NYHA) Class 2; and decreased left ventricular ejection fraction (LVEF) ≤40%.
Key exclusion criteria: Atrial fibrillation due to a reversible cause, moderate or severe mitral stenosis, conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve), stroke within the previous 7 days, a need for aspirin at a dose of >165 mg a day or for both aspirin and clopidogrel, and severe renal insufficiency (serum creatinine level of >2.5 mg/dL or calculated creatinine clearance of <25 mL/min).
INR=international normalized ratio.
Major bleeding was defined as clinically overt bleeding accompanied by ≥1 of the following1: A decrease in hemoglobin of ≥2 g/dL; transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial,‡ intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; and fatal bleeding.
†A dose of 2.5 mg twice daily was assigned to patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
‡Intracranial bleed includes intracerebral, intraventricular, subdural, and subarachnoid bleeding. Any type of hemorrhagic stroke was adjudicated and counted as intracranial major bleeding.
Mean percentage of time in therapeutic range (INR 2.0–3.0) was 62% for patients treated with warfarin.
§Scale from 0 to 6 to estimate stroke risk; higher scores predict greater risk.
TIA=transient ischemic attack.
Primary efficacy outcome: ELIQUIS was superior to aspirin in reducing the risk of stroke and systemic embolism1
AVERROES was stopped early on the basis of a prespecified interim analysis showing a significant reduction in stroke and systemic embolism for ELIQUIS compared with aspirin
ARR=absolute risk reduction; CI=confidence interval; HR=hazard ratio; RRR=relative risk reduction.
*RRR was calculated as (1-HR) X 100. ARR was calculated as the difference between the event rates.
|
ELIQUIS n=2798 n (%/year) |
aspirin n=2780 n (%/year) |
Hazard ratio (95% CI) |
P value | |
|---|---|---|---|---|
| Major | 45 (1.41) | 29 (0.92) | 1.54 (0.96, 2.45) | 0.07 |
| Fatal | 5 (0.16) | 5 (0.16) | 0.99 (0.23, 4.29) | – |
| Intracranial | 11 (0.34) | 11 (0.35) | 0.99 (0.39, 2.51) | – |
Bleeding events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints.
CI=confidence interval.
- In AVERROES, ELIQUIS was associated with an increase in bleeding compared to aspirin that was not statistically significant
- The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE, this occurred in 1.7% and 2.5% of patients treated with ELIQUIS and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on ELIQUIS and aspirin, respectively
- The most common adverse reactions observed in the ARISTOTLE and AVERROES clinical trials with ELIQUIS were related to bleeding
AVERROES Study Design
A phase III, double-blind, randomized trial designed to compare the effects of ELIQUIS 5 mg twice daily† (n=2807) and aspirin (n=2791) (81 mg–324 mg once daily) on the risk of stroke and systemic embolism in 5598 patients with NVAF thought not to be candidates for warfarin therapy, and with ≥1 additional risk factor for stroke: prior stroke or TIA; ≥75 years of age; arterial hypertension (receiving treatment); diabetes mellitus (receiving treatment); heart failure (≥ NYHA Class 2 at time of enrollment); LVEF ≤35%, or documented peripheral artery disease. Patients could not be receiving VKA therapy (e.g., warfarin), either because it had already been demonstrated or expected to be unsuitable for them. The mean follow-up period was approximately 1.1 years. The primary efficacy endpoint was stroke/systemic embolism, and the primary safety endpoint was major bleeding.1,8,9
INR=international normalized ratio; NVAF=nonvalvular atrial fibrillation; VKA=vitamin K antagonist.
†A dose of 2.5 mg twice daily was assigned to patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
Major bleeding was defined as clinically overt bleeding accompanied by ≥1 of the following8: A decrease in hemoglobin of ≥2 g/dL; transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; and fatal bleeding.
Bleeding definitions
Major bleeding was defined as clinically overt bleeding accompanied by ≥1 of the following8: A decrease in hemoglobin of ≥2 g/dL over 24 hours; transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; and fatal bleeding.
AVERROES: a phase III, randomized, double-blind trial vs aspirin in over 5500 patients with NVAF who were unsuitable for warfarin1,8,9
This trial included 5598 patients with NVAF thought not to be candidates for warfarin therapy with 1 or more additional risk factors for stroke.*
Primary objective: Determine how ELIQUIS 5 mg twice daily (2.5 mg twice daily† in selected patients) compared with aspirin (81 mg to 324 mg once daily) in reducing the risk of stroke or systemic embolism in patients with NVAF.
*Key inclusion criteria: NVAF and ≥1 additional risk factors for stroke, which included prior stroke or transient ischemic attack (TIA), age ≥75 years, arterial hypertension (receiving treatment), diabetes mellitus (receiving treatment), heart failure (New York Heart Association [NYHA] Class 2 or higher at the time of enrollment), left ventricular ejection fraction (LVEF) ≤35%, or documented peripheral artery disease. Patients could not be receiving vitamin K antagonist therapy (e.g., warfarin), either because it had already been demonstrated to be unsuitable for them or because it was expected to be unsuitable.
- Primary efficacy endpoint: Stroke/systemic embolism
- Primary safety endpoint: Major bleeding
Major bleeding was defined as clinically overt bleeding accompanied by ≥1 of the following8: A decrease in hemoglobin of ≥2 g/dL over 24 hours; transfusion of ≥2 units of packed red blood cells; bleeding that occurred in at least one of the following critical sites: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; and fatal bleeding.
†A dose of 2.5 mg twice daily was assigned to patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
References
- ELIQUIS® (apixaban) Package Insert. Bristol-Myers Squibb Company, Princeton, NJ, and Pfizer Inc, New York, NY.
- Granger CB, Alexander JH, McMurray JJV, et al; for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
- Protocol for: Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. Doi:10.1056/NEJMoa1107039.
- Data on File: APIX025. Bristol-Myers Squibb Company, Princeton, NJ.
- Data on File: APIX060. Bristol-Myers Squibb Company, Princeton, NJ.
- Data on File: APIX063. Bristol-Myers Squibb Company, Princeton, NJ.
- Data on File: APIX032. Apixaban 2.5 mg BID dose in ARISTOTLE and AVERROES. Bristol-Myers Squibb Company, Princeton, NJ.
- Connolly SJ, Eikelboom J, Joyner C, et al; for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817.
- Connolly SJ, Eikelboom J, Joyner C, et al; for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817, Protocol. http://nejm.org/doi/suppl/10.1056/NEJM/1007432/
suppl_file/
nejmoa1007432_appendix.pdf.
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
(A) Premature discontinuation of any oral anticoagulant, including ELIQUIS® (apixaban), 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.
(B) 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)
- 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 permanent paralysis. 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.
- Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome (APS): Direct-acting oral anticoagulants (DOACs), including ELIQUIS, are not recommended for use in patients with triple-positive APS. For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
- The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding.
- 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. Clarithromycin 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.
- The limited available data on ELIQUIS use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes. Treatment may increase the risk of bleeding during pregnancy and delivery, and in the fetus and neonate.
- Labor or delivery: ELIQUIS use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches.
- Breastfeeding is not recommended during treatment with ELIQUIS.
FEMALES AND MALES OF REPRODUCTIVE POTENTIAL
- Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including ELIQUIS should be assessed in these patients and those with abnormal uterine bleeding.
ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).
ELIQUIS is indicated 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.
ELIQUIS is indicated for the treatment of DVT and PE, and to reduce the risk of recurrent DVT and PE following initial therapy.
Please see U.S. FULL PRESCRIBING INFORMATION, including Boxed WARNINGS, and MEDICATION GUIDE.
ELIQUIS is available in 2.5 mg and 5 mg tablets.
ELIQUIS® and the ELIQUIS logo are trademarks of Bristol-Myers Squibb Company.
All other trademarks are the property of their respective owners.
© 2024 Bristol-Myers Squibb Company. 432-US-2400137 08/24
