Eliquis (Apixaban)
apixaban
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Stroke and systemic embolism prevention in NVAF | Adults | Long-term monotherapy | FDA Approved |
| DVT prophylaxis after hip or knee replacement | Adults | Short-course monotherapy (12–35 days) | FDA Approved |
| Treatment of DVT | Adults | Monotherapy (after initial loading) | FDA Approved |
| Treatment of PE | Adults | Monotherapy (after initial loading) | FDA Approved |
| Reduction in risk of recurrent DVT/PE | Adults (after ≥6 months initial therapy) | Extended prophylaxis | FDA Approved |
| Pediatric VTE treatment and recurrence prevention | From birth and older (after ≥5 days initial anticoagulation) | Weight-based dosing | FDA Approved (Apr 2025) |
Apixaban is a selective, reversible, direct factor Xa inhibitor that has become the most widely prescribed oral anticoagulant worldwide. Initially approved in 2012 for stroke prevention in nonvalvular atrial fibrillation based on the landmark ARISTOTLE trial, it subsequently gained indications for VTE prophylaxis after orthopedic surgery (ADVANCE program), acute DVT/PE treatment (AMPLIFY), extended VTE prevention (AMPLIFY-EXT), and most recently pediatric VTE (April 2025). Apixaban offers a favorable balance of efficacy and bleeding risk across all approved indications relative to historical comparators.
VTE prophylaxis in cancer patients: Used off-label in select ambulatory cancer patients at high thrombotic risk (Khorana score ≥2), supported by the AVERT trial. Guidelines vary. Evidence quality: Moderate.
Left ventricular thrombus: Small studies and case series suggest potential efficacy, but head-to-head data against warfarin are limited. Evidence quality: Low.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Stroke prevention in NVAF — standard dose | 5 mg PO BID | 5 mg PO BID | 10 mg/day | With or without food. No loading dose needed. ARISTOTLE: superior to warfarin for stroke/SE prevention (HR 0.79) with less major bleeding (HR 0.69). |
| Stroke prevention in NVAF — dose reduction criteria met | 2.5 mg PO BID | 2.5 mg PO BID | 5 mg/day | Reduce if ≥2 of 3 criteria: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL. All 3 criteria must be assessed; meeting only 1 does NOT warrant dose reduction |
| DVT prophylaxis — post hip replacement | 2.5 mg PO BID | 2.5 mg PO BID | 5 mg/day | Start 12–24 hours post-surgery. Duration: 35 days. ADVANCE-3 trial |
| DVT prophylaxis — post knee replacement | 2.5 mg PO BID | 2.5 mg PO BID | 5 mg/day | Start 12–24 hours post-surgery. Duration: 12 days. ADVANCE-1 and ADVANCE-2 trials |
| Acute DVT or PE — treatment phase | 10 mg PO BID × 7 days | 5 mg PO BID | 20 mg/day (first 7 days); then 10 mg/day | No parenteral lead-in required (single-drug approach). AMPLIFY: major bleeding RR 0.31 (0.17–0.55) vs enoxaparin/warfarin. After 7-day loading period, transition to 5 mg BID |
| Prevention of recurrent DVT/PE — extended therapy | 2.5 mg PO BID | 2.5 mg PO BID | 5 mg/day | Initiate after completing ≥6 months of anticoagulation for DVT/PE. AMPLIFY-EXT: 67% RRR in recurrent VTE vs placebo with no significant increase in major bleeding. |
Dose Adjustment for Combined P-gp and Strong CYP3A4 Inhibitors
| Current Apixaban Dose | Adjusted Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| 5 mg or 10 mg BID | Reduce by 50% | 2.5 mg or 5 mg BID | As adjusted | Applies with ketoconazole, itraconazole, ritonavir. Clarithromycin does NOT require dose adjustment per FDA PI. |
| 2.5 mg BID (any indication) | Avoid co-administration | N/A | N/A | If already on lowest dose, combined P-gp + strong CYP3A4 inhibitors should be avoided. |
Perioperative Management
| Bleeding Risk | When to Stop | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate or high bleeding risk | Discontinue ≥48 hours pre-procedure | Resume when hemostasis achieved | Per indication | Bridging anticoagulation generally not required during the 24–48-hour peri-procedural window. |
| Low bleeding risk | Discontinue ≥24 hours pre-procedure | Resume when hemostasis achieved | Per indication | Where bleeding is non-critical in location and easily controlled. |
Inappropriate dose reduction is a common prescribing error with apixaban. The 2.5 mg BID dose for NVAF requires the patient to meet at least TWO of three criteria: (1) age ≥80 years, (2) weight ≤60 kg, (3) serum creatinine ≥1.5 mg/dL. Meeting only one criterion does not warrant dose reduction. Underdosing has been associated with increased stroke risk without a meaningful reduction in bleeding. Reassess eligibility at each visit as patient weight and renal function may change over time.
Pharmacology
Mechanism of Action
Apixaban is a selective, reversible inhibitor of both free and clot-bound activated factor X (FXa), a serine protease central to the coagulation cascade. By inhibiting FXa, apixaban blocks the conversion of prothrombin to thrombin, thereby reducing thrombin generation, fibrin clot formation, and thrombin-mediated platelet activation. Unlike vitamin K antagonists, apixaban acts at a single point in the coagulation cascade and does not require antithrombin III as a cofactor. It has no direct effect on platelet aggregation but indirectly reduces platelet activation by decreasing thrombin generation. Apixaban exhibits predictable, dose-dependent anticoagulation that does not require routine coagulation monitoring. A specific reversal agent, andexanet alfa, is available to antagonize the anti-FXa effect in life-threatening or uncontrolled bleeding situations (FDA PI).
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~50% (up to 10 mg doses); Tmax 3–4 h; food has no clinically meaningful effect; absorbed throughout GI tract (~55% in distal small bowel and ascending colon) | Can be taken with or without food. Tablets may be crushed and given via NGT. Dose-proportional PK up to 10 mg; dissolution-limited at ≥25 mg. |
| Distribution | Vss ~21 L; protein binding ~87%; does not partition into red blood cells | Moderate distribution volume suggests primarily intravascular and tissue distribution. Not dialyzable due to high protein binding. |
| Metabolism | Primarily CYP3A4/5; minor contributions from CYP1A2, 2C8, 2C9, 2C19, 2J2; substrate of P-gp and BCRP; O-demethyl apixaban sulfate is major metabolite (inactive); no active circulating metabolites | CYP3A4 and P-gp dual substrate status is the basis for key drug interactions. Does not inhibit or induce CYP enzymes, so apixaban is unlikely to alter other drug levels. |
| Elimination | Apparent t½ ~12 h (clearance t½ ~6 h; prolonged absorption extends apparent t½); renal excretion ~27% of total clearance; feces ~56% of dose; urine ~25% of dose | The 12-hour apparent half-life supports twice-daily dosing. Multiple elimination pathways (renal, biliary, intestinal) reduce vulnerability to any single organ impairment. Anticoagulant effect persists ≥24 hours after last dose. |
Side Effects
| Adverse Effect | Incidence (Apixaban) | Clinical Note |
|---|---|---|
| Major bleeding (overall) | 2.13%/yr (vs 3.09%/yr warfarin; HR 0.69) | 31% relative reduction vs warfarin. Benefit consistent across subgroups including age, weight, CHADS2 score, and renal function. |
| GI bleeding | 0.83%/yr (vs 0.93%/yr warfarin; HR 0.89) | Unlike rivaroxaban and dabigatran, apixaban did not increase GI bleeding relative to warfarin in ARISTOTLE. |
| Intracranial hemorrhage | 0.33%/yr (vs 0.82%/yr warfarin; HR 0.41) | 59% relative reduction in ICH, one of the strongest differentiators from warfarin. |
| Fatal bleeding | 0.06%/yr (vs 0.24%/yr warfarin; HR 0.27) | 73% relative reduction in fatal bleeding events. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Epistaxis | 2.9% (vs 5.4% enox/warfarin) | Most common non-major bleeding event |
| Contusion | 1.8% (vs 3.6%) | Easy bruising; generally benign |
| Hematuria | 1.7% (vs 3.8%) | Evaluate for urinary tract pathology if persistent |
| Menorrhagia | 1.4% (vs 1.1%) | Counsel women of reproductive age; may require gynecologic management |
| Hematoma | 1.3% (vs 2.8%) | Post-traumatic or spontaneous; assess site and severity |
| Major bleeding | 0.6% (vs 1.8%; RR 0.31) | 69% relative risk reduction vs enoxaparin/warfarin (p<0.0001). Statistically superior primary safety endpoint. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Spinal/epidural hematoma | Rare | Hours to days following neuraxial procedure | FDA Boxed Warning. Can cause long-term or permanent paralysis. Remove catheter ≥24h after last dose; next dose ≥5h after catheter removal. If traumatic puncture, delay apixaban 48h. Urgent neurological assessment if symptoms develop. |
| Life-threatening / fatal bleeding | 0.06–0.6%/yr (varies by indication and comparator) | Any time during treatment | Discontinue apixaban. Reversal agent andexanet alfa available for adults. PCC may be considered but not evaluated in clinical studies. Activated charcoal within 2–6 hours of ingestion reduces absorption. |
| Thrombotic events on premature discontinuation | Increased rate observed | Days to weeks after stopping | FDA Boxed Warning. Increased stroke rate observed on discontinuation in AF trials. If stopping for reason other than pathological bleeding, bridge with another anticoagulant. |
| Anaphylaxis / severe hypersensitivity | <1% | Variable | Discontinue permanently. Contraindicated for future use. |
Bleeding is the primary safety concern with apixaban. For minor bleeding (epistaxis, bruising, gum bleeding), local measures and temporary dose holding usually suffice. For major or life-threatening bleeding, andexanet alfa is the FDA-approved specific reversal agent for adults. Four-factor PCC (25–50 U/kg) may be considered when andexanet alfa is unavailable. Activated charcoal within 2–6 hours of ingestion can reduce absorption by 27–50%. Hemodialysis is not effective due to high protein binding. Protamine and vitamin K have no effect on apixaban anticoagulation.
Drug Interactions
Apixaban is a substrate of both CYP3A4 and P-glycoprotein (P-gp). Drugs that simultaneously inhibit or induce both pathways can significantly alter apixaban exposure. However, apixaban does not inhibit or induce CYP enzymes and has minimal effect on the PK of other drugs. Co-administration with digoxin, naproxen, atenolol, or aspirin did not alter the PK of those agents (FDA PI).
Monitoring
- Renal FunctionBaseline, then annually or if clinical change
RoutineSerum creatinine is one of three NVAF dose reduction criteria (≥1.5 mg/dL). Changes in renal function may alter eligibility for 2.5 mg BID dosing. ~27% of apixaban clearance is renal. - Body WeightBaseline, then periodically
RoutineWeight ≤60 kg is one of three NVAF dose reduction criteria. Reassess at visits, especially in frail or elderly patients who may experience weight loss over time. - Signs of BleedingEvery visit; ongoing patient education
RoutineInquire about epistaxis, bruising, hematuria, melena, hemoptysis, menorrhagia. Check hemoglobin if bleeding is suspected. Educate patients on when to seek emergency care. - Hepatic FunctionBaseline
Trigger-basedNo dose adjustment for mild impairment (Child-Pugh A). Use with caution in moderate impairment (Child-Pugh B) due to intrinsic coagulation abnormalities. Not recommended in severe impairment (Child-Pugh C). - CBCBaseline; if bleeding suspected
Trigger-basedMonitor hemoglobin and hematocrit for occult bleeding. Anemia occurred in 2.6% of surgical prophylaxis patients. - Coagulation TestsNot routinely required
Trigger-basedRoutine PT/INR and aPTT monitoring is NOT recommended — apixaban affects these tests variably and results are not useful for dose adjustment. Anti-FXa assay (calibrated to apixaban) may confirm drug presence if needed in emergencies. - Neurological StatusPost-neuraxial procedure
Trigger-basedMonitor frequently for numbness, weakness of legs, or bowel/bladder dysfunction following spinal/epidural procedures. Urgent treatment if neurological compromise detected (FDA Boxed Warning).
Contraindications & Cautions
Absolute Contraindications
- Active pathological bleeding — discontinue immediately and evaluate source.
- Severe hypersensitivity to apixaban — including anaphylactic reactions.
Relative Contraindications (Specialist Input Recommended)
- Prosthetic heart valves: Safety and efficacy not established; use is not recommended (FDA PI).
- Triple-positive antiphospholipid syndrome: DOACs including apixaban are associated with increased thrombotic events compared to vitamin K antagonists in this population; not recommended.
- Hemodynamically unstable PE: Apixaban should not be initiated as an alternative to unfractionated heparin in patients who may need thrombolysis or pulmonary embolectomy.
- Severe hepatic impairment (Child-Pugh C): Not studied; not recommended due to potential for intrinsic coagulopathy and unpredictable drug response.
Use with Caution
- Moderate hepatic impairment (Child-Pugh B): Intrinsic coagulation abnormalities may exist; limited clinical experience.
- ESRD on dialysis: Dosing recommendations are based on PK data, not clinical efficacy/safety trials. Use with caution; dose per NVAF criteria (2.5 mg BID if dose reduction criteria met).
- Concurrent neuraxial anesthesia: Risk of epidural/spinal hematoma (Boxed Warning). Follow specific timing guidelines for catheter removal and re-dosing.
- Pregnancy: Not recommended. May increase hemorrhage risk during pregnancy and delivery. Use only if benefit clearly outweighs risk.
- Lactation: Advise not to breastfeed. Apixaban accumulates in rat milk (milk:plasma AUC ratio 30:1).
Premature discontinuation of any oral anticoagulant, including apixaban, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from apixaban to warfarin in atrial fibrillation trials. If discontinuation is necessary for a reason other than pathological bleeding or completion of therapy, strongly consider bridging with another anticoagulant.
Epidural or spinal hematomas may occur in patients treated with apixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Risk factors include indwelling epidural catheters, concomitant hemostasis-altering drugs, traumatic or repeated puncture, and history of spinal deformity or surgery. Indwelling catheters should not be removed earlier than 24 hours after the last apixaban dose, and the next dose should not be given earlier than 5 hours after catheter removal.
Patient Counselling
Purpose of Therapy
Apixaban is a blood thinner that helps prevent dangerous blood clots. Depending on your condition, it may be used to prevent stroke if you have atrial fibrillation, to treat blood clots in the legs or lungs, or to prevent blood clots after joint replacement surgery. It works by blocking a specific clotting factor in the blood and is taken as a tablet by mouth, usually twice a day.
How to Take
Take apixaban exactly as prescribed, with or without food. Tablets may be crushed and mixed with water, apple juice, or applesauce if you have difficulty swallowing. If you miss a dose, take it as soon as you remember on the same day, then resume your normal schedule. Do not double up on doses. Do not stop taking apixaban without talking to your provider, as stopping suddenly can increase the risk of blood clots or stroke.
Sources
- Bristol-Myers Squibb / Pfizer. Eliquis (apixaban) tablets, for oral use. Full Prescribing Information. Revised May 2025. BMS PI (2025) Primary source for all dosing, adverse reactions, PK data, boxed warnings, and drug interactions in this monograph.
- 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 ARISTOTLE trial (N=18,201): demonstrated superiority of apixaban over warfarin for stroke/SE prevention (HR 0.79), with less major bleeding (HR 0.69) and lower all-cause mortality (HR 0.89).
- Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–817. doi:10.1056/NEJMoa1007432 AVERROES trial: apixaban vs aspirin in warfarin-unsuitable AF patients; stopped early due to clear apixaban superiority for stroke prevention without excess bleeding.
- Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808. doi:10.1056/NEJMoa1302507 AMPLIFY trial (N=5,395): apixaban noninferior to enoxaparin/warfarin for VTE treatment with 69% less major bleeding (RR 0.31).
- Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699–708. doi:10.1056/NEJMoa1207541 AMPLIFY-EXT trial: apixaban 2.5 mg or 5 mg BID vs placebo for extended VTE prevention; 67% RRR in recurrent VTE without significant increase in major bleeding.
- Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487–2498. doi:10.1056/NEJMoa1006885 ADVANCE-3 trial: apixaban superior to enoxaparin for VTE prevention after hip replacement with no increase in bleeding.
- January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 guideline for management of patients with atrial fibrillation. Circulation. 2019;140(2):e125–e151. doi:10.1161/CIR.0000000000000665 Current AHA/ACC AF guideline recommending DOACs (including apixaban) over warfarin for eligible patients with NVAF.
- Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline. Chest. 2021;160(6):e545–e608. doi:10.1016/j.chest.2021.07.055 CHEST 2021 VTE guideline recommending DOACs over warfarin for initial and long-term VTE treatment in most patients.
- Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008;6(5):820–829. doi:10.1111/j.1538-7836.2008.02939.x Foundational preclinical study characterizing apixaban’s selectivity for FXa and antithrombotic efficacy in animal models.
- Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: a clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet. 2019;58(10):1265–1279. doi:10.1007/s40262-019-00775-z Comprehensive PK/PD review covering absorption, metabolism, renal/hepatic impairment, and drug interaction data for apixaban.
- Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–2424. doi:10.1056/NEJMoa1510991 ANNEXA-4 study: andexanet alfa demonstrated effective reversal of anti-FXa activity in patients with factor Xa inhibitor-related bleeding.