Eliquis (Apixaban) Received New Indications for DVT Prophylaxis After Hip/Knee Replacement Surgery and Risk Reduction for Recurrent DVT and PE

Approximately 900,000 Americans are affected by venous thromboembolism (VTE) annually.¹

VTE includes deep-vein thrombosis (DVT) and pulmonary embolism (PE). DVT is a blood clot that partially or totally blocks the blood flow through a vein, typically in the lower leg or thigh. The symptoms of DVT include discomfort, pain, edema, redness, and distended veins. DVT can progress to PE—a thrombus in the lungs—and can result in sudden death.² The adverse consequences of VTE are significant, including approximately 300,000 fatalities and hundreds of thousands of hospitalizations annually.¹

In addition to advancing patient age, the risk factors for VTE include a history of VTE, surgery or trauma within 3 to 6 months, hospitalization or nursing home confınement, active cancer, paralysis of the leg, obesity, venous catheterization, pregnancy and the postpartum period, estrogen use, and various medical conditions (eg, myocardial infarction, stroke, systemic lupus erythematosus, inflammatory bowel disease, and hematologic conditions).^3,4

Patients who undergo joint replacement procedures, including total hip replacement surgery and total knee replacement surgery, are at a high risk for VTE and require effective thromboprophylaxis.⁵ The American College of Chest Physicians has estimated that the baseline risk for symptomatic VTE and bleeding in the absence of prophylaxis is 4.3% for the first 35 days after major orthopedic surgery.⁵

The prevalence of total hip replacement surgery or total knee replacement surgery is increasing in the United States. Between 1990 and 2002, the rate of primary total hip replacement procedures per 100,000 persons increased by approximately 50%, and the corresponding rate of total knee replacement procedures nearly tripled.⁶ The current projections indicate that between 2005 and 2030, the total number of hip replacement procedures will reach nearly 600,000 annually.⁷

Strategies to reduce the risk for VTE in patients who are undergoing joint replacement surgery include low-molecular-weight heparin (LMWH), such as enoxaparin or dalteparin; fondaparinux; oral antithrombotic drugs, such as dabigatran or rivaroxaban; aspirin; vitamin K antagonists; and mechanical methods (eg, intermittent pneumatic compression device).⁸ The administration of prophylactic medications must be balanced against the hazard of symptomatic bleeding events, as well as their practical limitations.8 For example, LMWH and fondaparinux require subcutaneous injections; warfarin has a delayed onset of action, making it relatively ineffective in the immediate postsurgical time period. Furthermore, compression devices can be cumbersome and are relatively ineffective after hip replacement surgery.⁸

Novel oral antithrombotic agents combine the convenience of administration with efficacy and safety profiles that are comparable or superior to other methods.⁸ Rivaroxaban, a factor Xa inhibitor, was approved on July 1, 2011, by the US Food and Drug Administration (FDA) to reduce the risk for blood clots, DVT, and PE after knee or hip replacement surgery.^9,10 Dabigatran, a direct thrombin inhibitor, is not approved by the FDA for use in patients undergoing joint replacement surgery,¹¹ but it has been evaluated in several phase 3 clinical trials for the prevention of VTE in patients who undergo these procedures.^12-14

Because VTE is associated with several potentially serious complications, its economic burden on the US healthcare system is significant. Using a large, geographically diverse US managed care database, a 2009 study estimated the annualized total healthcare costs across the entire continuum of care for patients who presented with DVT and/or PE.¹⁵ The study showed that during and after DVT, PE, and DVT/PE events, the annualized median costs increased to $17,512, $18,901, and $25,554, respectively, compared with a median cost of $680 in the control group. The investigators concluded that clinical and economic benefits are likely to result from early detection and the appropriate treatment of DVT.¹⁵

Apixaban Receives New Indications in 2014

In 2014, apixaban (Eliquis; Bristol-Myers Squibb and Pfizer) received 2 new indications. On March 13, 2014, the FDA approved apixaban for the prophylaxis of DVT, which may lead to PE, in patients who have undergone hip or knee replacement surgery.^16,17 On August 21, 2014, apixaban received supplemental approval for the treatment of DVT and PE, and for risk reduction of recurrent DVT and PE after initial therapy.^18,19

Apixaban was first approved by the FDA on December 28, 2012, to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).^19,20 This approval was contingent on the manufacturer’s provision of a Risk Evaluation and Mitigation Strategies program to inform healthcare professionals about the increased risk for thrombotic events, including stroke, when apixaban is prematurely discontinuing without an adequate alternative anticoagulant use.¹⁹

The FDA approved apixaban for DVT prophylaxis and for the prevention of PE, in patients who have undergone hip or knee replacement surgery, after reviewing data from studies conducted as a part of the ADVANCE trial program.^8,17,19,21 The pooled data from 2 of the ADVANCE trials showed that apixaban was more effective than enoxaparin for the prevention of VTE in patients undergoing hip or knee replacement surgery.²¹

The approval of apixaban for the treatment of DVT and PE, and for risk reduction for recurrent DVT and PE after initial therapy, was based on data from 2 global studies—AMPLIFY and AMPLIFY-EXT.^18,22,23 In AMPLIFY, apixaban demonstrated efficacy comparable with standard of care using a composite efficacy end point of recurrent symptomatic VTE or VTE-related death.^19,22 In addition, apixaban demonstrated superiority in the primary safety end point of major bleeding, as well as fewer clinically rele­­vant nonmajor bleeding events.^19,22

In the AMPLIFY-EXT clinical trial, patients who had completed 6 to 12 months of anticoagulant therapy without having a recurrent event were randomized to receive apixaban or placebo for 12 months.^19,23 Both doses of apixaban (ie, 5 mg and 2.5 mg) were superior to placebo in the primary end point of symptomatic recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death.^19,23

Mechanism of Action

Apixaban is an oral selective factor Xa in­hibitor. By inhibiting this key blood clotting protein, apixaban decreases thrombin generation and blood clot formation.¹⁹ Apixaban decreases thrombin generation and thrombus development by selectively inhibiting free and clot-bound factor Xa. Apixaban does not require antithrombin III for antithrombotic activity, and it has no direct effect on platelet aggregation.¹⁹

Dosing and Administration

For the prophylaxis of DVT after hip or knee replacement surgery, the recommended dose of apixaban is 2.5 mg orally twice daily, with or without food. The first dose should be administered 12 to 24 hours after surgery. Patients who undergo hip replacement surgery should take apixaban for a total of 35 days, and patients who undergo knee replacement surgery should take apixaban for 12 days (Table 1).¹⁹

For the treatment of DVT and PE, apixaban should be dosed at 10 mg orally twice daily for 7 days, followed by 5 mg orally twice daily.¹⁹

To reduce the risks for recurrence after at least 6 months of treatment for DVT or PE, the recommended dose of apixaban is 2.5 mg orally twice daily.¹⁹

For patients who are unable to swallow tablets, the 5-mg and 2.5-mg apixaban tablets may be crushed and suspended in a dextrose solution and immediately delivered through a nasogastric tube.¹⁹

The ADVANCE Clinical Trials: Prophylaxis of DVT After Hip or Knee Replacement Surgery

Overall, 3 double-blind, multinational studies documented the clinical efficacy of apixaban in adults who underwent orthopedic procedures: ADVANCE-1 (knee replacement surgery), ADVANCE-2 (knee replacement surgery), and ADVANCE-3 (hip replacement surgery).^8,19,21 A total of 11,659 patients were randomized in these 3 clinical trials to apixaban (N = 5770) or to enoxaparin (N = 5755); overall, the studies included 1866 patients aged ≥75 years, 1161 patients with low body weight (≤60 kg), 2528 patients with a body mass index of ≥33 kg/m2, and 625 patients with severe or moderate renal impairment.¹⁹

Each clinical trial compared oral apixaban with subcutaneously administered enoxaparin, and the primary efficacy end point was a composite of adjudicated asymptomatic and symptomatic DVT, nonfatal PE, and all-cause death at the end of the intended treatment period. In the ADVANCE-1 trial, the primary end point was tested for noninferiority of apixaban to enoxaparin. In the ADVANCE-2 and the ADVANCE-3 trials, the primary end point was tested for noninferiority, then superiority, of apixaban to enoxaparin.^8,19,21

The ADVANCE clinical trials randomized more than 11,000 patients to assess the safety and efficacy of apixaban in preventing DVT in patients who have undergone hip or knee replacement surgery.^8,17,21

Efficacy
The phase 3 studies demonstrated that apixaban was more effective than enoxaparin for the prevention of VTE in patients undergoing hip or knee replacement surgery.^17,19 The efficacy data for apixaban and enoxaparin from the ADVANCE-1 and the ADVANCE-2 trials (ie, patients undergoing knee replacement surgery) are summarized in Table 2.¹⁹

Efficacy data for apixaban and enoxaparin from the ADVANCE-3 trial (ie, patients undergoing hip replacement surgery) are summarized in Table 3.¹⁹ The efficacy of apixaban was generally consistent across patient subgroups, including age, sex, race, body weight, and renal impairment.¹⁹

Safety
Apixaban 2.5 mg twice daily for up to 38 days was evaluated in 4 clinical trials (1 phase 2 study and 3 phase 3 studies) with a total of 5924 patients undergoing elective hip or knee replacement surgery.¹⁹ Adverse reactions were observed in 11% of the patients who received apixaban 2.5 mg twice daily.¹⁹

Table 4 summarizes the bleeding results during the treatment period in the phase 3 studies. In each study, bleeding was assessed starting with the first dose of the double-blind study drug.¹⁹

Other adverse reactions that occurred in ≥1% of patients undergoing hip or knee replacement surgery included nausea (2.6% for apixaban and 2.7% for enoxaparin); anemia (including postoperative and hemorrhagic anemia), and respective laboratory parameters (2.6% vs 3.0%, respectively); contusion (1.4% vs 1.9%, respectively); hemorrhage, including hematoma, and vaginal and urethral hemorrhage (1.1% vs 1.4%, respectively); postprocedural hemorrhage, including postprocedural hematoma, wound hemorrhage, vessel puncture–site hematoma, and catheter-site hemorrhage (0.9% vs 1.0%, respectively); increased transaminases, including increased alanine aminotransferase and abnormal alanine aminotransferase (0.8% vs 1.2%, respectively); increased aspartate aminotransferase (0.8% vs 1.2%, respectively); and increased gamma-glutamyltransferase (0.6% vs 1.1%, respectively).¹⁹

AMPLIFY and AMPLIFY-EXT Trials: Treatment of DVT and PE, and Reduction in Risk for Recurrent DVT and PE After Initial Therapy

The 2 double-blind, randomized clinical trials, AMPLIFY and AMPLIFY-EXT, supported the approval of apixaban for the treatment of DVT and PE, and for risk reduction of recurrent DVT and PE after initial therapy. In these studies, 2676 patients received apixaban 10 mg twice daily, 3359 patients received apixaban 5 mg twice daily, and 840 patients received apixaban 2.5 mg twice daily.^19,22,23

AMPLIFY was a randomized, double-blind clinical trial that investigated the efficacy and safety of apixaban for the treatment of patients with confirmed symptomatic DVT or PE. In AMPLIFY, apixaban was compared with the standard of care (ie, initial enoxaparin treat­ment for at least 5 days), followed by warfar­in therapy (international normalized ratio range, 2.0-3.0) for 6 months in patients with confirmed symptomatic DVT and/or PE.^19,22 The primary efficacy end point was a composite of recurrent symptomatic VTE, or VTE-related death. The primary safety end point was major bleeding.^19,22

Of the 5244 patients who were evaluable for efficacy in the AMPLIFY trial, the mean age was 57 years.¹⁹ Overall, 59% of these patients were male and 83% were Caucasian. Approximately 90% of the patients had an unprovoked DVT or PE at baseline. The balance of patients with a provoked DVT or PE were required to have an additional ongoing risk factor, such as a previous episode of DVT or PE, immobilization, history of cancer, active cancer, and a known prothrombotic genotype.¹⁹

In the AMPLIFY-EXT trial, 2 doses of apixaban (2.5 mg and 5 mg orally twice daily) were compared with placebo in patients who had been treated for DVT and/or PE for 6 to 12 months with anticoagulant therapy without having a recurrent event.^19,23 A total of 2486 patients were enrolled in the AMPLIFY-EXT trial, which involved 328 sites in 28 countries.²³ The primary efficacy end point was symptomatic recurrent VTE or all-cause death, and the primary safety end point was major bleeding.^19,23 Recurrent VTE included nonfatal PE and nonfatal DVT.¹⁹ Death was classified as VTE-related, cardiovascu­lar disease–related, bleeding-related, or as a result of other causes.²³

Of the 2482 patients who were enrolled in the AMPLIFY-EXT trial, the mean age was 57 years; the majority of these patients were male (57%) and Caucasian (85%).¹⁹ In addition, approximately 33% of the patients had participated in the AMPLIFY trial before enrollment in the AMPLIFY-EXT trial.¹⁹

Efficacy
The AMPLIFY trial showed that apixaban was noninferior to enoxaparin plus warfarin for the primary end point of recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death during 6 months of therapy.^19,22 The efficacy data for apixaban and enoxaparin plus warfarin are summarized in Table 5.¹⁹

Patients in the AMPLIFY trial were stratified according to their index event of PE (with or without DVT) or DVT (without PE), and the efficacy of apixaban in the initial treatment of VTE was consistent between these subgroups.^19,22

In the AMPLIFY-EXT trial, both doses of apixaban were superior to placebo in the composite end point of symptomatic recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death.^19,23 These data are summarized in Table 6.¹⁹

Safety
In the AMPLIFY trial, adverse reactions related to bleeding occurred in 15.6% of patients who received apixaban compared with 24.6% of patients who received enoxaparin plus warfar­in.¹⁹ The rates of discontinuation as a result of bleeding events were 0.7% in the apixaban group and 1.7% in the enoxaparin plus warfarin group.¹⁹

The AMPLIFY trial showed that apixaban was significantly superior to enoxaparin plus warfarin in the primary safety end point of major bleeding.^19,22 The relative risk for major bleeding was 0.31 (95% confidence interval, 0.17-0.55; P <.001).¹⁹

The adverse reactions that occurred in ≥1% of patients in the AMPLIFY trial included epistaxis, contusion, hematuria, menorrhagia, hematoma, hemoptysis, rectal hemorrhage, and gingival bleeding.¹⁹

Adverse reactions that were related to bleeding occurred in 13.3% of patients who received apixaban compared with 8.7% of patients who received placebo in the AMPLIFY-EXT trial.¹⁹ The rates of major bleeding were 0.2% in the apixaban 2.5-mg group, 0.1% in the apixaban 5-mg group, and 0.5% in the placebo group.¹⁹ The rates of discontinuation as a result of bleeding events were approximately 1% in the apixaban group and 0.4% in the placebo group.¹⁹

The adverse reactions that occurred in ≥1% of patients in the AMPLIFY-EXT study included epistaxis, hematuria, hematoma, contusion, and gingival bleeding.^19,23

Contraindications

Apixaban is contraindicated in patients with active pathologic bleeding and in patients who have had severe hypersensitivity reactions, including anaphylaxis, to apixaban.¹⁹

Warnings and Precautions

Boxed warning
The prescribing information for apixaban includes a boxed warning about several risks that are associated with this medication, including increased risk for stroke that is associated with the premature discontinuation of apixaban in patients with NVAF who do not maintain adequate anticoagulation.¹⁹

In addition, the boxed warning cautions about the risk for epidural or spinal hematoma. Patients who are receiving neuroaxial anesthesia or who are undergoing spinal puncture and are treated with antithrombotic agents for the prevention of VTE may develop hematomas (spinal or epidural) that can cause long-term or permanent paralysis. The postoperative use of indwelling epidural catheters or the concomitant use of other drugs that affect hemostasis may increase the risk for these events. Indwelling epidural or intrathecal catheters should not be removed until 24 hours after the last apixaban dose, and the next apixaban dose should be administered at least 5 hours after catheter removal.¹⁹

Furthermore, the discontinuation of apixaban in the absence of adequate alternative anticoagulation increases the risk for thrombotic events.¹⁹ In clinical trials that involved patients with atrial fibrillation, an increased rate of stroke was observed during the transition from apixaban to warfarin. If apixaban must be discontinued for a reason other than pathologic bleeding or the completion of a course of therapy, coverage with another anticoagulant should be considered.¹⁹

Bleeding
Apixaban can cause serious, potentially fatal bleeding.¹⁹ The concomitant use of drugs that affect hemostasis increases the risk for bleeding; these drugs include antiplatelet agents (eg, aspirin), anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs. Patients should be counseled about the signs and symptoms of blood loss and should be instructed to report them immediately or to visit an emergency department.¹⁹

Patients with active pathologic hemorrhaging should discontinue the use of apixaban.¹⁹ The anticoagulant effects of apixaban, which can be expected to persist for at least 24 hours after the last dose, cannot be reversed by any established method, and no specific antidote is available. Hemodialysis does not appear to have a substantial effect on apixaban exposure.¹⁹

Traumatic or repeated epidural or spinal puncture can increase the risk for hematoma.¹⁹ If traumatic puncture occurs, the administration of apixaban should be delayed for 48 hours. Patients should be frequently monitored for the signs and symptoms of neurologic impairment (eg, numbness or weakness of the legs, bowel, or bladder dysfunction).¹⁹

Furthermore, urgent diagnosis and treatment are necessary if neurologic compromise is observed. For patients who take anticoagulants and for patients who plan to take anticoagulants for thromboprophylaxis, the potential benefit of epidural or spinal intervention should be weighed against the risk.¹⁹

Prosthetic heart valves
Because the safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves, the use of apixaban is not recommended in these patients.¹⁹

Acute PE in hemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy. Patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy should not receive initial treatment with apixaban as an alternative to unfractionated heparin.¹⁹

Use in Specific Populations

Pediatric use
The safety and effectiveness of apixaban have not been established in pediatric patients.¹⁹

Geriatric use
In the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical trials, 50% of the patients were aged ≥65 years and 16% of the patients were aged ≥75 years.¹⁹ In the AMPLIFY and AMPLIFY-EXT trials, more than 32% of patients were aged ≥65 years, and more than 13% of patients were aged ≥75 years.¹⁶ Comparisons of patients in various age-groups showed no significant differences in the drug’s safety or efficacy.¹⁹

Pregnancy
Adequate and well-controlled studies of apixaban in pregnant women have not been conducted. Because treatment is likely to increase the risk for hemorrhage during pregnancy and delivery, apixaban should be used during pregnancy only if the potential benefit outweighs the potential risk for the mother and the fetus.¹⁹

Labor and delivery
The safety and efficacy of apixaban during labor and delivery have not been studied in clinical trials. The risks for bleeding and for stroke with apixaban use should be considered in this setting.¹⁹

Nursing mothers
It is not known whether apixaban or its metabolites are excreted in human milk. Based on the importance of the drug to the mother, women should either discontinue breastfeeding or discontinue the use of apixaban, taking into account the importance of the drug to the mother.¹⁹

End-stage renal disease (ESRD)
Patients with ESRD with or without hemodialysis were not included in the clinical efficacy and safety studies of apixaban.¹⁶ For patients with ESRD that is maintained with hemodialysis, the recommended dose of apixaban is 5 mg orally twice daily. For patients with ESRD that is maintained with hemodialysis and are either aged ≥80 years or have a body weight of ≤60 kg, the dose of apixaban should be reduced to 2.5 mg twice daily.¹⁹

Conclusion

Apixaban is an antithrombotic agent that selectively inhibits factor Xa to decrease thrombin generation and blood clot formation. Apixaban offers a safe, effective, and convenient oral alternative for patients undergoing total hip replacement surgery or total knee replacement surgery, patients who require treatment for VTE, and patients in whom prophylaxis is needed to reduce the risk for recurrent VTE after initial therapy. In addition, apixaban does not require routine coagulation testing and monitoring, which adds to its convenience. In clinical trials, apixaban had significantly lower rates of major bleeding events compared with enoxaparin plus warfarin, a serious concern in patients undergoing surgery, such as hip or knee replacement surgery.

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References

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