Informing the United States Medicare Drug Price Negotiation for Apixaban and Rivaroxaban: Methodological Considerations for Value Assessments Many Years After Launch.

OBJECTIVES: To demonstrate how health technology assessment methods can be used to support Medicare's price negotiations for apixaban and rivaroxaban. METHODS: Following the statutory outline of evidence that will be considered by Medicare, we conducted a systematic literature review, network meta-analyses, and decision analyses to evaluate the health outcomes and costs associated with apixaban and rivaroxaban compared with warfarin and dabigatran for patients with nonvalvular atrial fibrillation. Our methods inform discussions about the therapeutic impact of apixaban and rivaroxaban and suggest price premiums above their therapeutic alternatives over a range of cost-effectiveness thresholds. RESULTS: Network meta-analyses found apixaban resulted in a lower risk of major bleeding compared with warfarin and dabigatran and a lower risk of stroke/systemic embolism compared with warfarin but not compared with dabigatran. Rivaroxaban resulted in a lower risk of stroke/systemic embolism versus warfarin but not dabigatran, and there was no difference in major bleeding. Decision-analytic modeling of apixaban suggested annual price premiums up to $4350 above the price of warfarin and up to $530 above the price for dabigatran at cost-effectiveness thresholds up to $200 000 per equal value of life-years gained. Analyses of rivaroxaban showed an annual price premium of up to $3920 above warfarin and no premium above that paid for dabigatran. CONCLUSIONS: Although health technology assessment is typically performed near the time of regulatory approval, with modifications, we produced comparative clinical and relative cost-effectiveness findings to help guide negotiations on a "fair" price for drugs on the market for over a decade.

From basic science to life-saving therapy: the rationale, and drug discovery efforts that led to the direct factor Xa inhibitor eliquis.

Over the past few decades, drug discovery directed at the treatment and prevention of thromboembolic diseases has been challenged by the need to balance robust efficacy with improved safety relative to the standard of care. To this end, the most impactful advance to date has been the discovery and development of oral factor Xa inhibitors. In this essay, a brief account of the program that culminated in the discovery of Eliquis (apixaban) and the commitment to identify a compound with an optimal profile are described.

Ovarian stimulation for fertility preservation in an oncology patient with etonogestrel implant in place.

PURPOSE: To describe a case of a young woman who presented for fertility preservation and underwent ovarian stimulation with an etonogestrel implant in place. METHODS: A 24-year old, gravida 0, with an etonogestrel implant and newly diagnosed lower extremity sarcoma and DVT desiring oocyte cryopreservation prior to adjuvant chemotherapy and radiation. To avoid delay in her oncologic care and allow for continued use of contraception post-retrieval, the patient underwent controlled ovarian hyperstimulation (COH) without removal of the etonogestrel implant. RESULTS: Baseline labs included follicle-stimulating hormone 9 mIU/mL, luteinizing hormone 4.9 mIU/mL, estradiol 42 pg/mL, anti-Müllerian hormone 5.1 ng/mL, and antral follicle count greater than 40. The patient was placed on an antagonist protocol and stimulated with 125 IU Gonal-F and 75 IU Menopur. She received a total of 12 days of gonadotropin stimulation. On the day of trigger, her estradiol was 1472 pg/mL, lead follicle 21.5 mm with a total of 25 follicles measured > 12 mm. She was triggered with 5000 U hCG. She had a total of 23 oocytes retrieved, 17 of which were metaphase II and vitrified. CONCLUSIONS: COH and successful oocyte cryopreservation can be achieved in patients with an etonogestrel implant in situ without apparent detrimental effects to oocyte yield or maturity. Due to the etonogestrel implant's inhibitory effects on LH, it is recommended to use an hCG trigger for final oocyte maturation.

Apixaban (Eliquis)-Induced Rash: A Case Report.

Many anticoagulants are indicated as prophylaxis and treatment for conditions that may lead to thromboembolisms or atrial fibrillation. Among those, apixaban, a reversible direct inhibitor of factor Xa, is one of the most popular. Apixaban is known to cause a variety of side effects; however, for this paper, the focus is on hypersensitivity reactions. Although several cases will be referenced from the literature, we present a case with a history of a dermatological disease before the use of a direct oral anticoagulant. A 74-year-old female patient with a history of pemphigus vulgaris and a diagnosis of pulmonary embolism and right distal vein thrombosis managed with apixaban presented with a pruritic coalescent erythematous dermatitis throughout her torso, back, and lower extremities three days post-apixaban treatment. In accordance with her physical examination, the apixaban regimen was withdrawn, and oral dabigatran, a direct thrombin inhibitor, was initiated. At the patient's five-day follow-up, clinical improvement was noted. Through clinical diagnosis, it is believed that this dermatitis was a reaction to the apixaban treatment course.

Prospective randomized trial of antithrombotic strategies following great saphenous vein ablation using injectable polidocanol endovenous microfoam (Varithena).

OBJECTIVE: Postablation deep vein thrombosis (DVT) represents a potentially serious complication after Varithena polidocanol endovenous microfoam (PEM) ablation. The following primary outcomes were assessed: whether (1) adjunctive apixaban anticoagulation or (2) mechanical deep venous system (DVS) saline flushing could decrease saphenofemoral junction (SFJ) thrombus extension (postablation superficial thrombus extension [PASTE]) and/or DVT compared with compression alone, after great saphenous vein (GSV) PEM ablation. METHODS: Varithena 1% PEM ablation patients were randomized to (1) SFJ compression, (2) compression and DVS saline flushing, or (3) compression, DVS saline flushing, and 5 days of postprocedural 5 mg oral apixaban anticoagulation twice daily. Duplex imaging was obtained 7 to 10 days after PEM ablation and PASTE/DVT incidence (primary end point) was compared between groups at this time point. RESULTS: We treated 304 limbs in 257 patients with PEM. Overall, 103 limbs received SFJ compression (group C, 33.8%), 101 received compression and deep venous flushing (group D, 32.9%), and 100 received compression, deep flush, and anticoagulation (group A, 33.2%). Mean ultrasound follow-up time was 9.7 days (all patients) with a primary GSV closure rate of 92.4%. SFJ PASTE (II-IV) occurred in 0.9%, 1.0%, and 0% (groups C, D, and A, respectively). DVT occurred in 16.7%, 14.7%, and 1.98% (groups C, D, and A; χ2, P = .002). Patients in group A receiving apixaban anticoagulation had a significant reduction in DVT compared with patients in group C (1.98% vs 16.7%, χ2; P < .001); likewise, patients in group A had a significantly decreased DVT occurrence compared with group D (14.7% vs 1.98%; χ2, P = .00162), whereas patients in groups C and D were not statistically different (16.7% vs 14.7%; χ2, P = .60). CONCLUSIONS: (1) Neither adjunctive DVS flushing nor anticoagulation decreased clinically relevant SFJ PASTE (II-IV) incidence, which remained similarly low across all groups and ranged between 0% and 1%, regardless of adjunctive DVS flushing or anticoagulation. This rate was significantly lower than prior reports (2.3%-4.1%). (2) DVS flushing had no influence on the rate of DVT. Observed PEM-induced DVT incidence using SFJ compression alone or compression with DVS flushing (16.7% and 14.7%, respectively) was significantly higher than prior reports (2.5%-9.6%). This finding may relate to the greater extent of AK/BK GSV territory treated in the present study. (3) Five days of postprocedural oral apixaban anticoagulation, 5 mg given twice daily, significantly decreased DVT occurrence to 1.98%, compared with nonanticoagulated patients (16.7%). This finding is comparable with the DVT rates reported after endovenous thermal ablation (0.7-1.7%). (4) Postprocedural apixaban anticoagulation may have a significant preventive role in decreasing DVT occurrence after PEM ablation.

The Safety and Efficacy of Apixaban (Eliquis) in 5017 Post-bariatric Patients with 95.3% Follow-up: a Multicenter Study.

BACKGROUND: Thromboprophylaxis in bariatric surgery is widely debated; however, few large articles evaluate treatment plans and their efficacy. Herein, we make the first large-scale report of the safety and efficacy of apixaban (Eliquis) for thrombus prevention following bariatric surgery. PURPOSE: To evaluate the safety and efficacy of apixaban following bariatric surgery. SETTING: Three private institutes, USA. MATERIALS AND METHODS: Data from 5017 consecutive bariatric patients that were placed on postoperative apixaban for thromboprophylaxis were used for retrospective analysis. The dose prescribed to patients was 2.5 mg PO BID for a total of 30 days starting on day 3 postoperatively. RESULTS: In total, of the 5017 patients, 59.7%, 31.2%, 4.4%, 2.5%, 1.8%, and 0.1% of the patients had undergone sleeve gastrectomy (SG), single-anastomosis duodeno-ileal bypass with SG (SADI-S), Roux-en-Y gastric bypass (RYGB), conversion from SG to SADI, small bowel reconstruction, and RYGB reversal, respectively. The 30-day follow-up rate was 95.3%. In total, 1.7% of patients experienced apixaban-related side effects. The most common side effects were menorrhagia and rash. Two (0.03%) side effects developed into Clavien-Dindo grade II complications. Overall, 10 (0.1%) patients experienced thromboembolic complications (five (0.09%) PVTs and five (0.09%) PEs). In each case, the protocol was not followed for extenuating circumstances. There were no deaths or thromboembolic events in cases where the protocol was able to be fully followed. CONCLUSIONS: In conclusion, 30 days of postoperative apixaban appears to be safe and effective with minimal side effects while preventing thromboembolic events.

Elevated International Normalized Ratio Due to Apixaban in Patient With End-Stage Renal Disease on Hemodialysis.

Apixaban is known to prolong international normalized ratio (INR) per some observational and in vitro studies. In patients with elevated INR secondary to apixaban use, median INR of 1.4-1.7 has been reported. Extreme elevation in INR is rare with apixaban. In patients with end-stage renal disease (ESRD) on hemodialysis (HD), there are no labeled indications for apixaban use; however, there are some pharmacokinetic data supporting its use in such patients. We present a case of a 68-year-old Hispanic man with ESRD who presented to the emergency room (ER) with INR of 27.42. INR testing was done as a part of routine workup in rehabilitation facility. Medication list was reviewed and included apixaban 2.5 mg twice daily which was recently started for postoperative thromboprophylaxis. INR testing was repeated for confirmation in ER and was reported as >18.5 and prothrombin time >200 seconds. His liver function tests were stable as compared to baseline testing five days ago with normal bilirubin, low normal transaminases, and mild hypoalbuminemia. The patient didn't have any active bleeding. An elevation of INR to >20 with apixaban is a rare event. No other factors including patient characteristics, laboratory results, co-existing conditions, or other medications except the direct oral anticoagulant (DOAC) were found to be responsible for elevated INR. Liver cirrhosis or vitamin K deficiency as cause for INR elevation was ruled out as the baseline INR was normal prior to starting apixaban, liver function tests were stable and INR normalized again shortly after discontinuing the medication. Plasma concentration of DOACs has been found to be correlating with the INR according to a pharmacokinetic study which potentially means that the high INR likely was secondary to high serum concentration of apixaban in this patient. However, INR monitoring is not recommended for monitoring anticoagulant activity of DOACs. As of note, renal clearance accounts for 27% of apixaban clearance. Pharmacokinetic studies have concluded that half dose apixaban, i.e., 2.5 mg twice daily in patients on hemodialysis (dose used in this case) results in drug exposure similar to that of the standard dose of 5 mg twice daily in patients with preserved renal function. Future studies are necessary to address questions about safety of DOACs in patients with ESRD, further elucidate the clinical significance of such high INR values associated with DOACs, and establish appropriate management guidelines. Andexanet alfa has since been approved for apixaban reversal in patients with life-threatening bleeding; however, would not be indicated in such cases when there is no evidence of bleeding.

Acute COVID-19-Associated Cardiac Arrhythmia: A Case Series and Literature Review.

Coronavirus disease 2019 (COVID-19) is a highly contagious infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report two cases of COVID-19-associated atrial fibrillation (AF) in two elderly females and a case of atrial flutter (AFlutter) in a middle-aged male patient. We believe this case series will contribute to the literature on new-onset AF and AFlutter in patients with acute COVID-19 infection. This case series illustrates various case scenarios of patients developing cardiac arrhythmia with acute COVID-19 infection without any prior history or other explicable cause of AF/AFlutter. The exact mechanism behind COVID-19 infection leading to AF or AFlutter is still unknown. Of the three patients reported, two converted to sinus rhythm following medical management, and one did not convert to sinus rhythm despite medical treatment.

A Possible Drug-Drug Interaction Between Eliquis and Amiodarone Resulting in Hemopericardium.

According to the ARISTOTLE trial, apixaban was superior to warfarin because it was associated with fewer strokes, systemic embolism, and bleeding. Hemopericardium was one of the major bleeding events reported in this trial. However, the percentage of patients that developed hemopericardium was not stated in the trial results. We present a case of hemopericardium in an 80-year-old man admitted for dyspnea, cough, and lower extremity edema. He was recently diagnosed with paroxysmal atrial fibrillation and started on apixaban for stroke prevention. Prior to admission, he was taking metoprolol succinate and amiodarone for atrial fibrillation. His symptoms resolved after undergoing successful pericardiocentesis. Although hemopericardium is a rare side effect associated with the use of non-vitamin K oral anticoagulants (NOACs), we suspect that a drug-drug interaction between apixaban and amiodarone (via the cytochrome p450 system and p-glycoprotein efflux pumps), the patient's advanced age, and borderline creatinine are possible risk factors.

Spontaneous Spinal Epidural Hematoma Associated With Apixaban Therapy: A Report of two Cases.

Spontaneous spinal epidural hematoma (SSEH) is a rare clinical entity that can result in severe neurological deficit and warrants emergent neurosurgical evaluation and management. The exact etiology of this entity remains unknown, but certain risk factors exist, including the use of anticoagulant medications. There are few published reports of the association of SSEH with direct factor Xa inhibitors. We aimed to present 2 cases of SSEH in patients on chronic apixaban therapy. To the best of our knowledge, there is only 1 other report of SSEH in the setting of apixaban therapy. A comparison between the cases suggests the importance of rapid recognition and management of SSEH in order to achieve favorable neurological outcomes.

Adrenal Hemorrhage in a Patient Anticoagulated with Apixaban with Antiphospholipid Syndrome.

Atraumatic adrenal hemorrhage is a rare injury, often due to the disruption of normal hemostasis secondary to sepsis, autoimmune disease, or chronic anticoagulation. We present a case of recurrent adrenal hemorrhage in a patient with antiphospholipid syndrome previously maintained on warfarin for deep vein thrombosis and pulmonary embolism prophylaxis who worsened shortly after transition to apixaban therapy. Initial left-sided adrenal hemorrhage occurred four weeks after beginning apixaban, followed by the development of retinal hemorrhage and later right-sided adrenal hemorrhage. This is, to date, the first reported case of adrenal hemorrhage in a patient receiving chronic anticoagulation with apixaban.

Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma Receiving Immunomodulatory Therapy.

Immunomodulatory drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide, have improved survival of patients with multiple myeloma (MM). However, these therapies are associated with an increased risk of venous thromboembolism (VTE). Apixaban has been approved for treatment of acute VTE and for risk reduction of recurrent VTE following initial therapy. In this phase IV single-arm study (NCT02958969), we aim to prospectively evaluate the safety and efficacy of apixaban for primary prevention of VTE in patients with MM. The primary efficacy objective of this trial is to determine the rate of symptomatic VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), over 6 months. The primary safety objective is to determine the rate of major bleeding in MM patients receiving apixaban prophylaxis. If proven safe and effective, apixaban will emerge as a promising option for oral VTE prophylaxis in MM patients.

Andexanet alfa for reversal of factor Xa inhibitor-associated anticoagulation.

BACKGROUND: Review of clinical data on andexanet alfa for the reversal of factor Xa (FXa) inhibitor associated anticoagulation. DATA SOURCES: In the present review, we identified articles via PubMed using the combined keywords andexanet alfa, apixaban, enoxaparin, edoxaban, and rivaroxaban. Additional online searches via PubMed, Google Scholar, and Lexicomp were conducted for both prescribing and cost information. Portola Pharmaceuticals was contacted for information used for United States Food and Drug Administration approval of andexanet alfa. STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials and reviews published between January 2008 and April 2019 were included for review. Bibliographies of selected articles were reviewed manually for relevant publications, focusing on reversal strategies for apixaban, enoxaparin, edoxaban, or rivaroxaban associated anticoagulation using andexanet alfa. Review articles were excluded. DATA SYNTHESIS: The safety and tolerability of andexanet alfa were evaluated in one phase I, two phase II, and one phase III clinical trials. The use of andexanet alfa for reversing FXa inhibitor-associated anticoagulation were evaluated in the phase III ANNEXA-4 study. CONCLUSIONS: Studies evaluating laboratory parameters for coagulation show that andexanet alfa rapidly neutralizes the anticoagulant effects of apixaban, enoxaparin, edoxaban, and rivaroxaban. Clinical studies show that andexanet alfa improves markers related to coagulation, and reverses major bleeding in healthy volunteers and patients with life-threatening bleeding. Interruption of anticoagulation may result in thromboembolic and ischemic events. The use of andexanet alfa requires close monitoring for signs and symptoms of thromboembolic events, ischemic events, and cardiac arrest. Furthermore, anticoagulation should be resumed following the administration of andexanet alfa as soon as medically appropriate.

Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

PURPOSE: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects. SUBJECTS AND METHODS: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo. Doses were separated by a ≥5-day washout. Blood samples were collected for the determination of apixaban plasma concentration, clotting times (international normalized ratio [INR], activated partial thromboplastin time, and modified prothrombin time [mPT]), and ex vivo thrombin generation (TG). Urine samples were collected for the analysis of apixaban concentration. RESULTS: Ascending single doses of apixaban 2.5-50 mg were safe and well tolerated by all subjects. Apixaban exposure increased the dose proportionally up to 10 mg. Apixaban reached maximum concentrations (C max) 3-4 h postdose, with mean C max ranging from 52.5-485.0 to 44.8-494.3 ng/mL in Japanese and Caucasian subjects. The mean half-life was ~8 and ~13 h and the renal clearance was 1.1 and 0.8 L/h in Japanese and Caucasian subjects, respectively. Pharmacodynamic assessments were similar between ethnic groups, with comparable dose-related prolongation of INR and mPT and inhibition of TG. CONCLUSION: Ascending single doses of apixaban over a 20-fold dose range were safe and well tolerated in Japanese and Caucasian subjects in this study. The consistency between pharmacokinetic and pharmacodynamic measures in Japanese and Caucasian subjects indicates that apixaban may be administered as a fixed dose with no need for adjustment in Japanese patients.