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To demonstrate how health technology assessment methods can be used to support Medicare's price negotiations for apixaban and rivaroxaban. 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. 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. 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. • With modifications, health technology assessment can be used to assess drugs deep into their brand lifecycle. • Observational data can play a valuable role in postlaunch health technology assessments. • In jurisdictions in which the quality-adjusted life year is prohibited, the equal-value life year can provide a feasible alternative measure of health gain because it ensures that extended life is assigned an equal value for everyone regardless of baseline quality of life. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Charles Frost,1 Andrew Shenker,1 Stanford Jhee,2 Zhigang Yu,1 Jessie Wang,3 Alexander Bragat,1 Janice Pursley,4 Frank LaCreta1 1Exploratory Clinical and Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA; 2PAREXEL International Early Phase, Glendale, CA, USA; 3Exploratory Development Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA; 4Analytical and Bioanalytical Development, Bristol Myers Squibb, Princeton, NJ, USA 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 (Cmax) 3–4 h postdose, with mean Cmax 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. Keywords: safety, pharmacokinetics, pharmacodynamics, Japanese, apixaban, anticoagulation, Asian, novel, Eliquis

Apixaban is the only NOA the administration of which is associated with a reduction in the incidence of both stroke and major bleeding. Therefore, apixaban is the drug of choice in patients with non-valvular AF, including elderly patients, patients with a high risk of bleeding complications, as well as in patients with impaired renal function. In clinical practice, the efficacy and safety of apixaban are not inferior to those obtained in the ARISTOTLE trial. Apixaban is safe when used during cardioversion and catheter ablation. The results of pre-clinical studies provide implications for further investigation into the possibility of administration of apixaban in patients with «valvular» AF.

Novel oral anticoagulants (NOACs) are becoming popular management options for stroke prophylaxis in nonvalvular atrial fibrillation as well as deep vein thrombosis and pulmonary embolism treatment and prophylaxis. NOACs have similar efficacy to warfarin along with noninferior safety profiles. Patient comorbidities, size, renal and hepatic function, and concomitant drug regimen play a role in which NOAC a physician may choose.

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; χ 2 , 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%, χ 2 ; P < .001); likewise, patients in group A had a significantly decreased DVT occurrence compared with group D (14.7% vs 1.98%; χ 2 , P = .00162), whereas patients in groups C and D were not statistically different (16.7% vs 14.7%; χ 2 , 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., (Copyright © 2023. Published by Elsevier Inc.)

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., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2019.)