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.

Deep Venous Thrombosis Within a Complete Duplication of the Left Femoral Vein.

Venous duplications, particularly in the femoral vein, are rare anatomical variations that can complicate the clinical presentation and management of deep venous thrombosis (DVT). This case describes an elderly female who was diagnosed by her primary care physician with a left lower extremity DVT one week prior to her presentation and had been prescribed Xarelto. Despite strict adherence to therapy, her left leg pain, swelling, and discoloration worsened, prompting her hospital admission. On physical examination, her left leg was markedly swollen, violaceous, and tender. A repeat compression ultrasound upon admission revealed an occlusive thrombus within the left common femoral vein. Given the diagnosis of phlegmasia, cerulea dolens, the patient was at risk for irreversible venous gangrene and possible limb loss. Therefore, she was taken to the operating room for venography and a mechanical thrombectomy. Venography of the left lower extremity uncovered an extensive thrombus within a complete duplication of the left femoral vein, as well as in the left common femoral and iliac veins. Thrombosis in a duplicated femoral vein, though rare, is a significant clinical entity. This case highlights the importance of considering anatomical anomalies in patients with refractory symptoms and emphasizes the role of detailed imaging for accurate diagnosis and tailored treatment.

Suspected Rivaroxaban-Induced Anaphylaxis Secondary to Ingestion of Rivaroxaban and Nimesulide Without Cross-Reactivity to Dabigatran - A Case Report.

Here, we describe a case of anaphylaxis secondary to rivaroxaban in a 61-year-old woman 24 hours after orthopedic surgery. 10-15 minutes after ingestion of rivaroxaban and nimesulide, the patient's palms started itching, her face and lips swelled, her face flushed, she developed shortness of breath and subsequently lost consciousness. Serum tryptase levels at the time of the anaphylactic reaction were elevated, with subsequent measurement one month later returning a value within the normal range. Dabigatran and meloxicam were identified as suitable alternative drugs by oral provocation at an allergy clinic. Even though rivaroxaban rarely causes serious allergic reactions, when prescribing it, it is important to analyze patients' medical history for possible previously experienced drug-induced allergic reactions and to be aware of the risks of possible undesired drug interactions.

On Absorption Modeling and Food Effect Prediction of Rivaroxaban, a BCS II Drug Orally Administered as an Immediate-Release Tablet.

The present work evaluates the food effect on the absorption of rivaroxaban (Riva), a BCS II drug, from the orally administered commercial immediate-release tablet (Xarelto IR) using physiologically based pharmacokinetic (PBPK) and conventional in vitro-in vivo correlation (IVIVC) models. The bioavailability of Riva upon oral administration of Xarelto IR tablet is reported to exhibit a positive food effect. The PBPK model for Riva was developed and verified using the previously reported in vivo data for oral solution (5 and 10 mg) and Xarelto IR tablet (5 and 10 mg dose strength). Once the PBPK model was established, the in vivo performance of the tablet formulation with the higher dose strength (Xarelto IR tablet 20 mg in fasted and fed state) was predicted using the experimentally obtained data of in vitro permeability, biorelevant solubility and in vitro dynamic dissolution data using United States Pharmacopeia (USP) IV flow-through cell apparatus. In addition, the mathematical IVIVC model was developed using the in vitro dissolution and in vivo profile of 20 mg strength Xarelto IR tablet in fasted condition. Using the developed IVIVC model, the pharmacokinetic (PK) profile of the Xarelto IR tablet in fed condition was predicted and compared with the PK parameters obtained via the PBPK model. A virtual in vivo PK study was designed using a single-dose, 3-treatment cross-over trial in 50 subjects to predict the PK profile of the Xarelto® IR tablet in the fed state. Overall, the results obtained from the IVIVC model were found to be comparable with those from the PBPK model. The outcome from both models pointed to the positive food effect on the in vivo profile of the Riva. The developed models thus can be effectively extended to establish bioequivalence for the marketed and novel complex formulations of Riva such as amorphous solid dispersions.

A Ghost in Coronary Artery - Coronary Artery Embolism After Discontinuation of Rivaroxaban in a Patient With Atrial Fibrillation: Case Report and Review of Literature.

Coronary artery embolism (CAE) is a rare clinical entity that can cause acute myocardial infarction (AMI). The exact prevalence of coronary artery embolism is unknown. CAE was found to be associated with conditions that can lead to thrombo-embolism, including infective endocarditis, atrial fibrillation, mitral valve disease, valve surgery. Herein, we report a 78-year-old male with a past medical history of atrial fibrillation on rivaroxaban who presented to the hospital emergency department complaining of chest pain. The patient's anticoagulation therapy was recently held due to a concern for gastrointestinal bleeding. After further evaluation of the patient's symptoms and reviewing his electrocardiogram (ECG) which showed ST-depression in lateral leads and ST-elevation in aVR, urgent cardiac catheterization was done which showed left main coronary artery thrombosis extending into the left anterior descending artery (LAD) and left circumflex artery (LCX). The patient was started on a heparin drip and underwent a successful aspiration thrombectomy with subsequent improvement in his symptoms.

Spontaneous Spinal Epidural Hematoma Secondary to Rivaroxaban Use in a Patient With Paroxysmal Atrial Fibrillation.

A spontaneous spinal epidural hematoma (SSEH) is a rare condition of intraspinal bleeding in the epidural space. It is often associated with disorders of anticoagulation, intraspinal tumors, vascular malformations, and pertinent to this case, anticoagulation therapy. This surgical emergency requires early diagnosis and management in order to minimize permanent neurologic deficits. We report the case of a 72-year-old female with a past medical history of paroxysmal atrial fibrillation treated with rivaroxaban who presented to the emergency department with acute-onset, midline, lower back pain with no known trauma or injury to the area. At the time of emergency department (ED) admission, the patient was fully ambulatory and alert and oriented. However, within hours, she developed bilateral lower extremity motor paralysis and diminished sensation with urinary and bowel incontinence. SSEHs are rare, progressive neurologic emergencies that can present with non-specific lower back pain. This condition presents a diagnostic challenge that can result in permanent neurologic defects if not recognized early. Emergency physicians regularly encounter patients with both acute lower back pain and atrial fibrillation. This case can contribute to the possibility of SSEH to a differential diagnosis.

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.

Fatal pulmonary hemorrhage after taking anticoagulation medication.

We describe a 64-year-old man with extensive diffuse acute lung hemorrhage, presumably as a result of anticoagulation therapy. We evaluated reports in the literature concerning acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. We also evaluated autopsy tissue in this case in order to determine the cause of death in this 64-year-old man, who was initially thought to have an asbestos-related disease. Based on the autopsy findings, this man died as a result of anticoagulation therapy; specifically, the use of Xarelto(®) (rivaroxaban).

[Critical haematuria after prostate biopsies with RIVAROXABAN. Case report]. / Hématurie critique post-biopsies de prostate sous RIVAROXABAN. Cas clinique.

Managing patients with new oral anticoagulants in perioperative period is not yet well protocolized. We report a clinical case of a critical haematuria after prostate biopsies to a patient treated with RIVAROXABAN. Monitoring and treatment of the haematuria have been difficult due to the lack of biological control and antidote for this treatment.