Budget impact analysis of apixaban to treat and prevent venous thromboembolism in Italy

BACKGROUND: Venous thromboembolism (VTE), a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious vascular condition associated to high economic and clinical burden. Apixaban, a Novel Oral Anticoagulant (NOAC) has shown non-inferiority efficacy versus the current standard of care (low molecular weight heparin [LMWH]/vitamin K antagonist [VKA]) in the acute treatment and prevention of VTE and a significant reduction in the risk of bleeding.AIM: Evaluate the economic impact of the use of apixaban for treatment and prevention of DVT and PE from the perspective of the Italian National Health System (NHS).METHODS: A budget impact model was adapted in order to compare clinical outcomes and economic consequences associated to apixaban vs. LMWH/VKA and others NOACs over a three-year time horizon in the Italian setting. In the analysis two scenario were compared: status quo scenario without apixaban and an alternative scenario with apixaban. Only direct healthcare costs have been considered.RESULTS: Assuming a population of patients receiving apixaban over the first 3 years equal to 20,957, the introduction of apixaban is associated to an incremental saving of € 821,748 in the first years, € 1,250,454 in the second year, and € 1,866,466 in the third year. The total net saving over the 3-year period is € 3,938,668, which is a 2.47% decrease from the total budget for the status quo scenario without apixaban. This saving is mainly due to reduced VTE events and bleeds by apixaban. Indeed apixaban is associated with less VTE events (both fatal and non-fatal), less major bleeding and less Clinical Relevant Non Major (CRNM) bleeding with a total of 52 fatal events avoided.CONCLUSIONS: The listing of apixaban for the treatment of VTE (both DVT and PE) and the prevention of recurrent VTE provides both significant clinical advantages, in terms of deaths and events avoided, and economical advantages, consisting in a reduction in the total expenditure on the Italian NHS

Cost‑effectiveness analysis of apixaban versus other NOACs for the prevention of stroke in Italian atrial fibrillation patients

OBJECTIVES: The study evaluated the cost‑effectiveness of apixaban in preventing thromboembolic events in non‑valvular atrial fibrillation (NVAF) patients, as compared to other three available novel oral anticoagulant agents (NOACs), from the Italian Health System (SSN) perspective.METHODS: A previously published lifetime Markov model was adapted for the Italian context. Baseline clinical risks were assigned based on the demographic and clinical features of the patients; effectiveness and safety parameters derived from adjusted indirect comparison using warfarin as link. The main clinical events considered in the model are ischemic and hemorrhagic stroke, systemic thromboembolism, bleeds (both major and clinically relevant minor) and cardiovascular hospitalizations, besides treatment discontinuations. Expected survival was projected beyond trial duration using national mortality data adjusted for clinical risks and weighted by published utilities. Unit costs were collected from published Italian sources and actualized to 2013. Costs and health gains occurring after the first year were discounted at an annual 3.5% rate. The primary outcome measure of the economic evaluation was the incremental cost effectiveness ratio (ICER), where effectiveness is measured in terms of life‑years and quality adjusted life‑years gained. Deterministic and probabilistic sensitivity analyses (DSA&PSA) were carried out.RESULTS: In the short to medium term, apixaban was associated with marginal LYs and QALYs gains and slight savings, as compared to other NOACs. However, as apixaban extended expected survival versus dabigatran (110mg), dabigatran (150mg) and rivaroxaban (0.13, 0.08, and 0.06 LYs or 0.11, 0.07, and 0.05 QALYs), expected total lifetime costs exceeded those of these comparators (€ 319, € 282, and € 16). Corresponding ICERs were estimated in € 2,911, € 3,882 and € 327 per QALY gained. The most influential parameter according to DSA was daily costs of NOACs, but the corresponding ICERs remained well below commonly accepted WTP values. In PSA, the probabilities of apixaban being cost effective with a WTP threshold of 20,000 €/QALY gained were 99%, 92% and 93% for the same comparisons.CONCLUSIONS: Apixaban is expected to be more effective than dabigatran and rivaroxaban in Italian NVAF population, and marginally more costly due to consume healthcare resources for a longer period of time. The ICERs have a high likelihood of being below conventional thresholds of WTP for health benefits of the SSN and suggest that apixaban is cost‑effective compared with other three available NOACs

Budget impact analysis of apixaban versus other NOACs for the prevention of stroke in Italian atrial fibrillation patients

OBJECTIVE: This study aims to perform a budget impact analysis of the use of three available novel oral anticoagulant agents (NOACs) for preventing thromboembolic events in Italian patients with non‑valvular atrial fibrillation (NVAF).METHODS: Estimated Italian population of patients was run through a previously published lifetime decision tree/Markov model simulating their treatment with the available therapeutic options: dabigatran at two dose levels (110 mg/bid for the over 80 years old, 150 mg/bid for younger NVAF patients), rivaroxaban (20 mg/uid), and apixaban (5 mg/bid). Effectiveness and safety estimates derive from an adjusted indirect treatment comparison using warfarin as link. The main clinical events considered in the model are ischemic and hemorrhagic stroke, systemic thromboembolism, bleeds (both major and clinically relevant minor) and cardiovascular hospitalizations, besides treatment discontinuations. Epidemiological data and unit costs, actualized to 2013, are collected from Italian published sources. The budget impact analysis evaluates the financial impact of apixaban introduction by comparing expected 1,2, and 3 years costs in hypothetical scenarios: with and without apixaban. Italian NVAF patient population estimation is based on official apixaban reimbursement criteria, applying the characteristics of the trial population to national epidemiologic data. Numbers of patients for each regimen are estimated by projecting share evolution. Sensitivity analysis is performed on an alternative non‑experimental population of NVAF patients.RESULTS: Among available NOACs, apixaban was expected to be the least expensive in an estimated patient population of 364,000 Italian patients, allowing for savings of € 1,180,549, € 3,841,429 and € 5,368,918 at 1,2, and 3 years, respectively. Results of the simulation run on an alternative non‑experimental population of NVAF patients yields comparable estimates.CONCLUSIONS: The different safety and effectiveness profiles of the three available NOACs emerging from the adjusted indirect comparison indicate that apixaban could improve health care expenditure control while maintaining or increasing therapeutic appropriateness in the Italian NVAF population

The economic impact associated with cerebrovascular events related to non-valvular atrial fibrillation (NVAF) in Italy: the role of apixaban

<a href="http://dx.doi.org/10.7175/fe.v15i1S.972">http://dx.doi.org/10.7175/fe.v15i1S.972</a

Comparative pharmacoeconomic assessment of apixaban vs. standard of care for the prevention of stroke in Italian atrial fibrillation patients

OBJECTIVES: The aim of this study was to evaluate the cost‑effectiveness of apixaban in the prevention of thromboembolic events in patients with non‑valvular atrial fibrillation (NVAF) relatively to standard of care (warfarin or aspirin) from the Italian National Health System (SSN) perspective.METHODS: A previously published lifetime Markov model was adapted for Italian context. Clinical effectiveness data were acquired from head‑to‑head randomized trials (ARISTOTLE and AVERROES); main events considered in the model were ischemic and hemorrhagic stroke, systemic thromboembolism, bleeds (both major and clinically relevant minor) and cardiovascular hospitalizations, besides treatment discontinuations. Expected survival was projected beyond trial duration using national mortality data adjusted for individual clinical risks and adjusted by utility weights for health states acquired from literature. Unit costs were collected from published Italian sources and actualized to 2013. Costs and health gains accruing after the first year were discounted at an annual 3.5% rate. The primary outcome measure of the economic evaluation was the incremental cost effectiveness ratio (ICER), where effectiveness is measured in terms of life‑years and quality adjusted life‑years gained. Deterministic and probabilistic sensitivity analyses (PSA) were carried out to assess the effect of input uncertainty.RESULTS: Apixaban is expected to reduce the incidence of ischemic events relative to aspirin and to improve bleeding safety profile when compared to warfarin. Incremental LYs (0.31/0.19), QALYs (0.28/0.20), and costs (1,932/1,104) are predicted with the use of apixaban relative to aspirin and warfarin, respectively. The ICERs of apixaban were € 6,794 and € 5,607 per QALY gained, respectively. In PSA, the probability of apixaban being cost effective relative to aspirin and warfarin was 95% and 93%, respectively, for a WTP threshold of € 20,000 per QALY gained. Univariate analyses indicate that results were most sensitive to variations of the absolute risk reduction for cardiovascular events with apixaban.CONCLUSIONS: Apixaban is expected to increase life expectancy and quality‑adjusted life expectancy, but also costs dedicated to Italian NVAF patients, as compared to standard of care. The resulting ICERs have high probabilities of being below the conventional thresholds of WTP for health benefits of the SSN, indicating efficient allocation of health care resources

Cost-effectiveness Comparison of Ceftazidime/Avibactam Versus Meropenem in the Empirical Treatment of Hospital-acquired Pneumonia, Including Ventilator-associated Pneumonia, in Italy

Purpose: Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose combination antibiotic approved in Europe and the United States for patients with hospitalacquired pneumonia, including ventilator-associated pneumonia (HAP/VAP). The economic benefits of a new drug such as CAZ-AVI are required to be assessed against those of available comparators, from the perspective of health care providers and payers, through cost-effectiveness and cost-utility analyses. The objective of this analysis was to compare the cost-effectiveness of CAZ-AVI versus meropenem in the empirical treatment of appropriate hospitalized patients with HAP/VAP caused by gram-negative pathogens, from the perspective of publicly funded health care in Italy (third-party perspective, based on the data from the REPROVE (Ceftazidime-Avibactam Versus Meropenem In Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia) clinical study; ClinicalTrials.gov NCT01808092). Methods: A patient-level, sequential simulation model of the HAP/VAP clinical course was developed using spreadsheet software. The analysis focused on direct medical costs. The time horizon of the model selected was 5 years, with an annual discount rate of 3% on costs and quality-adjusted life-years (QALYs). Clinical inputs for treatment comparisons were mainly obtained from the REPROVE clinical study data. In addition to clinical outcomes observed in the trial, the model incorporated impact of resistance pathogens, based on data from published studies and expert opinion. Certain assumptions were made for some model parameters due to a lack of data. Findings: The analysis demonstrated that the intervention sequence (CAZ-AVI followed by colistin + high-dose meropenem) versus the comparator sequence (meropenem followed by colistin + high-dose meropenem) provided a better clinical cure rate (+13.52%), which led to a shorter hospital stay (−0.40 days per patient), and gains in the number of life-years (+0.195) and QALYs (+0.350) per patient. The intervention sequence had an estimated net incremental total cost of V1254 ($1401) per patient, and the estimated incremental cost-effectiveness ratio was V3581 ($4000) per QALY gained, well below the willingness-topay threshold of V30,000 ($33,507) per QALY in Italy. Implications: The model results showed that CAZAVI is expected to provide clinical benefits in hospitalized patients with HAP/VAP in Italy at an acceptable cost compared to meropenem

Comparative analysis of local angular rotation between the Ring Laser Gyroscope GINGERINO and GNSS stations

The study of local deformations is a hot topic in geodesy. Local rotations of the crust around the vertical axis can be caused by deformations. In the Gran Sasso area the ring laser prototype GINGERINO and the GNSS array are operative. One year of data of GINGERINO is compared with the ones from the GNSS stations, homogeneously selected around the position of GINGERINO, aiming at looking for rotational signals with period of days common to both systems. At that purpose the rotational component of the area circumscribed by the GNSS stations has been evaluated and compared with the GINGERINO data. The coherences between the signals show structures that even exceed 60$\%$ coherence over the 6-60 days period; to validate this unprecedented analysis two different methods have been used to evaluate the local rotation using the GNSS stations. The analysis reveals that the shared rotational signal's amplitude in both instruments is approximately $10^{-13} rad/s$, an order of magnitude lower than the amplitudes of the signals examined using the coherence method. The ring laser array GINGER is at present under construction, and the confrontation of the ring laser data with GNSS antennas provides evidence of the fruibility and validity of the ring laser data for very low frequency investigation

Cost-effectiveness analysis of ceftazidime/avibactam compared to imipenem as empirical treatment for complicated urinary tract infections

Abstract Ceftazidime/avibactam (CAZ-AVI) is a novel, fixed-dose combination antibiotic that has been approved in Europe and the United States for patients with complicated urinary tract infections (cUTIs) based on results of a Phase III, randomized, comparative study (RECAPTURE study). The present analysis evaluated cost-effectiveness of CAZ-AVI as an empirical treatment for hospitalized patients with cUTIs from the Italian publicly funded healthcare (third-party payer) perspective. A sequential, patient-level simulation model was developed that followed the clinical course of cUTI and generated 5000 pairs of identical patients (CAZ-AVI or imipenem as empirical treatment). The model included additional impact of resistant pathogens; patients who did not respond to empirical treatment were switched to second-line treatment of colistin+high dose carbapenem in both groups. The time horizon of the model was five years, with an annual discount rate of 3% applied to both costs and quality-adjusted life-years (QALYs). The analysis demonstrated that an intervention sequence (CAZ-AVI followed by colistin+high dose carbapenem) compared with a comparator sequence (imipenem followed by colistin+high dose carbapenem) was associated with a net incremental cost of €1015 per patient but provided better health outcomes in terms of clinical cure (97.65% vs. 91.08%; ∆ = 6.57%), shorter hospital stays (10.65 vs. 12.55 days; ∆ = 1.90 days), and QALYs gained per patient (4.190 vs. 4.063; ∆ = 0.126). The incremental cost-effectiveness ratio was €8039/QALY, which is well below the willingness-to-pay threshold of €30 000/QALY in Italy. The results showed that CAZ-AVI is expected to be a cost-effective treatment compared with imipenem for cUTI in Italy

Multiple functionalization of fluorescent nanoparticles for specific biolabeling and drug delivery of dopamine

The development of fluorescent biolabels for specific targeting and controlled drug release is of paramount importance in biological applications due to their potential in the generation of novel tools for simultaneous diagnosis and treatment of diseases. Dopamine is a neurotransmitter involved in several neurological diseases, such as Parkinson's disease and attention deficit hyperactivity disorder (ADHD), and the controlled delivery of its agonists already proved to have beneficial effects both in vitro and in vivo. Here, we report the synthesis and multiple functionalization of highly fluorescent CdSe/CdS quantum rods for specific biolabeling and controlled drug release. After being transferred into aqueous media, the nanocrystals were made highly biocompatible through PEG conjugation and covered by a carbohydrate shell, which allowed specific GLUT-1 recognition. Controlled attachment of dopamine through an ester bond also allowed hydrolysis by esterases, yielding a smart nanotool for specific biolabeling and controlled drug release

Mechanisms of endothelial cell dysfunction in cystic fibrosis

Although cystic fibrosis (CF) patients exhibit signs of endothelial perturbation, the functions of the cystic fibrosis conductance regulator (CFTR) in vascular endothelial cells (EC) are poorly defined. We sought to uncover biological activities of endothelial CFTR, relevant for vascular homeostasis and inflammation. We examined cells from human umbilical cords (HUVEC) and pulmonary artery isolated from non-cystic fibrosis (PAEC) and CF human lungs (CF-PAEC), under static conditions or physiological shear. CFTR activity, clearly detected in HUVEC and PAEC, was markedly reduced in CF-PAEC. CFTR blockade increased endothelial permeability to macromolecules and reduced trans‑endothelial electrical resistance (TEER). Consistent with this, CF-PAEC displayed lower TEER compared to PAEC. Under shear, CFTR blockade reduced VE-cadherin and p120 catenin membrane expression and triggered the formation of paxillin- and vinculin-enriched membrane blebs that evolved in shrinking of the cell body and disruption of cell-cell contacts. These changes were accompanied by enhanced release of microvesicles, which displayed reduced capability to stimulate proliferation in recipient EC. CFTR blockade also suppressed insulin-induced NO generation by EC, likely by inhibiting eNOS and AKT phosphorylation, whereas it enhanced IL-8 release. Remarkably, phosphodiesterase inhibitors in combination with a β2 adrenergic receptor agonist corrected functional and morphological changes triggered by CFTR dysfunction in EC. Our results uncover regulatory functions of CFTR in EC, suggesting a physiological role of CFTR in the maintenance EC homeostasis and its involvement in pathogenetic aspects of CF. Moreover, our findings open avenues for novel pharmacology to control endothelial dysfunction and its consequences in CF