Carla Rognoni

Apixaban, dabigatran, and rivaroxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis.

Background and objectiveNon-valvular atrial fibrillation (NVAF) increases the risk of systemic thromboembolic events; therefore, anticoagulant treatment with vitamin K antagonists is widely prescribed. Recently, new oral anticoagulants (NOAs) directly inhibiting thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban) demonstrated their non-inferiority with respect to warfarin in reducing the thromboembolic risk. The aim of this study was to estimate the cost effectiveness of NOAs in an Italian setting.MethodsA Markov decision model including ten health states and death was developed, and a 3-month Markov cycle and lifetime horizon were adopted. Transition probabilities and quality of life were estimated from three randomized trials and from additional reports in the literature. Analysis was performed in the context of the Italian National Health System. First- and second-order sensitivity analyses were made to test the robustness of the results. The mean European cost of dabigatran (€2.58/day) was assigned to each NOA.ResultsThe incremental cost-utility ratio was below €25,000/quality-adjusted life-year (QALY) gained for each NOA and each CHADS2 level, but differences among drugs were found. This result was sensitive to the time in (warfarin) therapeutic range and time horizon.ConclusionsOur analysis suggests that NOAs are a cost-effective treatment for the prevention of stroke in patients with NVAF in the Italian healthcare setting.

No difference in outcome between children and adolescents transplanted for acute lymphoblastic leukemia in second remission

Acute lymphoblastic leukemia (ALL) in second complete remission is one of the most common indications for allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients. We compared the outcome after HCST of adolescents, aged 14 to 18 years, with that of children (ie, patients < 14 years of age). Enrolled in the study were 395 patients given the allograft between January 1990 and December 2007; both children (334) and adolescents (61) were transplanted in the same pediatric institutions. All patients received a myeloablative regimen that included total body irradiation in the majority of them. The donor was an HLA-identical sibling for 199 patients and an unrelated volunteer in the remaining 196 patients. Children and adolescents had a comparable cumulative incidence of transplantation-related mortality, disease recurrence, and of both acute and chronic graft-versus-host disease. The 10-year probability of overall survival and event-free survival for the whole cohort of patients were 57% (95% confidence interval, 52%-62%) and 54% (95% confidence interval, 49%-59%), respectively, with no difference between children and adolescents. This study documents that adolescents with ALL in second complete remission given HSCT in pediatric centers have an outcome that does not differ from that of patients younger than 14 years of age.

Edoxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis

Edoxaban, an oral direct factor Xa inhibitor, has been found non-inferior to warfarin for preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), with a lower rate of intracranial bleeding. The aim of our investigation was to assess the cost-effectiveness of edoxaban versus warfarin from the perspective of the Italian health-care system. A Markov decision model was used to evaluate lifetime cost and quality-adjusted life expectancy of NVAF patients treated with warfarin or edoxaban. Transition probabilities were obtained from the ENGAGE AF-TIMI 48 trial, cost estimates were based on Italian prices and tariffs, utilities were obtained from the literature. One-way and second-order sensitivity analyses were performed. In the base case, lifetime costs were €18,658 for edoxaban and €14,060 for warfarin. Discounted quality-adjusted survival was 9.022xa0years for edoxaban and 8.425xa0years for warfarin, leading to an incremental cost-utility ratio of €7,713 per quality-adjusted life year (QALY) gained. Results were sensitive to time horizon, time in therapeutic range of warfarin and to the relative impact of warfarin versus edoxaban therapy onto quality of life. Probabilistic sensitivity analysis showed edoxaban to be cost-effective versus warfarin in 92.3xa0% of the simulations at a willingness-to-pay threshold of €25,000 per QALY. In conclusion, edoxaban proved to be a cost-effective alternative to warfarin in patients with moderate-to-high-risk NVAF.

Hematopoietic stem cell transplantation for children with high-risk acute lymphoblastic leukemia in first complete remission: a report from the AIEOP registry

Children with high-risk acute lymphoblastic leukemia in first complete remission can benefit from allogeneic hematopoietic stem cell transplantation. We analyzed the outcome of 211 children with high-risk acute lymphoblastic leukemia in first complete remission who were given an allogeneic transplant between 1990 and 2008; the outcome of patients who, despite having an indication for transplantation and a suitable donor, did not receive the allograft for different reasons in the same time period was not analyzed. Sixty-nine patients (33%) were transplanted between 1990 and 1999, 58 (27%) between 2000 and 2005, and 84 (40%) between 2005 and 2008. A matched family donor was employed in 138 patients (65%) and an unrelated donor in 73 (35%). The 10-year probabilities of overall and disease-free survival were 63.4% and 61%, respectively. The 10-year cumulative incidences of transplantation-related mortality and relapse were 15% and 24%, respectively. After 1999, no differences in either disease-free survival or transplant-related mortality were observed in patients transplanted from unrelated or matched family donors. In multivariate analysis, grade IV acute graft-versus-host disease was an independent factor associated with worse disease-free survival. By contrast, grade I acute graft-versus-host disease and age at diagnosis between 1 and 9 years were favorable prognostic variables. Our study, not intended to evaluate whether transplantation is superior to chemotherapy for children with acute lymphoblastic leukemia in first complete remission and high-risk features, shows that the allograft cured more than 60% of these patients; in the most recent period, the outcome of recipients of grafts from matched family and unrelated donors was comparable.

Cost-Effectiveness and Cost-Utility of Beclomethasone/Formoterol versus Fluticasone Propionate/Salmeterol in Patients with Moderate to Severe Asthma

AbstractBackground: Asthma is a chronic disease characterized by acute symptomatic episodes with variable severity and duration. Pharmacological asthma management aims to achieve and maintain control without side effects, thus improving quality of life and reducing the economic impact. Recently, a clinical trial showed the non-inferiority of beclomethasone/formoterol (BDP/F) versus fluticasone propionate/salmeterol (FP/S) in adults with moderate to severe persistent asthma. However, this study did not provide evidence on costs and did not quantify quality-of-life parameters.n Objective: The objective of the present study was to assess the cost effectiveness and cost utility of BDP/F versus FP/S in patients with moderate to severe asthma from the perspective of the Italian National Health Service (NHS).n Methods: A Markov model (MM) was used, with five health states for the different levels of asthma control: successful control, sub-optimal control, outpatient-managed exacerbation, inpatient-managed exacerbation, and death. Model data were derived from the ICAT SE study and from expert panels. Three outcomes were considered: time spent in successful control state, costs and quality-adjusted life-years (QALYs).n Results: The model shows that BDP/F treatment led to a slight increase of weeks in successful control compared with FP/S, with a lower cost. The probabilistic sensitivity analysis highlights that in 64% and 68% of the Monte Carlo simulations, BDP/F outperformed FP/S in terms of weeks in successful control and QALYs. Considering the expected cost of the two strategies, in 90% of simulations BDP/F was the least expensive choice. In particular, BDP/F was cost saving as compared with FP/S in about 63% and 59% of simulations as shown by the cost-utility and cost-effectiveness analysis, respectively.n Conclusion: Overall, from the Italian NHS perspective, BDP/F treatment is associated with a reduction in cost and offers a slight increase of effectiveness in terms of weeks spent in successful control and QALYs.

Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma: systematic review and meta-analyses

Trans-arterial radioembolization (TARE) is a recognized, although not explicitly recommended, experimental therapy for unresectable hepatocellular carcinoma (HCC). A systematic literature review was performed to identify published studies on the use of TARE in intermediate and advanced stages HCC exploring the efficacy and safety of this innovative treatment. Twenty-one studies reporting data on overall survival (OS) and time to progression (TTP), were included in a meta-analysis. The pooled post-TARE OS was 63% (95% CI: 56-70%) and 27% (95% CI: 21-33%) at 1- and 3-years respectively in intermediate stage HCC, whereas OS was 37% (95% CI: 26-50%) and 13% (95% CI: 9-18%) at the same time intervals in patients with sufficient liver function (Child-Pugh A-B7) but with an advanced HCC because of the presence of portal vein thrombosis. When an intermediate and advanced case-mix was considered, OS was 58% (95% CI: 48-67%) and 17% (95% CI: 12-23%) at 1- and 3-years respectively. As for TTP, only four studies reported data: the observed progression probability was 56% (95% CI: 41-70%) and 73% (95% CI: 56-87%) at 1 and 2 years respectively. The safety analysis, focused on the risk of liver decompensation after TARE, revealed a great variability, from 0-1% to more than 36% events, influenced by the number of procedures, patient Child-Pugh stage and treatment duration. Evidence supporting the use of radioembolization in HCC is mainly based on retrospective and prospective cohort studies. Based on this evidence, until the results of the ongoing randomized trials become available, radioembolization appears to be a viable treatment option for intermediate-advanced stage HCC.

A network meta-analysis of everolimus plus exemestane versus chemotherapy in the first- and second-line treatment of estrogen receptor-positive metastatic breast cancer.

The goal of this study was to compare the efficacy and toxicity of chemotherapy to exemestane plus everolimus (EXE/EVE) through a network meta-analysis (NMA) of randomized controlled trials. NMA methods extend standard pairwise meta-analysis to allow simultaneous comparison of multiple treatments while maintaining randomization of individual studies. The method enables “direct” evidence (i.e., evidence from studies directly comparing two interventions) and “indirect” evidence (i.e., evidence from studies that do not compare the two interventions directly) to be pooled under the assumption of evidence consistency. We used NMA to evaluate progression-free survival (PFS) and time to progression (TTP) curves in 34 studies, and response rate (RR) and the hazard ratios (HRs) of the PFS/TTP in 36 studies. A number needed to treat (NNT) analysis was also performed as well as descriptive comparison of reported toxicities. The NMA for PFS/TTP curves and for HR shows EXE/EVE is more efficacious than capecitabine plus sunitinib, CMF, megestrol acetate and tamoxifen, with an average of related-PFS/TTP difference ranging from about 10xa0months for capecitabine plus sunitinib to more than 6xa0months for tamoxifen. The NMA for overall RR shows that EXE/EVE provides a better RR than bevacizumab plus capecitabine, capecitabine, capecitabine plus sorafenib, capecitabine plus sunitinib, CMF, gemcitabine plus epirubicin plus paclitaxel, EVE plus tamoxifen, EXE, FEC, megestrol acetate, mitoxantrone, and tamoxifen. Finally, the NMA for NNT shows that EXE/EVE is more beneficial as compared to BMF, capecitabine, capecitabine plus sunitinib, CMF, FEC, megestrol acetate, mitoxantrone, and tamoxifen. The combination of EXE/EVE as first- or second-line therapy for ER+ve/HER2−ve metastatic breast cancer is more efficacious than several chemotherapy regimens that were reported in the literature. Toxicities also favored EXE/EVE in most instances.

Efficacy and Safety of Ferric Carboxymaltose and Other Formulations in Iron-Deficient Patients: A Systematic Review and Network Meta-analysis of Randomised Controlled Trials.

BackgroundIron deficiency is very common in a number of medical conditions. Ferric carboxymaltose is a new stable iron preparation that can be administered in single infusions over short periods of time. The aim of this study was to conduct a systematic review of randomised controlled trials (RCTs) regarding the efficacy and safety of the novel complex compared with other iron formulations. In addition, the feasibility of a network meta-analysis for indirect comparisons was investigated.MethodsA systematic literature review was performed for published RCTs on the use of ferric carboxymaltose in iron deficiency between July and October 2014. Indirect comparisons were also addressed using terms referring to competing iron formulations. We further supported the qualitative results of the systematic review by a network meta-analysis that allows pooling the evidence around different intervention outcomes in the absence of trials involving a direct comparison.ResultsThe initial search yielded 1027 citations, which was decreased to 21 studies eligible for inclusion in the review. Studies were heterogeneous in the number of patients randomised, iron deficiency-related conditions addressed, trial inclusion criteria, time horizon, treatment dosage and outcomes assessed. Six studies with the same time horizon (i.e. 6xa0weeks) were included in the network meta-analysis. Considering the differences between final and initial outcome values for each iron formulation, the mean difference of these differences (delta) was estimated for each couple of treatments involving ferric carboxymaltose. Significant improvements in serum ferritin (µg/l) were obtained with ferric carboxymaltose compared to oral iron (delta 172.8; 95xa0% CI 66.7–234.4) and in haemoglobin (g/dl) with respect to ferric gluconate (delta 0.6; 95 % CI 0.2–0.9), oral iron (delta 0.8; 95 % CI 0.6–0.9) and placebo (delta 2.1; 95 % CI 1.2–3.0).ConclusionsAll currently available intravenous iron preparations appear to be safe and effective, but ferric carboxymaltose seems to provide a better and quicker correction of haemoglobin and serum ferritin levels in iron-deficient patients.

Adding docetaxel to cisplatin and fluorouracil in patients with unresectable head and neck cancer: a cost–utility analysis

BACKGROUNDnAdding docetaxel (Taxotere, T) to induction chemotherapy with platinum/infusional 5-FU (PF) has been shown to improve overall survival of patients with head and neck cancer. The aim of the study was to analyze the cost-utility of TPF in patients with unresectable disease.nnnDESIGNnWe developed a Markov model to represent patients weekly transitions among different health states, related to treatment or disease status. Transition probabilities were obtained from the TAX 324 clinical trial report and from the European Organization for Research and Treatment of Cancer (EORTC) 24971/TAX 323 raw data. Costs were estimated in Italy from a Regional Healthcare System perspective. A 5-year temporal horizon was adopted and a 3.5% yearly discount rate was applied.nnnRESULTSnWhen compared with PF, TPF treatment increases life expectancy by 0.33 quality-adjusted life-years (QALYs) in TAX 323 and 0.41 QALYs in TAX 324. The benefit was achieved at a cost of €11,822/QALY for TAX 323 and €6757/QALY for TAX 324. Monte Carlo sensitivity analysis showed that 69% (TAX 323) and 99% (TAX 324) of the results lie below the threshold of €50,000/QALY saved.nnnCONCLUSIONSnIn our analysis, TPF induction chemotherapy proved to be cost-effective when compared with PF, having a cost-utility ratio comparable to other widely accepted healthcare interventions.

From decision to shared-decision

OBJECTIVEnTaking into account patients preferences has become an essential requirement in health decision-making. Even in evidence-based settings where directions are summarized into clinical practice guidelines, there might exist situations where it is important for the care provider to involve the patient in the decision. In this paper we propose a unified framework to promote the shift from a traditional, physician-centered, clinical decision process to a more personalized, patient-oriented shared decision-making (SDM) environment.nnnMETHODSnWe present the theoretical, technological and architectural aspects of a framework that encapsulates decision models and instruments to elicit patients preferences into a single tool, thus enabling physicians to exploit evidence-based medicine and shared decision-making in the same encounter.nnnRESULTSnWe show the implementation of the framework in a specific case study related to the prevention and management of the risk of thromboembolism in atrial fibrillation. We describe the underlying decision model and how this can be personalized according to patients preferences. The application of the framework is tested through a pilot clinical evaluation study carried out on 20 patients at the Rehabilitation Cardiology Unit at the IRCCS Fondazione Salvatore Maugeri hospital (Pavia, Italy). The results point out the importance of running personalized decision models, which can substantially differ from models quantified with population coefficients.nnnCONCLUSIONSnThis study shows that the tool is potentially able to overcome some of the main barriers perceived by physicians in the adoption of SDM. In parallel, the development of the framework increases the involvement of patients in the process of care focusing on the centrality of individual patients.