Costs and benefits in patients with NYHA class III heart failure treated with CardioMEMS in Italy.

Background: CardioMEMS is a device suitable for telemedicine that is currently being evaluated by the Regional Health Technology Assessment (HTA) Committee of Tuscany. Two detailed HTA reports are available in the specialized literature, the results of which need to be transferred to our regional setting. These decisions in Tuscany are made by the so-called Centro Operativo HTA. Aim: To validate, with local cost-effectiveness data, the decision on CardioMEMS that will be made in the Tuscany region. Methods: Two detailed international HTA reports were rearranged and adapted to our regional setting to generate a simplified analysis that could form the basis of our decision. Two willingness-to-pay (WTP) thresholds of €20,000/quality-adjusted life year (QALY) and €50,000/QALY were considered. Results: Based on epidemiological and regulatory information, the target population in Tuscany for this device is 166 cases. The value-based price of CardioMEMS is estimated to be €4,332 and €16,662 at WTP thresholds of 20,000/QALY and 50,000/QALY, respectively. Its current price in Italy is €12,000. Conclusion: In our region, the introduction of CardioMEMS is likely to be gradual, around 50 patients/year (or €0.60 million/year at current price). This example highlights the need to adapt the information published in the international literature to the local context in which the approval decision is made. In this context, simplified analyses are easier to apply than complex Markov models.

Mitraclip Versus Medical Therapy or Surgery in Patients With Mitral Regurgitation: Long-Term Outcomes Determined by the Reconstruction of Individual Patient Data.

Although MitraClip has been studied in numerous trials, its evidence in the long term is based on a few original studies. We used an original technique of evidence synthesis to review long-term comparative trials evaluating MitraClip. We searched the PubMed database to select long-term comparative trials of MitraClip. The endpoint was all-cause mortality (minimum follow-up, one year). Included trials were analyzed using the IPDfromKM (reconstruct Individual Patient Data from published Kaplan-Meier survival curves) method to reconstruct individual patient data from Kaplan-Meier curves. Standard survival statistics were used to interpret these long-term efficacy data. The survival benefit per patient was estimated from the restricted mean survival time (RMST). Six comparative studies of MitraClip were included; 973 patients were treated with MitraClip (six arms), 717 with medical therapy (five arms), and 80 with surgical repair or replacement (one arm). In our main analysis, the outcomes observed in patients treated with MitraClip were significantly better than those of medical therapy (hazard ratio for all-cause mortality, 0.5276; 95% confidence interval, 0.4412 to 0.6309; p < 0.001); the number of patients treated with surgery was too small to make reliable comparisons. Median survival was 30.4 months for medical therapy versus not reached for the other two groups. RMST was 43.931 and 33.756 months for MitraClip and controls, respectively, yielding a gain per patient of 10.17 months (95% confidence interval, 7.47 to 12.88). In our simplified cost-effectiveness evaluation, a gain of approximately 10 months per patient compared favorably with the device cost. Our analysis provided an original interpretation of the long-term evidence available on MitraClip.

Selection, engineering, and in vivo testing of a human leukocyte antigen-independent T-cell receptor recognizing human mesothelin.

BACKGROUND: Canonical α/ß T-cell receptors (TCRs) bind to human leukocyte antigen (HLA) displaying antigenic peptides to elicit T cell-mediated cytotoxicity. TCR-engineered T-cell immunotherapies targeting cancer-specific peptide-HLA complexes (pHLA) are generating exciting clinical responses, but owing to HLA restriction they are only able to target a subset of antigen-positive patients. More recently, evidence has been published indicating that naturally occurring α/ß TCRs can target cell surface proteins other than pHLA, which would address the challenges of HLA restriction. In this proof-of-concept study, we sought to identify and engineer so-called HLA-independent TCRs (HiTs) against the tumor-associated antigen mesothelin. METHODS: Using phage display, we identified a HiT that bound well to mesothelin, which when expressed in primary T cells, caused activation and cytotoxicity. We subsequently engineered this HiT to modulate the T-cell response to varying levels of mesothelin on the cell surface. RESULTS: The isolated HiT shows cytotoxic activity and demonstrates killing of both mesothelin-expressing cell lines and patient-derived xenograft models. Additionally, we demonstrated that HiT-transduced T cells do not require CD4 or CD8 co-receptors and, unlike a TCR fusion construct, are not inhibited by soluble mesothelin. Finally, we showed that HiT-transduced T cells are highly efficacious in vivo, completely eradicating xenografted human solid tumors. CONCLUSION: HiTs can be isolated from fully human TCR-displaying phage libraries against cell surface-expressed antigens. HiTs are able to fully activate primary T cells both in vivo and in vitro. HiTs may enable the efficacy seen with pHLA-targeting TCRs in solid tumors to be translated to cell surface antigens.

A Comparison of Statistical Analysis Between "Real" Patients Reported in Kaplan-Meier Curves and "Reconstructed" Patients Estimated Through the IPDfromKM Method: Analysis of Eight Trials Evaluating Catheter Ablation of Ventricular Tachycardia.

Time-to-event endpoints are most widely used in oncology and, to a lesser extent, in cardiology. Typical statistical parameters employed in this context include overall survival, progression-free survival, and recurrence-free survival. The graphical presentation of the results is based on the Kaplan-Meier plot. When Kaplan-Meier curves are included in a meta-analysis, the typical methodological approach is a simplified one because the results of each trial (as well as those of the meta-analysis itself) are expressed through a 2x2 contingency; the methodological simplification is that the follow-up is left out from the analysis and, consequently, the Kaplan-Meier curves are omitted as well. The IPDfromKM method, developed in 2021, is an artificial intelligence algorithm designed to be used in these situations. According to this method, to keep the Kaplan-Meier curves in the meta-analysis, each curve is converted into a database of individual patients (which are denoted as "reconstructed" individual patients). In this way, for the purposes of the meta-analysis, the statistical methods are based on individual patients (like those of clinical trials) so that the Kaplan-Meier curves must not be excluded, and the effect of the follow-up can, therefore, be investigated. This technical report describes the IPDfromKM method in all of its operational details. To present the method, a meta-analysis investigating the effects of catheter ablation to prevent ventricular tachyarrhythmia (VT) has been taken as an example. The original meta-analysis, which included nine controlled trials, was published in February 2023 and adopted the simplified approach based on 2x2 contingency tables. We have reanalyzed these trials by using the IPDfromKM method. Overall, both the standard binary meta-analysis and the IPDfromKM method showed that ablation significantly reduces VT recurrence (hazard ratio, 0.820 for binary meta-analysis vs 0.728 for the IPDfromKM method). By contrast, while no heterogeneity was found by the binary method, the IPDfromKM found significant heterogeneity, which was confirmed by visual inspection of the Kaplan-Meier curves. This suggests that the results of the IPDfromKM method are more accurate because they include the effect of the follow-up on patients' outcomes. In conclusion, our reanalysis confirms the significant benefit determined by ablation, but a more pronounced degree of between-trial heterogeneity has been found. Finally, it should be stressed that, outside the field of meta-analysis, the IPDfromKM method is also applicable to carry out an indirect comparison between treatments that have never been compared in real clinical trials. In this case, reconstructed patients are analyzed by conducting a simulated comparative trial.

Managing Tenders in the Procurement of Advanced Medical Devices: An Original Model Based on the Net Monetary Benefit Combined With Three Clinical Endpoints.

In medical devices, recent studies have proposed original approaches for standardizing competitive tenders with the aim of promoting reproducibility, avoiding discretional decisions, and applying value-based principles. In the framework of tenders' standardization, the net monetary benefit (NMB) method has attracted much interest, but its mathematical complexity has prevented a wide application. In the present work, we developed a procurement model that simplifies clinical information management for high-technology devices purchased for our public hospitals. Our objective was to promote the application of NMB in competitive tenders, particularly at the final stage of the procurement process, where the tender scores are determined. Software to facilitate this task in everyday practice has been developed. This software is made available through the present technical report. We surveyed the most relevant literature about NMB to select the main models commonly used in the studies published thus far. Standard equations of cost-effectiveness were identified. A simplified computation model based on three clinical endpoints was developed to estimate the NMB with less mathematical complexity. This model is proposed as an alternative to the standard approach based on a full economic analysis. The model developed herein has been implemented in a web-based software freely available on the Internet. This software is accompanied by a detailed description of the equations by which the NMB is estimated. A detailed application example is reported; a real tender carried out in 2021 has been re-examined for this purpose. In this re-analysis, the new software has been used to calculate the NMB of three devices. To our knowledge, this is the first experience in which an institution of the Italian healthcare system has evaluated the NMB as a tool for determining tender scores. The model is designed to offer performance similar to a full economic analysis. Our preliminary results are encouraging and suggest a wider application of this method. This approach has important implications regarding cost-effectiveness and cost containment because a value-based procurement is known to maximize effectiveness without determining an increase in costs.

Simplified figure to present direct and indirect comparisons: Revisiting the graph 10 years later.

A "simplified" figure was proposed in 2011 to summarize the results of controlled trials that evaluate different treatments aimed at the same disease condition. The original criteria for classifying individual binary comparisons included superiority, inferiority and no significance difference; hence, they did not differentiate between no proof of difference vs proof of no difference. We updated the criteria employed in the original "simplified" figure in order to include this differentiation. A revised version of the simplified figure is proposed and described herein. An example of application is also presented. The example is focused on first-line treatments for paroxysmal atrial fibrillation. Three treatments (medical therapy, cryoballoon ablation, radiofrequency ablation) are compared with one another through direct and indirect comparisons.

Development of a structural epitope mimic: an idiotypic approach to HCV vaccine design.

HCV vaccine development is stymied by the high genetic diversity of the virus and the variability of the envelope glycoproteins. One strategy to overcome this is to identify conserved, functionally important regions-such as the epitopes of broadly neutralizing antibodies (bNAbs)-and use these as a basis for structure-based vaccine design. Here, we report an anti-idiotype approach that has generated an antibody that mimics a highly conserved neutralizing epitope on HCV E2. Crucially, a mutagenesis screen was used to identify the antibody, designated B2.1 A, whose binding characteristics to the bNAb AP33 closely resemble those of the original antigen. Protein crystallography confirmed that B2.1 A is a structural mimic of the AP33 epitope. When used as an immunogen B2.1 A induced antibodies that recognized the same epitope and E2 residues as AP33 and most importantly protected against HCV challenge in a mouse model.

Long-term outcomes in chronic obstructive pulmonary disease patients: exploring the effects of inhalatory devices and their influence on the outcome.

PURPOSE: Numerous systematic reviews have examined the outcomes in patients with chronic obstructive pulmonary disease managed with different therapeutic strategies. However, no such studies have specifically focused on the effect of inhalation devices. METHODS: A standard PubMed search was carried out in which we identified all randomized placebo-controlled trials conducted in patients with moderate-to-severe or severe chronic obstructive pulmonary disease. The clinical end points were exacerbations rate, incidence of pneumonia, and mortality. Meta-regression was employed to assess the effect of the device. For the incidence of exacerbations, an equivalence analysis was also carried out. RESULTS: A total of 37 studies were analyzed. Four different devices were used across these trials (Respimat(®), HandiHaler(®), Diskus, and Turbuhaler(®)). Our meta-regression analysis failed to show any significant difference between devices with regard to exacerbation rate. Equivalence was shown for some comparisons (HandiHaler(®) vs Respimat(®)), but not for others. In analyzing mortality, Respimat(®) was shown to worsen this end point in comparison with Turbuhaler(®) and HandiHaler(®). Moreover, Turbuhaler(®) showed a protective effect over Diskus in the incidence of pneumonia. CONCLUSION: The results of our analysis represent the first attempt to explore the effect of the type of device on long-term outcomes. One important limitation was that most drugs were associated with one particular device, and so the effects of drugs and devices could not be reliably differentiated from one another.

Economic analysis of not running tenders for recombinant Factor VIII procurement: a simplified analysis to estimate an otherwise unknown pharmacoeconomic index.

BACKGROUND: Two approaches to the procurement of recombinant Factor VIII products are used by health systems: (A) the most common approach where acquisition tenders are not carried out; (B) the approach tested in the UK in which procurement is based on tenders. The respective cost-effectiveness is not known. OBJECTIVE: To estimate the incremental cost-effectiveness ratio (ICER) for the comparison A vs B. METHODS: The analysis evaluated: (i) Factor VIII cost with/without tenders; (ii) inhibitor development caused by switching between products; (iii) clinical and economic consequences of inhibitors. Information on these items was obtained from a literature search. Because of the scarce evidence available on some items, our analysis considered the 'most favourable' scenario-that is, some extreme though reasonable assumptions were adopted that were intentionally biased towards improving the ICER of the no-tender option. RESULTS AND DISCUSSION: We estimated an ICER for A vs B of £486 409 (€657 139; £1=€1.351) per quality-adjusted life year (QALY). Since pharmacoeconomic thresholds are ∼£30 000 per QALY, our results indicate that the cost-effectiveness of acquisition strategies that avoid tenders is prohibitive. Because of the simplified nature of our analysis, this estimate is preliminary. CONCLUSIONS: The 'true' ICER of A vs B remains unknown, but its value is likely to be even worse than the unfavourable ICER of £486 409 (€657 139) per QALY.

First-line treatments for chronic lymphocytic leukaemia: interpreting efficacy data by network meta-analysis.

When multiple treatments are available, network meta-analysis can synthesize evidence and rank relative effectiveness. We applied this approach to current treatments for previously untreated chronic lymphocytic leukaemia. Data search was conducted in PubMed and websites of regulatory agencies (year 2000 through present time). Our analysis included randomized controlled trials assessing treatments for previously untreated chronic lymphocytic leukaemia. The endpoint of the analysis was the rate of progression-free survival at 3 years. At least two reviewers abstracted study data and outcomes. Agents examined for their relative effectiveness included four monotherapies (chlorambucil, fludarabine, bendamustine, alemtuzumab) and four combination treatments (cyclophosphamide + fludarabine, cyclophosphamide + cladribine, cyclophosphamide + fludarabine + rituximab, cyclophosphamide + fludarabine + alemtuzumab). A Bayesian network meta-analysis was conducted to comparatively evaluate these treatments. Nine trials (3620 patients) were included in the analysis. Odds ratio (with 95 % credible intervals) was estimated for all direct and indirect comparisons. Combinations treatments were found to be significantly more effective than single-agent treatments. Ranking in effectiveness was as follows: (1) cyclophosphamide + fludarabine + rituximab, (2) alemtuzumab, (3) cyclophosphamide + fludarabine + alemtuzumab, (4) cyclophosphamide + fludarabine and (at same ranking) cyclophosphamide + cladribine, (6) fludarabine, (7) bendamustine and (8) chlorambucil. Bendamustine fared worse in our analysis than in its pivotal trial. Overall, the estimated rankings appeared to be robust according to probabilistic analysis. Numerous indirect comparisons were assessed in the absence of RCTs. In conclusion, we generated an updated synthesis of the effectiveness of these treatments and we ranked them according to a Bayesian probabilistic model. In our probabilistic analysis, cyclophosphamide + fludarabine + rituximab ranked first in the base case while the worst-case scenario of this analysis placed this treatment at a remarkable second place.

Testing the therapeutic equivalence of novel oral anticoagulants for thromboprophylaxis in orthopedic surgery and for prevention of stroke in atrial fibrillation.

BACKGROUND: In studying the comparative effectiveness of novel oral anticoagulants (NOACs) in orthopedic surgery and in non-valvular atrial fibrillation, previous meta-analyses have found no proof of difference in head-to-head indirect comparisons between individual agents. However, the question of their therapeutic equivalence remains unanswered. OBJECTIVES: The objective of this analysis was to test the equivalence of three NOACs (dabigatran, rivaroxaban, apixaban) in orthopedic surgery and four NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in non-valvular atrial fibrillation. METHODS: Standard pairwise meta-analysis and network meta-analysis for indirect comparisons were combined with equivalence testing. The endpoint was venous thromboembolism in orthopedic surgery and a composite of stroke or systemic embolism in atrial fibrillation. Comparisons were expressed as risk difference (RD). Margins for equivalence testing were derived from the original trials. RESULTS: Our results indicate that rivaroxaban and apixaban (but not dabigatran) are equivalent for thromboprophylaxis in orthopedic surgery. In atrial fibrillation, all the four NOACs we tested were found to meet the criterion of therapeutic equivalence. Some concern, however, is raised by some findings focused on adverse events of these agents, in which the equivalence was not proven in all analyses. CONCLUSIONS: Regardless of clinical implications, our results can be the basis to develop local acquisition tenderings on NOACS. In Italy, a new law has been issued according to which equivalence analyses have become a mandatory prerequisite for local tenderings.

[Direct and indirect costs of luteinising hormone-releasing hormone analogues in the treatment of locally advanced or metastatic prostate cancer in Italy]. / Analoghi sintetici dell'ormone di rilascio dell'ormone luteinizzante per il trattamento del carcinoma prostatico localmente avanzato o metastatico: analisi dei costi diretti e indiretti nello scenario italiano

BACKGROUND: When analyzing the use of luteinizing hormone-releasing hormone (LHRH) analogues for different clinical indications, current available evidence does not support a presumed drug class effect among the various LHRH in the treatment of prostate cancer. METHODS: The following search key words were entered in the PubMed database and the NICE and FDA websites: "LHRH agonist AND prostatic cancer", "androgen deprivation therapy", "androgen suppression", "buserelin", "leuprorelin", "goserelin","triptorelin", "degarelix". The direct costs included the following items: follow-up visits, diagnostic exams (e.g. prostate-specific antigen PSA) and drug costs. The indirect costs included working days lost by the patient. RESULTS: With intermittent therapy as a reference, leuprorelin injectable solution of 22,25 mg was associated with the lowest cost and degarelix with the highest cost. However, given the mandatory presence of a nurse for drug injection, the buserelin depot formulation was associated with the lowest cost. If the costs for hospital visits were added to drug costs, differences between the various therapeutic strategies were less remarkable. CONCLUSIONS: Our study showed how various factors (e.g. route of administration, frequency of administration, presence of a nurse for drug reconstitution and injection) should be taken into account by decision makers in addition to the price of drugs.