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.

Pulsed-field ablation for paroxysmal atrial fibrillation: An indirect comparison of effectiveness among three proprietary devices conducted in the absence of randomized trials.

INTRODUCTION: In patients with paroxysmal atrial fibrillation, pulsed-field ablation has been developed as an alternative to thermal ablation. Three devices are currently available: Farawave by Boston, PulseSelect by Medtronic, and Varipulse by Johnson. In the present report, we studied the outcomes at 12 months of these three devices using indirect comparisons. METHODS: A standard PubMed search was conducted that identified all studies evaluating these devices in patients with paroxysmal atrial fibrillation. The endpoint was freedom from arrhythmia recurrence. Kaplan-Meier curves were subjected to the IPDfromKM method that generated reconstructed patients. Standard time-to-event statistical testss (including heterogeneity assessment) were performed. RESULTS: Our analysis included 9 studies (8 single-arm and 1 randomized trial based on Farawave for a total of 1916 patients). A significant heterogeneity was found across the trials using Farawave because the outcomes found in the single-arm trials were better than those found in the randomized trial. Farawave (according exclusively to the results of the randomized trial), PulseSelect, and Varipulse showed a similar time-course of their respective outcomes with no significant difference. The single-arm trials using Farawave showed better outcomes than the randomized trial using Farawave and the pivotal trials using PulseSelect and Varipulse. DISCUSSION: Our study provided an updated overview of all the studies that have so far used pulsed-fileld ablation in patients with paroxysmal atrial fibrillation.

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.

Estimation of Value-Based Price for 48 High-Technology Medical Devices.

Value-based price is estimated quite frequently for medicines, but its application to medical devices is scarce. While some reports have been published in which this parameter has occasionally been determined for devices, no large-scale application has yet been reported. Our objective was to pursue a systematic analysis of the literature published on value-based prices of medical devices. Pertinent papers were selected upon the criterion that the value-based price was reported for the device examined. The real prices of the devices were compared with their values of value-based price and the ratios between real price versus value-based price were calculated. A total of 239 economic articles focused on high-technology medical devices were selected from a standard PubMed search. Among these, the proportion of analyses unsuitable for value-based price estimation was high (191/239; 80%), whereas adequate clinical and economic information for estimating this parameter was available in 48 cases (20%). Standard equations of cost-effectiveness were applied. The value-based price was determined according to a willingness-to-pay threshold of 60,000 € per quality-adjusted life year. Real prices of devices were compared with the corresponding estimates of value-based prices. From each analysis, we extracted also the value of incremental cost-effectiveness ratio (ICER). Our final dataset included 47 analyses because one was published twice. There were five analyses in which the ICER could be estimated for the treatment, but not for the device. In the dataset of 42 analyses with complete information, 36 out of 42 devices (86%) were found to have an ICER lower than the pre-specified threshold (favorable ICER). Three ICERs were borderline. A separate analysis was conducted on the other three devices that showed an ICER substantially greater than the threshold (unfavorable ICER). Regarding value-based prices, the values of real price were appreciably lower than the corresponding value-based price in 36 cases (86%). For three devices, the real price was substantially higher than the value-based price. In the remaining three cases, real prices and value-based prices were very similar. To our knowledge, this is the first experience in which a systematic analysis of the literature has been focused on the application of value-based pricing in the field of high-technology devices. Our results are encouraging and suggest a wider application of cost-effectiveness in this field.

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.

Current treatments for inoperable mesothelioma: indirect comparisons based on individual patient data reconstructed retrospectively from 4 trials.

In inoperable pleural mesothelioma, pemetrexed + cisplatin as first line is considered the standard of care, but novel treatments have been recently proposed. Our objective was to comparatively examine the information on overall survival (OS) with these new agents. The Shiny technique was employed for reconstructing individual patient data. Cox statistics was run to estimate hazard ratios (HRs). After a standard literature search, four new treatments were identified (nivolumab + ipilimumab, bevacizumab + pemetrexed + cisplatin, pembrolizumab monotherapy, and durvalumab + pemetrexed + cisplatin). Pemetrexed + ciplatin was the treatment for controls. Nivolumab + ipilimumab and bevacizumab + pemetrexed + cisplatin showed a better OS compared with controls (HR, 0.79 and 0.79, respectively; p < 0.05). Pembrolizumab determined only a numerical improvement (p > 0.05). In contrast, OS worsened with durvalumab + pemetrexed + cisplatin. Our analysis indicates that the novel treatments for inoperable mesothelioma have similar efficacy and, in general, provide a small though significant survival benefit compared with standard of care. Further research is needed to identify agents determining a more substantial OS improvement.

Estimation of Value-Based Price for Five High-Technology Medical Devices Approved by a Regional Health Technology Assessment Committee in Italy.

Background and objectives Value-based pricing (VBP) is used quite frequently for medicines, but its application to medical devices is very limited. The objective of the present study was to conduct a pilot experience of systematic estimation of the value-based price of medical devices from the perspective of our national health system. Our experience was focused on high-technology devices (class IIb/III and active implantable). The objective was to evaluate the applicability of VBP in a real-world setting and to estimate the value-based price of devices in all cases where this estimation was feasible. Methods The dataset analysed in this work consists of 24 new devices approved consecutively in the Tuscany region over the period from January 2020 to December 2021. Since the calculation of value-based price requires the availability of a cost-effectiveness analysis, we searched for this information for each of these devices. The Cost-Effectiveness Analysis (CEA) Registry of Tufts Medical Center (US) and the health technology assessment (HTA) reports of our region were considered adequate sources of these data. Standard equations of cost-effectiveness were applied to determine the value-based price for these devices, and these prices were compared with the corresponding real prices charged in our region. Results We found adequate information for five devices (21%) out of the total of 24. In three of these cases, the published analysis taken as a reference was based on Markov modelling. The comparison between value-based prices and real prices generally showed an acceptable concordance, though with a couple of outliers. An important finding is that, in a large proportion of cases (79%), the information needed for this calculation was lacking. Conclusion To our knowledge, this is the first experience in which an institution of the healthcare system has tried a systematic application of VBP in the field of high-technology devices. Our results are encouraging and suggest a wider application of cost-effectiveness in this field.

Medical Therapy, Radiofrequency Ablation, or Cryoballoon Ablation as First-Line Treatment for Paroxysmal Atrial Fibrillation: Interpreting Efficacy Through the Shiny Method.

In patients with paroxysmal atrial fibrillation, cryoballoon ablation (CBA) and radiofrequency ablation (RFA) represent two therapeutic approaches supported by increasing literature. While both these ablation techniques play a role during different stages of the patient's therapeutic pathway, their use as first-line is being increasingly recognized. This scoping review comparatively examined the evidence of effectiveness for these two ablation techniques. Our analysis was limited to the evaluation of the end-point of time to recurrence of atrial fibrillation (or other forms of atrial arrhythmias), which was the primary end-point in most clinical trials. The method used for pooling the information from clinical trials (Shiny method) is original and based on an artificial intelligence (AI) method that reconstructs individual patient data from published Kaplan-Meier time-to-event curves. Because a network meta-analysis has been published on this same clinical material, one objective of the present work was to compare the meta-analytic results with those generated by the Shiny method. A standard literature search was conducted on PubMed/Medline. Only randomized studies comparing CBA versus medical therapy, RFA versus medical therapy, or CBA versus RFA in previously untreated patients were eligible. Trials presenting a Kaplan-Meier curve to present the above-mentioned end-point were included. Patient-level data were reconstructed by application of the Shiny method. These individual patient data were then analyzed by standard statistical testing based on hazard ratio (HR) for risk of recurrence and medians of time to recurrence. Our analysis compared the two ablation treatments and medical therapy. A total of five trials were identified through our literature search. Information from these trials was pooled according to the three treatments (CBA: three trials, n = 365; RFA: two trials, n = 99; medical therapy: five trials, n = 457). CBA showed higher effectiveness than medical therapy (HR, 0.51; 95% confidence interval (CI): 0.38 to 0.67). In comparison with medical therapy, RFA showed a numerical trend that remained far from statistical significance (HR, 0.89; 95% CI: 0.62 to 1.27). Medians for time to recurrence were 14.1 months (95% CI: 10.0 to not reached) for RFA and 11.5 months (95% CI: 9.3 to 25.3) for medical therapy. This parameter was not reached for CBA. The current evidence from five randomized trials suggests that CBA ranks first in effectiveness, followed by RFA and medical therapy. In our comparison between the results generated by the Shiny method with those published in the previous meta-analysis, the Shiny method confirmed its ability to account for the length of follow-up in individual trials, whereas the meta-analytic approach confirmed its ability to account for the effects of randomizations performed in the trials.

Relationship Between Price and Diagnosis-Related Group Tariff for Medical Devices Assessed by a Regional Health Technology Assessment Committee.

Introduction Medical devices (MDs) make up an important share of total in-hospital expenditure. At the level of individual patients, this share is represented by the ratio of the cost of MD incurred by the patient vs. the total cost of in-hospital care for the same patient. If tariffs rather than costs are considered, the denominator of this ratio is given by the diagnosis-related group (DRG) and the ratio is the cost of MD over DRG tariff. The objective of this paper is to present a retrospective analysis comparing the ratio of price vs. DRG tariff for a group of devices belonging to risk class III or active implantable. These devices are those assessed in the years 2020 and 2021 by two committees of the Tuscany region in Italy. Materials and methods The information on price and DRG was taken from the health technology assessment (HTA) reports concerning MDs evaluated by the two above-mentioned regional committees in the years 2020 and 2021. In these reports, the information on the cost-effectiveness ratio was reported for a subset of MDs. In all cases, a preliminary qualitative assessment was carried out to determine the presence or absence of a healthcare impact in the post-discharge phase. In these preliminary analyses, the perspective of NHS was adopted. Results Our analysis was focused on 24 devices of either class III or active implantable. According to our results, a wide variability was found in the ratios between device price and DRG associated with its use. This ratio ranged from a minimum of about 3% in the case of the Hyalobarrier gel (Nordic Pharma GmbH, Zürich, Switzerland) for post-surgical adhesion to a maximum of 132% in the case of the Neovasc Reducer (EPS Vascular AB, Viken, Sweden), a device indicated in the narrowed coronary sinus. Three devices, i.e., PuraStat (3-D Matrix, Ltd., Tokyo, Japan), Ascyrus Medical Dissection Stent (AMDS, CryoLife, Inc., Kennesaw, GA), and Tendyne (Abbott Cardiovascular, Plymouth, MN), were found to be priced more than the reimbursement tariff (i.e., ratio > 100%). Ratios between 50% and 100% were found in about half of the devices. From our preliminary assessment on the presence of a post-discharge impact, 15 devices out of 24 (62%) were found to determine a substantial impact, while the remaining nine (38%) did not. In general, when costs and benefits of a device do not extend beyond the patients' discharge, the presence of a ratio > 100% reliably suggests the conclusion that the device price needs to be reduced and/or the tariff needs to be increased. On the other hand, in cases where the device extends its impact beyond the patient's hospital stay, the decision of reducing price or increasing tariff becomes more complex, and so these adjustments cannot be determined unless more information on some critical aspects is made available. Conclusions Until the above-mentioned improvements do not take place, rational interventions on DRG are virtually unfeasible owing to this lack of critical information. On the other hand, it is also difficult to intervene on device prices, again owing to the lack of critical information.

Medical therapy, radiofrequency ablation or cryoballoon ablation as first-line treatment for paroxysmal atrial fibrillation: interpreting efficacy through restricted mean survival time and network meta-analysis.

When multiple treatments are available, network meta-analysis can evaluate data to rank the relative effectiveness. We applied this approach to first-line treatments for paroxysmal atrial fibrillation (medical therapy, radiofrequency ablation or cryoballoon ablation). Individual trials were analysed based on the restricted mean survival time (RMST). Randomised controlled trials (RCT) assessing first-line treatments for paroxysmal atrial fibrillation were referenced from PubMed and the websites of regulatory agencies. The primary end-point was atrial fibrillation recurrence-free survival at 12 months. The treatments assessed for their relative effectiveness were medical therapy, radiofrequency ablation and cryoballoon ablation. Individual trials were examined based on RMST. A Bayesian network meta-analysis was conducted to comparatively evaluate these treatments. Five trials were included in the analysis: two compared radiofrequency with medical treatment and three cryoballoon ablation with medical treatment. The indirect comparison of radiofrequency ablation vs cryoballoon ablation was assessed in the absence of RCTs. Differences in RMST (with 95% credible intervals) were estimated for all binary comparisons (direct or indirect). Radiofrequency and cryoballoon ablation showed significantly increased effectiveness compared with medical treatment. In the indirect comparison, radiofrequency showed a non-significant advantage over cryoballoon ablation. The ranking of effectiveness was as follows: (1) radiofrequency; (2) cryoballoon ablation; (3) medical treatment. In conclusion, we found that radiofrequency was the most effective treatment for paroxysmal atrial fibrillation according to a Bayesian probabilistic model.

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.

The restricted mean survival time as a replacement for the hazard ratio and the number needed to treat in long-term studies.

AIMS: We applied the restricted mean survival time (RMST) to analyse the survival data reported in the PARADIGM-HT trial in which sacubitril + valsartan was studied in comparison with enalapril in patients with heart failure. The estimates of this parameter were compared with the published values of hazard ratio (HR). METHODS: Two endpoints were evaluated: a composite of death or hospitalization and cardiovascular death. Our analyses were performed by considering the original follow-up of 41.4 months and on the basis of a lifetime perspective. All statistical calculations were carried out using specific packages developed under the R-platform. RESULTS: According to our RMST analysis, the results for the composite endpoint in the comparison of sacubitril + valsartan vs. enalapril showed an improvement from 32.9 to 34.2 months (gain of 1.25 months). This result is based on a time horizon of 41.4 months. The results for the cardiovascular mortality endpoint showed a RMST of 37.2 months for sacubitril + valsartan vs. 36.2 for enalapril (gain of 0.96 months). In the two lifetime analyses, the improvements were much more relevant and yielded a gain of 25.8 months for the composite endpoint and 27.6 months for survival free from cardiovascular death. CONCLUSIONS: Using the data of the PARADIGM-HT trial, our analysis confirmed that the RMST has documented advantages over the HR, particularly when the clinical study is characterized by a long follow-up. The number needed to treat (NNT) has a more specific methodological role and cannot be replaced by the RMST.

First-line treatments for chronic lymphocytic leukemia: Analysis of 7 trials based on the restricted mean survival time.

OBJECTIVE: The purpose of this study was to assess the effectiveness of the newest first-line treatments for chronic lymphocytic leukemia (CLL), used alone or in combination, in comparison with standard treatments. MATERIALS AND METHODS: We selected 15 cohorts of patients published in 7 clinical trials. The restricted mean survival time (RMST) was used for analyzing survival curves, performing the comparisons and ranking the treatments based on their effectiveness. The endpoint was progression-free survival (PFS). RESULTS: 15 patient cohorts receiving 11 different first-line treatments were studied. Overall, all of the newest treatments had a positive effect on PFS compared with the old standards. As compared with chlorambucil monotherapy, the improvement in PFS resulting from targeted therapies ranged from 5.4 to 7.3 months per patient. Excluding chlorambucil alone or combined with obinutuzumab, the remaining 11 targeted treatments showed nearly identical values of PFS. Numerically but not statistically, ibrutinib plus venetoclax was associated with the longest PFS. Post-hoc pairwise comparisons were calculated to better interpret these results. CONCLUSION: Our results provide an updated overview of the efficacy of the newest first-line treatments for CLL. Our findings confirm the good performance of RMST in this type of analyses.