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.

Efficacy of Immune Checkpoint Inhibitors vs. Tyrosine Kinase Inhibitors/Everolimus in Adjuvant Renal Cell Carcinoma: Indirect Comparison of Disease-Free Survival.

BACKGROUND: The proven efficacy of mTOR inhibitors (mTORIs), tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (RCC) suggests that these agents should be investigated as adjuvant therapy with the aim of eliminating undetectable microscopic residual disease after curative resection. The aim of our study was to compare the efficacy of these treatments using an innovative method of reconstructing individual patient data. METHODS: Nine phase III trials describing adjuvant RCC treatments were selected. The IPDfromKM method was used to reconstruct individual patient data from Kaplan-Meier (KM) curves. The combination treatments were compared with the control arm (placebo) for disease-free survival (DFS). Multi-treatment KM curves were used to summarize the results. Standard statistical tests were performed. These included hazard ratio and likelihood ratio tests for heterogeneity. RESULTS: In the overall population, the study showed that two ICIs (nivolumab plus ipilimumab and pembrolizumab) and one TKI (sunitinib) were superior to the placebo, whereas both TKIs and mTORIs were inferior. As we assessed DFS as the primary endpoint for the adjuvant comparison, the overall survival benefit remains unknown. CONCLUSIONS: This novel approach to investigating survival has allowed us to conduct all indirect head-to-head comparisons between these agents in a context where no "real" comparative trials have been conducted.

Low-Intensity and Chemo-Free Treatments in Ph+ ALL: Progression-Free Survival Based on Indirect Comparisons.

In Philadelphia chromosome-positive B-cell (Ph+) acute lymphoblastic leukemia (LLA), growing evidence has accumulated regarding the efficacy of low-intensity and chemo-free regimens. Our objective was to analyze all recent trials evaluating these treatments and to compare them in terms of efficacy. We applied the Shiny method, an artificial intelligence technique, to analyze Kaplan-Meier curves and reconstruct patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and subjected to indirect head-to-head treatment comparisons. The endpoint was progression-free survival (PFS). Based on 432 reconstructed patients, eight trials were analyzed. The survival data from these trials were pooled into three types of treatments: (i) treatments based on tyrosine kinase inhibitors (TKIs) combined with reduced-intensity chemotherapy (denoted as TKICHE); (ii) TKIs associated with steroids with no chemotherapy (TKISTE); (iii) chemotherapy-free combinations of blinatumomab plus TKIs (TKIBLI). According to the Shiny method, the three PFS curves were reported in a single Kaplan-Meier graph and subjected to survival statistics. In terms of PFS, TKIBLI ranked first, TKICHE second, and TKISTE third; the differences between these three regimens were statistically significant. This multi-treatment Kaplan-Meier graph, generated through the Shiny method, summarized the current evidence on these treatments in both qualitative and quantitative terms.

Tislelizumab plus chemotherapy vs. pembrolizumab plus chemotherapy for the first-line treatment of advanced non-small cell lung cancer: systematic review and indirect comparison of randomized trials.

BACKGROUND: Pembrolizumab (PEM) and tislelizumab (TIS), in combination with chemotherapy, have demonstrated significant clinical benefits in first-line treatment of advanced non-small cell lung cancer (NSCLC). However, no head-to-head clinical trial has yet compared these two treatments. METHODS: We conducted a literature search of randomized trials, in which TIS plus chemotherapy or PEM plus chemotherapy were studied for the first-line treatment of NSCLC. Randomized design and the endpoint of progression-free survival (PFS) were the inclusion criteria for our analysis. Adjusted indirect comparison between TIS and PEM was performed by application of the IPDfromKM-Shiny method. This method is based on the reconstruction of individual patient data from Kaplan-Meier curves. Outcomes in terms of PFS were expressed as hazard ratio (HR) with 95% and 90% confidence interval (CI). RESULTS: Data were extracted from five randomized trials involving nearly 2,000 participants. In comparing PEM plus chemotherapy (n=748) or TIS plus chemotherapy (n=462) vs. chemotherapy alone (n=782), the Shiny method found a significant advantage in terms of PFS (HR =0.5856, 95% CI: 0.4986-0.6876 for TIS; HR =0.5573, 95% CI: 0.4969-0.6251 for PEM), thus confirming the results of the original trials. The indirect comparison of PEM plus chemotherapy vs. TIS plus chemotherapy showed a substantial equivalence between these two regimens (HR =0.952; 95% CI: 0.775-1.168; 90% CI: 0.801-1.130) suggesting an acceptable degree of equivalence according to regulatory criteria. Medians were 8.89 months for PEM combination, 7.97 months for TIS combination, and 5.69 for the controls. CONCLUSIONS: The PFS of TIS combined with chemotherapy was similar to that of PEM combined with chemotherapy. Based on the HR with 90% CI, these two agents met an equivalence criterion for PEM vs. TIS ranging from -19.9% to +13.0%.

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.

Progression-Free and Overall Survival of First-Line Treatments for Advanced Renal Cell Carcinoma: Indirect Comparison of Six Combination Regimens.

BACKGROUND: Recently, numerous combination therapies based on immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors have been proposed as first-line treatments for advanced renal cell carcinoma (aRCC). Our study aimed to compare the efficacy of these combination regimens by the application of an innovative method that reconstructs individual patient data. METHODS: Six phase III studies describing different combination regimens for aRCC were selected. Individual patient data were reconstructed from Kaplan-Meier (KM) curves through the "Shiny method". Overall survival (OS) and progression-free survival (PFS) were compared among combination treatments and sunitinib. Results were summarized as multi-treatment KM curves. Standard statistical testing was used, including hazard ratio and likelihood ratio tests for heterogeneity. RESULTS: In the overall population of aRCC patients, pembrolizumab + lenvatinib showed the longest median PFS and was expected to determine the longest OS. Pembrolizumab + axitinib, nivolumab + cabozantinib and nivolumab + ipilimumab were similar in terms of PFS, but pembrolizumab + axitinib also demonstrated a better OS. Our subgroup analysis showed that sunitinib is still a valuable option, whereas, in intermediate-poor risk patients, pembrolizumab + axitinib and nivolumab + ipilimumab significantly improve OS compared to sunitinib. CONCLUSION: The Shiny method allowed us to perform all head-to-head indirect comparisons between these agents in a context in which "real" comparative trials have not been performed.

Application of the IPDfromKM-Shiny Method to Compare the Efficacy of Novel Treatments Aimed at the Same Disease Condition: A Report of 14 Analyses.

In the area of evidence-based medicine, the IPDfromKM-Shiny method is an innovative method of survival analysis, midway between artificial intelligence and advanced statistics. Its main characteristic is that an original software investigates the Kaplan-Meier graphs of trials so that individual-patient data are reconstructed. These reconstructed patients represent a new form of original clinical material. The typical objective of investigations based on this method is to analyze the available evidence, especially in oncology, to perform indirect comparisons, and determine the place in therapy of individual agents. This review examined the most recent applications of the IPDfromKM-Shiny method, in which a new web-based software-published in 2021-was used. Reported here are 14 analyses, mostly focused on oncological treatments. Indirect comparisons were based on overall survival or progression free survival. Each of these analyses provided original information to compare treatments with one another and select the most appropriate depending on patient characteristics. These analyses can also be useful to assess equivalence from a regulatory viewpoint. All investigations stressed the importance of heterogeneity to better interpret the evidence generated by IPDfromKM-Shiny investigations. In conclusion, these investigations showed that the reconstruction of individual patient data through this online tool is a promising new method for analyzing trials based on survival endpoints. This new approach deserves further investigation, particularly in the area of indirect comparisons.

Survival in Patients with Relapsed-Refractory Multiple Myeloma: Indirect Comparison of Six New Treatments.

In recent years, new treatments have been studied for relapsed-refractory multiple myeloma (RRMM), including two CAR-T products and a variety of non-CAR-T agents. Since direct comparisons between these innovative treatments are not available, indirect comparisons can be of interest. Reconstruction of individual patient data from Kaplan-Meier graphs (e.g., according to the Shiny method) has been the subject of numerous reports that have fully validated their performance. In the present systematic review, we evaluated six treatments proposed for RRMM, including two CAR-T products (ciltacabtagene autoleucel and idecabtagene vicleucel) and four treatments not based on a CAR-T (melflufen plus dexamethasone, isatuximab plus dexamethasone, selinexor, and belantamab). The endpoint was overall survival (OS). Our results showed statistically significant differences in OS across these treatments. In particular, ciltacabtagene autoleucel showed better OS than idecabtagene vicleucel. As regards non-CAR-T treatments, the ranking in OS was headed by isatuximab plus dexamethasone, followed by belantamab, selinexor, and melflufen plus dexamethasone. In conclusion, while the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons have offered some original clues to interpret the results of OS published in these studies.

Adjuvant Nivolumab in Esophageal or Gastroesophageal Junction Cancer: the Improvement in Progression-Free Survival Is Small.

Esophageal cancer is the seventh most common cancer globally, accounting more than a half million deaths per year. Despite several therapeutic options in neoadjuvant setting, including chemoradiotherapy and surgery, no adjuvant treatment has been established for patients at high risk of recurrence. Even so, findings from the recently published CheckMate 577 trial seem to suggest an important clinical impact, in terms of disease-free progression, for the use of adjuvant nivolumab, a PDL-1 inhibitor, in resected esophageal cancer or gastroesophageal junction cancer. The authors reported a benefit for the treatment arm of 22.4 months compared with 11.0 in the placebo group. Although median is commonly used as an endpoint in survival studies, it can be influenced by the timing of a few events in the descending portion of the Kaplan-Meier curve. Restricted mean survival time (RMST) considers the entire time-course of the curve and does not assume that event risks are constant over the follow-up. This may be helpful to a more realistic interpretation of survival outcomes. In this letter, we re-analyzed the study curves of the CheckMate 577 trial by application of RMST. While confirming the disease-free progression benefits for nivolumab compared with placebo (28.54 months for the treatment arms versus 22.70 for the controls), our analysis allows us to interpret the survival benefit in a more conservative manner.

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.