Immunosuppression with Generics in Liver and Kidney Transplantation: A Real-World Evidence Study.

Purpose: This study evaluates the use, benefit-risk profile, and economic impact of generic immunosuppressants (tacrolimus-TAC, cyclosporine-CsA, and mycophenolate-MYC) in kidney and liver transplant recipients compared to brand-name drugs. Patients and Methods: A retrospective multicentre observational study, involving four Italian regions, was conducted based on the national transplant Information system and regional healthcare claims data. The analysis focused on incident patients who received kidney and liver transplants between 2013 and 2019 and evaluated the use of generic of CsA, TAC, and MYC during the 30-day period following discharge. For each type of transplant and immunosuppressive agent, the benefit-risk profile of generic vs branded drugs in a two-year window was estimated by multivariate Cox models (HR; 95% CI). Furthermore, the potential cost savings per person associated with one year of treatment using generics were calculated. Results: The utilization of generic drugs showed a significant increase; over the study years, the proportion of users among kidney recipients ranged from 14.2% to 40.5% for TAC, from 36.9% to 56.7% for MYC, and from 18.2% to 94.7% for CsA. A great variability in generic uptake for region was found. A comparable risk-benefit profile between generic and branded formulations was shown for all immunosuppressors considered. Choosing generic immunosuppressants during maintenance could result in yearly savings of around 2000 euros per person for each therapy ingredient. Conclusion: The study shows an increasing proportion of patients using generic immunosuppressive drugs over time suggesting a growing acceptance of generics within the transplant community and reveals comparable risk-benefit profiles between the generic and branded formulations of TAC, CsA, and MYC. A significant variability in the use of generics immunosuppressive agents was found both at the regional level and among transplant centers and future research should delve into regional prescribing variations.

Effectiveness and safety of immunosuppressive regimens used as maintenance therapy in kidney transplantation: The CESIT study.

Maintenance immunosuppressive therapy used in kidney transplantation typically involves calcineurin inhibitors, such as tacrolimus or cyclosporine, in combination with mycophenolate or mechanistic target of rapamycin (mTORi) with or without corticosteroids. An Italian retrospective multicentre observational study was conducted to investigate the risk-benefit profile of different immunosuppressive regimens. We identified all subjects who underwent kidney transplant between 2009 and 2019, using healthcare claims data. Patients on cyclosporine and tacrolimus-based therapies were matched 1:1 based on propensity score, and effectiveness and safety outcomes were compared using Cox models (HR; 95%CI). Analyses were also conducted comparing mTORi versus mycophenolate among tacrolimus-treated patients. Patients treated with cyclosporine had a higher risk of rejection or graft loss (HR:1.69; 95%CI:1.16-2.46) and a higher incidence of severe infections (1.25;1.00-1.55), but a lower risk of diabetes (0.66;0.47-0.91) compared to those treated with tacrolimus. Among tacrolimus users, mTORi showed non-inferiority to MMF in terms of mortality (1.01;0.68-1.62), reject/graft loss (0.61;0.36-1.04) and severe infections (0.76;0.56-1.03). In a real-life setting, tacrolimus-based immunosuppressive therapy appeared to be superior to cyclosporine in reducing rejection and severe infections, albeit with an associated increased risk of diabetes. The combination of tacrolimus and mTORi may represent a valid alternative to the combination with mycophenolate, although further studies are needed to confirm this finding.

Determinants of immunosuppressive therapy in renal transplant recipients: an Italian observational study (the CESIT project).

BACKGROUND: Very scanty evidence is available on factors influencing the choice of immunosuppressive drug therapy after kidney transplantation. METHODS: An Italian multiregional real-world study was conducted integrating national transplant information system and claims data. All patients undergoing kidney transplantation for the first time during 2009-2019 (incident patients) were considered. Multilevel logistic models were used to estimate Odds Ratio (OR) and corresponding 95% Confidence intervals. Factors with statistically significance were identified as characteristics associated with treatment regimens: cyclosporin-CsA vs tacrolimus-Tac and, within the latter group, mTOR inhibitors vs mycophenolate-MMF. RESULTS: We identified 3,622 kidney patients undergoing transplantation in 17 hospitals located in 4 Italian regions, 78.3% was treated with TAC-based therapy, of which 78% and 22% in combination with MMF and mTOR, respectively. For both comparison groups, the choice of immunosuppressive regimens was mostly guided by standard hospital practices. Only few recipient and donor characteristics were found associated with specific regimen (donor/receipt age, immunological risk and diabetes). CONCLUSIONS: The choice of post-renal transplant immunosuppressive therapy seems to be mostly driven by standard Centre practices, while only partially based on patient's characteristics and recognized international guidelines.

An Italian multicentre distributed data research network to study the use, effectiveness, and safety of immunosuppressive drugs in transplant patients: Framework and perspectives of the CESIT project.

The goal of post-transplant immunosuppressive drug therapy is to prevent organ rejection while minimizing drug toxicities. In clinical practice, a multidrug approach is commonly used and involves drugs with different mechanisms of action, including calcineurin inhibitors (CNI) (tacrolimus or cyclosporine), antimetabolite (antimet) (mycophenolate or azathioprine), inhibitors of mechanistic target of rapamycin (mTOR) (sirolimus or everolimus), and/or steroids. Although evidence based on several randomized clinical trials is available, the optimal immunosuppressive therapy has not been established and may vary among organ transplant settings. To improve the knowledge on this topic, a multiregional research network to Compare the Effectiveness and Safety of Immunosuppressive drugs in Transplant patients (CESIT) has been created with the financial support of the Italian Medicines Agency. In this article, we describe the development of this network, the framework that was designed to perform observational studies, and we also give an overview of the preliminary results that we have obtained. A multi-database transplant cohort was enrolled using a common data model based on healthcare claims data of four Italian regions (Lombardy, Veneto, Lazio, and Sardinia). Analytical datasets were created using an open-source tool for distributed analysis. To link the National Transplant Information System to the regional transplant cohorts, a semi-deterministic record linkage procedure was performed. Overall, 6,914 transplant patients from 2009-19 were identified: 4,029 (58.3%) for kidney, 2,219 (32.1%) for liver, 434 (6.3%) for heart, and 215 (3.1%) for lung. As expected, demographic and clinical characteristics showed considerable variability among organ settings. Although the triple therapy in terms of CNI + antimet/mTOR + steroids was widely dispensed for all settings (63.7% for kidney, 33.5% for liver, 53.3% for heart, and 63.7% for lung), differences in the active agents involved were detected. The CESIT network represents a great opportunity to study several aspects related to the use, safety, and effectiveness of post-transplant maintenance immunosuppressive therapy in real practice.

Temporal and spatial variability of immunosuppressive therapies in transplant patients: An observational study in Italy.

Background: In immunosuppression after transplantation, several multi-drug approaches are used, involving calcineurin inhibitors (CNI: tacrolimus-TAC or cyclosporine-CsA), antimetabolites (antiMs), mammalian target of rapamycin inhibitors (mTORis), and corticosteroids. However, data on immunosuppressive therapy by organ and its space-time variability are lacking. Methods: An Italian multicentre observational cohort study was conducted using health information systems. Patients with incident transplant during 2009-2019 and resident in four regions (Veneto, Lombardy, Lazio, and Sardinia) were enrolled. The post-transplant immunosuppressive regimen was evaluated by organ, region, and year. Results: The most dispensed regimen was triple-drug therapy for the kidneys [tacrolimus (TAC) + antiM + corticosteroids = 41.5%] and heart [cyclosporin + antiM + corticosteroids = 36.6%] and double-drug therapy for liver recipients (TAC + corticosteroids = 35.4%). Several differences between regions and years emerged with regard to agents and the number of drugs used. Conclusion: A high heterogeneity in immunosuppressive therapy post-transplant was found. Further studies are needed in order to investigate the reasons for this variability and to evaluate the risk-benefit profile of treatment schemes adopted in clinical practice.

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project.

BACKGROUND: Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. OBJECTIVE: The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. METHODS: A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010-2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. RESULTS: From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015-2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. CONCLUSION: The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010-2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings.

Bortezomib-based therapy in non-transplant multiple myeloma patients: a retrospective cohort study from the FABIO project.

INTRODUCTION: Randomized clinical trials showed that bortezomib, in addition to conventional chemotherapy, improves survival and disease progression in multiple myeloma (MM) patients not eligible for stem cell transplantation. The aim of this retrospective population-based cohort study is the evaluation of both clinical and economic profile of bortezomib-based versus conventional chemotherapy in daily clinical practice. METHODS: Healthcare utilization databases of six Italian regions were used to identify adult patients with non-transplant MM, who started a first-line therapy with bortezomib-based or conventional chemotherapy. Patients were matched by propensity score and were followed from treatment start until death, lost to follow-up or study end-point. Overall survival (OS) and restricted mean survival time (RMST) were estimated using the Kaplan-Meier method. Association between first-line treatment and risk of death was estimated by a conditional Cox proportional regression model. Average mean cumulative costs were estimated and compared between groups. RESULTS: In the period 2010-2016, 3509 non-transplant MM patients met the inclusion criteria, of which 1157 treated with bortezomib-based therapy were matched to 1826 treated with conventional chemotherapy. Median OS and RMST were 33.9 and 27.9 months, and 42.9 and 38.4 months, respectively, in the two treatment arms. Overall, these values corresponded to a HR of death of 0.79 (95% CI 0.71-0.89) over a time horizon of 84 months. Average cumulative cost were 83,839 € and 54,499 €, respectively, corresponding to an incremental cost-effectiveness ratio of 54,333 € per year of life gained, a cost coherent with the willingness-to-pay thresholds frequently adopted from Western countries. CONCLUSIONS: These data suggested that, in a large cohort of non-transplant MM patients treated outside the experimental setting, first-line treatment with bortezomib-based therapy was associated with a favourable effectiveness and cost-effectiveness profile.

Cardiovascular Risk After Adjuvant Trastuzumab in Early Breast Cancer: An Italian Population-Based Cohort Study.

BACKGROUND: Although trastuzumab (T) represents the standard of care for the adjuvant treatment of HER2-positive early-stage breast cancer, contrasting results are available about the cardiac toxicity associated to its use. We conducted a multiregional population-based cohort investigation aimed to assess both the short- and long-term cardiovascular (CV) outcomes in women with early breast cancer treated with T-based or standard adjuvant chemotherapy (CT). MATERIALS AND METHODS: We used health care use databases of six Italian regions, overall accounting for 42% of the Italian population. The study cohort was made by all women surgically treated for breast cancer who started a first-line adjuvant T-based or CT treatment. Patients treated with T were 1:2 matched to those treated with CT based on date of treatment start, age, and presence of CV risk factors. Short- and long-term CV outcomes (heart failure and cardiomyopathy) were measured, respectively, after 1 year and at the end of follow-up. RESULTS: Among 28,599 women who met the inclusion criteria, 6,208 T users were matched to 12,416 CT users. After a mean follow-up of 5.88 years, short- and long-term cumulative CV risk were 0.8% and 2.6% in patients treated with T and 0.2% and 2.8% in those treated with CT, respectively. Adjusted hazard ratios were 4.6 (95% confidence interval [CI], 2.6-8.0) for short-term and 1.2 (95% CI, 0.9-1.6) for long-term CV risk. DISCUSSION: In our large real-world investigation, T-associated cardiotoxicity was limited to the treatment period. The addition of T to adjuvant CT did not result in long-term worsening of CV events. IMPLICATIONS FOR PRACTICE: Adjuvant trastuzumab-based chemotherapy represents the backbone therapy in patients with HER2-positive early breast cancer. Although well tolerated, cardiovascular events can manifest during or after therapy because of treatment-related toxicities. In this wide multicenter and unselected cohort, long-term symptomatic cardiotoxicity was low and limited to the treatment period. The findings suggest that developing tools that would be adequately able to predict cardiac toxicity at an early stage remains an important area in which additional research efforts are needed.

Measuring multimorbidity inequality across Italy through the multisource comorbidity score: a nationwide study.

BACKGROUND: Multimorbidity is a growing concern for healthcare systems, with many countries experiencing demographic transition to older population profiles. A simple multisource comorbidity score (MCS) has been recently developed and validated. A very large real-world investigation was conducted with the aim of measuring inequalities in the MCS distribution across Italy. METHODS: Beneficiaries of the Italian National Health Service aged 50-85 years who in 2018 were resident in one of the 10 participant regions formed the study population (15.7 million of the 24.9 million overall resident in Italy). MCS was assigned to each beneficiary by categorizing the individual sum of the comorbid values (i.e. the weights corresponding to the comorbid conditions of which the individual suffered) into one of the six categories denoting a progressive worsening comorbidity status. MCS distributions in women and men across geographic partitions were compared. RESULTS: Compared with beneficiaries from northern Italy, those from centre and south showed worse comorbidity profile for both women and men. MCS median age (i.e. the age above which half of the beneficiaries suffered at least one comorbidity) ranged from 60 (centre and south) to 68 years (north) in women and from 63 (centre and south) to 68 years (north) in men. The percentage of comorbid population was lower than 50% for northern population, whereas it was around 60% for central and southern ones. CONCLUSION: MCS allowed of capturing geographic variability of multimorbidity prevalence, thus showing up its value for addressing health policy in order to guide national health planning.

Effectiveness and Costs Associated to Adding Cetuximab or Bevacizumab to Chemotherapy as Initial Treatment in Metastatic Colorectal Cancer: Results from the Observational FABIO Project.

Evidence available on the effectiveness and costs of biological therapies for the initial treatment of metastatic colorectal cancer (mCRC) is scarce and contrasting. We conducted a population-based cohort investigation for assessing overall survival and costs associated with their use in a real-world setting. Healthcare utilization databases were used to select patients newly diagnosed with mCRC between 2010 and 2016. Those initially treated with biological therapy (bevacizumab or cetuximab) added to chemotherapy were propensity-score-matched to those treated with standard chemotherapy alone, and were followed up to June 30th, 2018. Kaplan-Meier survival estimates, restricted mean survival time (RMST) and cumulative costs were compared between the two treatment arms. The study cohort included 1896 mCRC patients treated with biological therapy matched to 5678 patients treated with chemotherapy alone. Median overall survival was 21.8 and 20.2 months, respectively. After 84 months of follow-up, RMSTs were 30.9 and 31.9 months (p = 0.193), indicating no differences between the average survival time between treatment arms. Patients treated with biological therapy were associated with higher costs. Cumulative per capita costs were €59,663 and €44,399, respectively. In our study, first-line biological therapy did not improve long-term overall survival and was associated with higher costs as compared to standard chemotherapy.

Squamous-cell carcinoma of the tongue following therapy of rheumatoid arthritis with abatacept.

KEY CLINICAL MESSAGE: A patient affected by rheumatoid arthritis developed a squamous-cell carcinoma probably due to abatacept, according to Naranjo algorithm. The case describes this adverse reaction for the first time and highlights the need for additional studies to establish the long-term risk profile of abatacept.