Risk of hospitalization and sequelae in patients with COVID-19 treated with 3-day early remdesivir vs. controls in the vaccine and Omicron era: A real-life cohort study.

Recently, a benefit from administration of a 3-day course of early remdesivir (ER) in the outpatients' setting was reported. However, real-life data on its use is scarce. Therefore, we explored the ER clinical outcome in our outpatients' s cohort, compared to untreated controls. We included all patients who were prescribed ER from February to May 2022 and followed them up for 3 months and compared patients who received treatment with untreated controls. In the two groups the following outcomes were investigated: hospitalization and mortality rate, time of negativization and symptom's resolution, and postacute coronavirus disease 19 (COVID-19) syndrome prevalence. Overall, 681 patients were analyzed, mostly females (53.6%), and with a median age of 66 years (interquartile range: 54-77), 316 (46.4%) patients received ER, and 365 (53.6%) did not receive antiviral treatment (control group). Overall, 8.5% patients eventually required oxygen support, 8.7% were hospitalized for COVID-19, and 1.5% died. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization and ER (adjusted odds ratio [aOR]: 0.049 [0.015; 0.16], p < 0.001) independently reduced hospitalization risk. ER was significantly associated with a shorter duration of SARS-CoV-2 positivity at nasopharyngeal swabs (aß -8.15 [-9.21; -7.09], p < 0.001) and of symptoms (aß -5.11 [-5.82; -4.39], p < 0.001), and with lower rate of COVID-19 sequelae compared to control group (aOR: 0.18 [0.10; 0.31], p < 0.001). Even in the SARS-CoV-2 vaccination and Omicron era, in patients at high risk of developing severe disease, ER demonstrated to have a good safety profile and to significantly reduce the risk of disease progression and COVID-19 sequelae compared to untreated controls.

Survival with novel hormonal therapies in patients with nonmetastatic castration-resistant prostate cancer: indirect comparison of three randomized phase-III trials.

INTRODUCTION: In recent years, new treatments have been approved for nonmetastatic castration-resistant prostate cancer (M0CRPC). Because direct comparisons between these treatments are not available to guide treatment decisions, indirect comparisons can be of interest. METHODS: Our analysis evaluated second-generation hormone treatments proposed for M0CRPC. We searched multiple databases for articles published between 2010 and 2022. Phase-III clinical trials that studied these agents in M0CRPC patients were eligible. Among these, we included trials reporting overall survival (OS) through Kaplan-Meier curves. We performed the reconstruction of individual patient data from Kaplan-Meier graphs, according to the Shiny method, to indirectly compare the efficacy of the different agents. Indirect comparisons included testing for equivalence according to FDA criteria. Confidence intervals (CI) were 95% in all analyses except equivalence testing, where 90%CIs were used. RESULTS: Three studies met these inclusion criteria. Apalutamide (hazard ratio [HR]: 0.75, 95% confidence interval [CI] 0.64-0.88), darolutamide (HR 0.70, 95%CI 0.58-0.84), and enzalutamide (HR 0.77, 95%CI 0.65-0.90) were all significantly more effective than the placebo. Our results showed no difference in OS between any of these three agents, and in testing for equivalence, our estimates of HR met the 0.75-1.33 level. CONCLUSIONS: While the Shiny method has confirmed its validity in reconstructing individual patient data, our indirect comparisons based on mature OS demonstrated similar efficacy and substantial equivalence among these three second-generation androgen receptor inhibitors.

Evaluation of maintenance treatment with PARP inhibitors in ovarian carcinoma patients responding to platinum therapy: Use of restricted mean survival time as an index of efficacy.

BACKGROUND: Maintenance therapy using poly (ADP-ribose) polymerase inhibitors (PARPIs) is an important therapeutic option in advanced ovarian cancer after platinum-based chemotherapy. MATERIALS AND METHODS: We evaluated randomized studies (n = 5) describing the effect of maintenance therapy with PARPIs; they were obtained mainly by searching PubMed. Patient data for the analysis were derived from progression-free survival curves. Restricted mean survival time (RMST) and 95% confidence interval were estimated for individual arms of each trial. RESULTS: The three PARPIs used (olaparib, niraparib, rucaparib) all showed a higher effectiveness than placebo. The gains in progression-free survival were 6 - 8 months. CONCLUSION: Maintenance therapy studies provide evidence that olaparib, niraparib, rucaparib are effective treatments for advanced ovarian cancer.

Trastuzumab biosimilar in metastatic breast cancer: Evaluating equivalence with originator using network meta-analysis
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OBJECTIVE: The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have recently approved four different trastuzumab biosimilars, marketed by different pharmaceutical companies. Biosimilars, unlike their originators, are typically supported by less clinical data about safety and efficacy. The objective of our analysis was to demonstrate that one of the approved trastuzumab biosimilars (MYL-1401O) is as effective as its originator in terms of hazard ratio (HR) of progression-free survival (PFS). MATERIALS AND METHODS: We carried out a network meta-analysis to compare the HR values for biosimilar, originator, and standard of care (SOC). Our analysis included a preliminary pairwise meta-analysis. The pooled HR for all pairwise comparisons was the output of the analysis (fixed-effect inverse variance method), along with 95% confidence intervals (CIs). The indirect comparison between biosimilar and SOC was performed using a network meta-analysis software. RESULTS: We estimated an HR of 0.59 (95% CI: 0.52 - 0.66) for the comparison between PFS values of originator and SOC, 0.97 (95% CI: 0.74 - 1.28) for biosimilar vs. originator, and 0.61 (95% CI: 0.44 - 0.83) for biosimilar vs. SOC. Our network meta-analysis increased the overall number of evaluated patients from 458 to 1,955. CONCLUSION: According to the network meta-analysis, MYL-1401O biosimilar is as effective as its originator in terms of HR of PFS.
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Radiofrequency Ablation, Cryotherapy Ablation, or Pulsed-Field Ablation to Treat Paroxysmal Atrial Fibrillation Unresponsive to Pharmacological Treatments: Interpreting Efficacy Through Reconstruction of Individual Patient Data From Randomized Trials.

Three techniques of catheter ablation (CA; radiofrequency, cryoballoon, and pulsed-field ablation) are available to treat patients with paroxysmal atrial fibrillation (PAF) who do not adequately respond to pharmacological treatments. Our study was aimed at comparing these techniques based on the data of randomized studies because these are considered the best sources of efficacy data. After selecting pertinent trials, our analysis studied the time-to-event data published for these three techniques. An artificial intelligence method was used that reconstructs individual patient data from the Kaplan-Meier curves. The endpoint was an arrhythmia recurrence. A preliminary heterogeneity analysis was performed. Then, our main analysis was based on individual patient data reconstructed from Kaplan-Meier graphs. The hazard ratio (HR) was its main parameter. Three randomized trials were included. Our heterogeneity analysis confirmed an acceptable level of between-trial heterogeneity that allowed us to pool the curves from the different trials; however, cryoballoon ablation with a two-minute duration fared worse than the other techniques. Then, our main analysis estimated the following values of HR: pulsed-field ablation versus radiofrequency ablation, 0.549 (95%CI, 0.413-0.730; p<0.001); pulsed-field ablation versus cryoballoon ablation, 0.478 (95%CI, 0.364-0.633); radiofrequency ablation versus cryoballoon ablation, HR=0.871 (95%CI, 0.585-1.295; p=0.506). In conclusion, radiofrequency ablation and cryoballoon ablation showed similar effectiveness (except for the two-minute cryoballoon ablation, which fared worse). Our results showing the superiority of pulsed-field ablation versus thermal ablation must be interpreted with caution because the patients given pulsed-field ablation were limited, and their follow-up was shorter than that of patients receiving thermal ablation.

Polypharmacy in Children with Medical Complexity: A Cross-Sectional Study in a Pediatric Palliative Care Center.

BACKGROUND: Children with medical complexity (CMC) often require multiple medications, leading to polypharmacy, which seems to be linked to adverse effects, administration errors, and increased caregiver burden. This study aimed to describe the prevalence of polypharmacy, medication burden, off-label drug use, and associated costs. METHODS: Conducted at the Pediatric Palliative Care Center of Padua, Italy, from August to October 2021, this cross-sectional observational study included patients up to 23 years old with at least one prescribed drug. Data were collected from medical records and caregiver interviews. Drug costs were collected from the Italian Medicine Agency. Descriptive statistical analysis was performed. For comparisons among categorical variables, the Chi-square test was used, and for those among continuous variables, the ANOVA test was used. RESULTS: This study analyzed treatment regimens of 169 patients with a median age of 12.5 years (0.3-23). Polypharmacy was present in 52.7% of patients, and medication burden was observed in 44.4%, both varying significantly by primary diagnosis (p < 0.001). The median daily cost per patient was EUR 2.2 (IQR 0.9-7.1), with significant variation among subgroups. Only 34.6% of prescriptions were off-label. CONCLUSIONS: polypharmacy and medication burden are frequent among our CMC population, with some differences according to primary diagnosis.

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.

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%.

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.

Immune checkpoint inhibitors as first line in advanced melanoma: Evaluating progression-free survival based on reconstructed individual patient data.

BACKGROUND: In patients with advanced melanoma, immune-checkpoint inhibitors (ICIs) represent the mainstay for first line treatment. Recently, relatlimab+nivolumab was proposed as a new combination therapy. This review was aimed at summarizing the current data of effectiveness for ICIs. Progression-free survival (PFS) was the endpoint of our analysis. METHODS: After a standard literature search, Phase II/III studies comparing different ICI regimens in previously untreated advanced melanoma patients were analyzed. Patient-level data were reconstructed from Kaplan-Meier curves by application of the IPDfromKM method. These reconstructed datasets were used to perform indirect comparisons between treatments. Standard statistical testing was used, including hazard ratio and medians. A secondary analysis employed the restricted mean survival time. RESULTS: Six trials were included in our analysis. Information on PFS from these trials was pooled according to the following treatments: nivolumab or pembrolizumab as monotherapy, or in combination with ipilimumab, and relatlimab + nivolumab. Pembrolizumab+ipilimumab showed significantly better PFS compared with the other treatments; nivolumab+ipilimumab ranked second; the other treatments showed a similar survival pattern. CONCLUSIONS: The picture of comparative effectiveness resulting from our analysis is complex. The IPDfromKM method is advantageous because it accounts for the length of follow-up but loses the balance between treatment group and controls determined by randomization. Based on indirect comparisons, the combination of pembrolizumab+ipilimumab showed a particularly high efficacy, and so deserves further investigation. While the effect of between-trial differences in inclusion criteria plays an important role, our results do not support the proposal of relatlimab+nivolumab as a new standard of care.

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.

Factors influencing the acceptability of different devices for subcutaneous drug delivery: a cross-sectional observational study from the patient's point of view.

BACKGROUND: In recent years, an increasing number of patient-reported outcome assessment tools (PROs) have been developed specifically to ascertain patients' perceptions of different drug treatments. Among them, the injection process has been analysed, especially in patients chronically treated with chronic biological therapies. One of the main advantages of most current biological therapies is the possibility to self-administer medication at home through the use of a variety of devices, including prefilled syringes (PFS) and prefilled pens (PFP). OBJECTIVES: The aim of this study was to conduct qualitative research to assess the degree of preference between the different pharmaceutical forms PFS and PFP. METHODS: We performed a cross-sectional observational study in patients on biological drug therapy through the compilation of a web-based questionnaire at the time of routine delivery of biological therapy. Questions regarding primary diagnosis, adherence to therapy, the preferred pharmaceutical form and the main reason for preference among five possibilities already reported in the scientific literature were included. RESULTS: During the study period, data were collected from 111 patients and 68 (58%) indicated PFP as their preference. From the analysis of reasons that led a patient to choose one device over another, PFSs are chosen mainly out of habit (n=13 (28.3%) PFS vs n=2 (3.1%) PFP) while PFPs are chosen to avoid needle vision (n=15 (23.1%) PFP vs n=1 (2.2%) PFS). Both differences were found to be statistically significant (p<0.001). CONCLUSION: As biological subcutaneous drugs are increasingly prescribed for a wide variety of long-term therapies, further research focused on identifying patient factors which may enhance adherence to treatment will become even more valuable.

Hospital Pharmacy Response to Covid-19 Pandemic in Italy: What We Learned From the First Outbreak Wave.

BACKGROUND: When COVID-19 pandemic started, Italian hospital pharmacists faced multiple challenges and change their work practices. OBJECTIVES: The aim of this study was to describe the impact of COVID-19 emergency on pharmaceutical care provided by pharmacists during the first wave of the pandemic. Issues related to pharmacist's involvement in the pandemic management were: changes in activities, support received by authorities and pharmacists' own perceived role in the Health System. METHODS: A cross-sectional study based on a web survey was conducted between May and June 2020 collecting information from pharmacists, members of Italian Society of Clinical Pharmacy and Therapeutics. 113 (11.4%) completed the questionnaire. The cohort was divided in 2 arms: pharmacists who worked in severely COVID-19 affected areas (High Spread Regions) and those employed in less affected areas (Low Spread Regions). RESULTS: The changes in pharmacy work settings reflected the increase of logistics area and non-sterile clinical galenic, and reduction of clinical tasks. The most demanding challenge was referred to shortages of medical devices and drugs, 61/113 pharmacists reported difficulty in obtaining products compliant to quality standards. National Institutions and Regional Governments provided a greater perceived support. More than 50% of participants felt that their role did not change if compared to other health professionals. CONCLUSIONS: Despite some limitations related to their clinical activity, pharmacists played a crucial role in supplying personal protective equipment, medical devices and medications to improve health outcomes during this emergency. The results may guide pharmacists in future actions to improve the management of the pandemic.

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.

Best Possible Medication History Collection by Clinical Pharmacist in a Preoperative Setting: An Observational Prospective Study.

BACKGROUND: A Best Possible Medication History (BPMH) collected by clinical pharmacists is crucial for effective medication review, but, in Italy, it is often left to the nursing staff. This study aims to compare the quality and accuracy of a clinical pharmacist-documented BPMH with the current standard practice of ward staff-collected BPMH in an Italian preoperative surgical setting. METHODS: A 20-week prospective observational non-profit study was conducted in a major university hospital. The study comprised three phases: a feasibility, an observational, and an interventional phase. During the feasibility phase, 10 items for obtaining a correct BPMH were identified. The control group consisted of retrospectively analyzed BPMHs collected by the ward staff during the observational phase, while interventions included BPMHs collected by the clinical pharmacist during the third phase. Omissions between the two groups were compared. RESULTS: 14 (2.0%) omissions were found in the intervention group, compared with 400 (57.4%) found in the controls (p < 0.05); data collection was more complete when collected by pharmacists compared to the current modality (98.0% of completed information for the intervention versus 42.6%; p < 0.05). CONCLUSIONS: The involvement of a pharmacist significantly reduced the number of omissions in preoperative surgical-collected BPMHs. This intervention holds the potential to decrease the risk of medication errors associated with inaccurate or incomplete BPMHs prior to surgical hospitalization.