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.

The Restricted Mean Survival Time as a Tool for Ranking Comparative Outcomes in a Narrative Review that Evaluates a Network of Randomized Trials: An Example Based on PCSK9 Inhibitors.

INTRODUCTION: On the basis of two randomized trials, evolocumab and alirocumab have been approved in patients with cardiovascular disease. The evidence on these two agents has been studied through different methods of analysis that span from narrative approaches to network meta-analysis. In the present study, we assessed the performance of a narrative approach combined with the application of the restricted mean survival time (RMST). METHODS: We studied the two pivotal placebo-controlled trials focused on evolocumab and alirocumab. Our original framework of comparative assessment employed the RMST. Our objective was to show that in the context of a narrative review, the RMST can be an efficient although simple tool to make indirect comparisons. The endpoint was event-free survival, expressed in months. RESULTS: For each cohort of patients (13,784 patients administered evolocumab, 9462 patients administered alirocumab, 23,242 controls), we determined the RMST values with 95% confidence intervals (CI) [evolocumab: 33.60 months, 95% CI 33.46-33.74; alirocumab: 34.07 months, 95% CI 33.92-34.22]. These results, along with those of the control groups, were analyzed and interpreted narratively. Univariate statistics were conducted, but no network meta-analysis was performed. CONCLUSION: The experience presented herein indicates that a framework of evidence assessment focused on the RMST is a worthwhile option. Our study is in line with the growing literature that has recently emphasized the methodological advantages of 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.

Outcomes at 5 years in patients with severe aortic stenosis: reviewing current information using the restricted mean survival time.

The information about outcomes at 5 years in patients receiving transcatheter aortic valve replacement (TAVR) has grown. We interpreted the information on this topic using the restricted mean survival time (RMST). The purpose of our study was to summarise the current evidence using an original outcome measure with potential methodological advantages. Four cohorts of patients, previously published in the literature, met our criterion of 5 years of follow-up after the implant; another cohort was identified from a group of controls subjected to surgical replacement of the valve. The estimated values of RMST at 5 years for the 5 patient cohorts were the following (N = number of patients, all time values in years): a) real-world high surgical risk cohort: N = 114, RMST = 3.80; b) real-world cohort treated with Corevalve: N = 309, RMST = 3.79; c) a real-world cohort treated with Sapien: N = 180, RMST = 3.61; d) TAVR arm of a randomized trial in intermediate risk patients: N = 1,011; RMST = 3.73; e) surgical replacement arm of the same trial: N = 1,021, RMST = 3.72. The main result of our analysis based on the RMST is represented by the extreme homogeneity of the outcomes (RMSTs ranging from 3.61 to 3.80 years per patient) that remained virtually constant irrespective of the baseline risk of the patients (intermediate or high risk) and regardless of whether the intervention was transcatheter or by surgical replacement. Last but not least, our analysis showed the good methodological performance of the RMST in this disease condition.

Tuscan Consensus on the diagnosis, treatment and follow up of adult atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory disease with a chronic-relapsing course that is intensely itchy. A correct diagnosis of AD in adults and consequently appropriate clinical therapeutic management is a critical issue for extreme clinical expression heterogeneity and various grades of disease severity. In order to ensure high levels of care and standardization of clinical therapeutic management of Adult AD, the decision was taken to create an AD Tuscan Consensus Group (the Group), to work on and validate a consensus based regional clinical-therapeutic management model. The aims of the Group were to find agreement on the criteria for diagnosis, scoring of severity, multidisciplinary approach and treatment of adult atopic dermatitis and to create an easier way for patients to access specialized dermatology outpatient services and importantly to reduce waiting lists and costs related to the management of AD. The Tuscan Consensus Group adopted a simplified Delphi method, in three principal steps: 1) literature metanalysis and critical review of patient's clinical experience to identify the main areas considered questionable or uncertain; 2) discussion of those areas requiring consensus and statement definition through four different sub-committees (diagnosis, severity evaluation, scoring and comorbidities); 3) a consensus based simplified process with final approval of each statement by plenary vote with approval >80% of the participants. The Group here presents and discusses the consensus based recommendation statements on adult atopic dermatitis.

Tuscan consensus on the use of UVBnb phototherapy in the treatment of psoriasis.

Psoriasis (PSO) is traditionally defined as an immune-mediated, inflammatory dermatological disease characterized by a chronic-relapsing course and associated with multifactorial inheritance (genetic predisposition and influence of various environmental factors). Considered until recently a dermatological disease only, today PSO is correctly known as a systemic one because of the involvement of multiple organs with important impact on social life and relationships. PSO is found in the 0.3-4.6% of the world's population, while its prevalence in the Italian population is estimated at 2.8%. Therefore, if we consider that in Tuscany more than 100,000 people out of 3,672,202 suffer of psoriasis, it is of paramount importance to focus on a shared clinical and therapeutic protocol to manage the disease. With the aim of ensuring diagnostic-therapeutic suitability, high levels of care and standardization of treatment, a unique clinical-therapeutic management model has been developed and validated in Tuscany, involving all accredited regional dermatological centers. Among the possible alternatives to be implemented in the treatment of patients with mild, moderate-severe psoriasis, UVBnb phototherapy is widely used alone or in association with other systemic and non-systemic devices. Despite this, there is still no universally shared therapeutic protocol. In this context the CO.FO.TO working group (Consensus Fototerapia Toscana) is born with the aim of defining and validating the main guidelines in the use of phototherapy with UVBnb in psoriasis; the guidelines are based both on the real-life experience of the different centers of reference in the region and on the revision of the recent literature.

Treatment of psoriasis with topical agents: Recommendations from a Tuscany Consensus.

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real-life-based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real-life setting.

Reconstruction of a large leg defect with a combined hatchet flap technique.

The repair of lower leg defects, not amenable to primary closure, may be challenging, since the skin at this level is scarcely elastic and difficult to mobilize. Local skin flaps are generally utilized only to restore moderately sized losses, whereas grafting becomes a realistic choice in presence of larger wounds. We present the case of a 70-year-old man with a wide defect on his right leg following the surgical excision of a squamous cell carcinoma. The wound was successfully closed with a combination of three hatchet flaps. The various steps of the procedure and the subsequent outcome are illustrated. Our choice proved to be an easy, time-sparing, but effective reconstructive solution for a large skin defect involving the leg.