Bin-CE: A comprehensive web application to decide upon the best set of outcomes to be combined in a binary composite endpoint

The estimation of the Sample Size Requirement (SSR) when using a binary composite endpoint (i.e. two or more outcomes combined in a unique primary endpoint) is not trivial. Besides information about the rate of events for each outcome, information about the strength of association between the outcomes is crucial, since it can determine an increase or decrease of the SSR. Specifically, the greater the strength of association between outcomes the higher the SSR. We present Bin-CE, a free tool to assist clinicians for computing the SSR for binary composite endpoints. In a first step, the user enters a set of candidate outcomes, the assumed rate of events for each outcome and the assumed effect of therapy on each outcome. Since the strength of the association between outcomes is usually unknown, a semi-parametric approach linking the a priori clinical knowledge of the potential degree of association between outcomes with the exact values of these parameters was programmed with Bin-CE. Bin-CE works with a recursive algorithm to choose the best combination of outcomes that minimizes the SSR. In addition, Bin-CE computes the sample size using different algorithms and shows different figures plotting the magnitude of the sample size reduction, and the effect of different combinations of outcomes on the rate of the primary endpoint. Finally, Bin-CE is programmed to perform sensitivity analyses. This manuscript presents the mathematic bases and introduces the reader to the use of Bin-CE using a real example

Prevalence study of intermittent hormonal therapy of Prostate Cancer patients in Spain

Background: Although intermittent androgen deprivation therapy was introduced many years ago to improve patients' quality of life with the same carcinologic efficiency as continuous hormonal therapy, recent data suggest that intermittency could be underutilised. This study aims to estimate the prevalence of prostate cancer patients receiving intermittent androgen deprivation therapy in Spain. Methods: A retrospective, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities, which encompass 17.23 million inhabitants (36.22% of the total population in Spain). We estimated intermittent androgen therapy use (%IAD) and the prevalence of patients under intermittent androgen therapy in reference to the total number of PC patients using hormonal therapy (P IAD) and stratified by region. Other outcome variables included the pharmaceutical forms dispensed and the total direct annual expenditure on androgen deprivation therapy-associated medications. Results: A total of 863,005 dispensations corresponding to a total of 65,752 men were identified, treated with either luteinizing hormone-releasing hormone (LHRH) analogues (353,162) administered alone or in combination with anti-androgens (509,843). Overall, the mean (±SD) age of the patients was 76.9 (±10.4) years. Results revealed that the mean annual P IAD along the study was 6.6% in the total population studied, and the overall %IAD during the five-year study period was 5.6%. The mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens. Conclusions: Few prostate cancer patients in Spain use the intermittent androgen deprivation therapy suggesting underutilization of a perfectly valid option for a significant proportion of patients, missing the opportunity to improve their quality of life and to reduce costs for the National Health Service with comparable overall survival rates than continuous therapy.</p

Persistence with dual antiplatelet therapy after percutaneous coronary intervention for ST-segment elevation acute coronary syndrome: a population-based cohort study in Catalonia (Spain)

Objectives: Guidelines recommending 12-month dual antiplatelet therapy (DAPT) in patients with ST-elevation acute coronary syndrome (STEACS) undergoing percutaneous coronary intervention (PCI) were published in year 2012. We aimed to describe the influence of guideline implementation on the trend in 12-month persistence with DAPT between 2010 and 2015 and to evaluate its relationship with DAPT duration regimens recommended at discharge from PCI hospitals. Design: Observational study based on region-wide registry data linked to pharmacy billing data for DAPT follow-up. Setting: All PCI hospitals (10) belonging to the acute myocardial infarction (AMI) code network in Catalonia (Spain). Participants: 10 711 STEACS patients undergoing PCI between 2010 and 2015 were followed up. Primary and secondary outcome measures: Primary outcome was 12-month persistence with DAPT. Calendar year quarter, publication of guidelines, DAPT duration regimen recommended in the hospital discharge report, baseline patient characteristics and significant interactions were included in mixed-effects logistic regression based interrupted time-series models. Results: The proportion of patients on-DAPT at 12 months increased from 58% (56-60) in 2010 to 73% (71-75) in 2015. The rate of 12-month persistence with DAPT significantly increased after the publication of clinical guidelines with a time lag of 1 year (OR=1.20; 95% CI 1.11 to 1.30). A higher risk profile, more extensive and complex coronary disease, use of drug-eluting stents (OR=1.90; 95% CI 1.50 to 2.40) and a 12-month DAPT regimen recommendation at discharge from the PCI hospital (OR=5.76; 95% CI 3.26 to 10.2) were associated with 12-month persistence. Conclusion: Persistence with 12-month DAPT has increased since publication of clinical guidelines. Even though most patients were discharged on DAPT, only 73% with potential indication were on-DAPT 12 months after PCI. A guideline-based recommendation at PCI hospital discharge was highly associated with full persistence with DAPT. Establishing evidence-based, common prescribing criteria across hospitals in the AMI-network would favour adherence and reduce variability

Stability of SARS-CoV-2 spike antigens against mutations

Modern health care needs preventive vaccines and therapeutic treatments with stability against pathogen mutations to cope with current and future viral infections. At the beginning of the COVID-19 pandemic, our analytic and predictive tool identified a set of eight short SARS-CoV-2 S-spike protein epitopes that had the potential to persistently avoid mutation. Here a combination of genetic, Systems Biology and protein structure analyses confirm the stability of our identified epitopes against viral mutations. Remarkably, this research spans the whole period of the pandemic, during which 93.9% of the eight peptides remained invariable in the globally predominant 43 circulating variants, including Omicron. Likewise, the selected epitopes are conserved in 97% of all 1,514 known SARS-CoV-2 lineages. Finally, experimental analyses performed with these short peptides showed their specific immunoreactivity. This work opens a new perspective on the design of next-generation vaccines and antibody therapies that will remain reliable against future pathogen mutations.Dr. Lozano-Perez acknowledges the European Commission ERDF/FEDER Operational Program 'Murcia' CCI No. 2007ES161PO001 (Project No. 14-20/20). Miodrag Grbic acknowledges support from the NSERC Discovery grant (Canada). This work also has received funding from the Department of Education of the Basque Government via the Consolidated Research Group MATH MODE (IT1456-22). Besides, Ildefonso Martinez De la Fuente and Iker Malaina were supported by the UPV/EHU and Basque Center of Applied Mathematics, grant US21/27N

Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety

Es reproducción del documento publicado en http://dx.doi.org/10.1186/1471-2474-9-52Background: To analyse available evidence on the efficacy and safety of anti-TNF alpha drugs (infliximab, etanercept and adalimumab) for treating rheumatoid arthritis (RA). Methods: We searched systematically for randomised controlled clinical trials on treatment of RA with anti-TNF alpha drugs, followed by a systematic review with metaanalysis. Trials were searched from MEDLINE, EMBASE and Cochrane Library databases. The American College of Rheumatology (ACR) efficacy response criteria were used. Safety parameters provided by the trials were also assessed. Positive and undesired effects were estimated using combined relative risks (RR), number needed to treat (NNT) and number needed to harm (NNH). Heterogeneity was evaluated by Cochrane's Q and I-2 statistics. Results: Thirteen trials (7087 patients) met the inclusion criteria. The combined RR to achieve a therapeutic response to treatment with recommended doses of any anti-TNF alpha drug was 1.81 (95% CI 1.43 - 2.29) with a NNT of 5 (5 - 6) for ACR20. NNT for ACR50 [5 (5 - 6)] and ACR70 [7 (7 - 9)] were similar. Overall therapeutic effects were also similar regardless of the specific anti-TNF alpha drug used and when higher than recommended doses were administered. However, lower than recommended doses elicited low ACR70 responses (NNT 15). Comparison of anti-TNF alpha drugs plus methotrexate (MTX) with MTX alone in patients with insufficient prior responses to MTX showed NNT values of 3 for ACR20, 4 for ACR50 and 8 for ACR70. Comparison of anti-TNF alpha drugs with placebo showed a similar pattern. Comparisons of anti-TNF alpha drugs plus MTX with MTX alone in patients with no previous resistance to MTX showed somewhat lower effects. Etanercept and adalimumab administered as monotherapy showed effects similar to those of MTX. Side effects were more common among patients receiving anti-TNF alpha drugs than controls (overall combined NNH 27). Patients receiving infliximab were more likely to drop out because of side effects (NNH 24) and to suffer severe side effects (NNH 31), infections (NNH 10) and infusion reactions (NNH 9). Patients receiving adalimumab were also more likely to drop out because of side effects (NNH 47) and to suffer injection site reactions (NNH 22). Patients receiving etanercept were less likely to drop out because of side effects (NNH for control versus etanercept 26) but more likely to experience injection site reactions (NNH 5). Conclusion: Anti-TNF alpha drugs are effective in RA patients, with apparently similar results irrespective of the drug administered. Doses other than those recommended are also beneficial. The main factor influencing therapeutic efficacy is the prior response to DMARD treatment. The effect of treatment with etanercept or adalimumab does not differ from that obtained with MTX. The published safety profile for etanercept is superior but the fact that no patients are treated with higher than recommended doses requires explanation

Bin-CE : A comprehensive web application to decide upon the best set of outcomes to be combined in a binary composite endpoint

The estimation of the Sample Size Requirement (SSR) when using a binary composite endpoint (i.e. two or more outcomes combined in a unique primary endpoint) is not trivial. Besides information about the rate of events for each outcome, information about the strength of association between the outcomes is crucial, since it can determine an increase or decrease of the SSR. Specifically, the greater the strength of association between outcomes the higher the SSR. We present Bin-CE, a free tool to assist clinicians for computing the SSR for binary composite endpoints. In a first step, the user enters a set of candidate outcomes, the assumed rate of events for each outcome and the assumed effect of therapy on each outcome. Since the strength of the association between outcomes is usually unknown, a semi-parametric approach linking the a priori clinical knowledge of the potential degree of association between outcomes with the exact values of these parameters was programmed with Bin-CE. Bin-CE works with a recursive algorithm to choose the best combination of outcomes that minimizes the SSR. In addition, Bin-CE computes the sample size using different algorithms and shows different figures plotting the magnitude of the sample size reduction, and the effect of different combinations of outcomes on the rate of the primary endpoint. Finally, Bin-CE is programmed to perform sensitivity analyses. This manuscript presents the mathematic bases and introduces the reader to the use of Bin-CE using a real example

Dynamics of Emergency Cardiovascular Hospital Admissions and In-Hospital Mortality During the COVID-19 Pandemic: Time Series Analysis and Impact of Socioeconomic Factors

AimsThis study aimed to evaluate the decline in urgent cardiovascular hospital admissions and in-hospital mortality during the COVID pandemic in two successive waves, and to evaluate differences by sex, age, and deprivation index subgroups. Methods and ResultsWe obtained acute cardiovascular hospital episodes during the years 2019-2020 from region-wide data on public healthcare usage for the population of Catalonia (North-East Spain). We fitted time models to estimate the incidence rate ratios (IRRs) of the acute coronary syndrome (ACS) and acute heart failure (HF) admissions during the first pandemic wave, the between-waves period, and the second wave compared with the corresponding pre-COVID-19 periods and to test for the interaction with sex, age, and area-based socioeconomic level. We evaluated the effect of COVID-19 period on in-hospital mortality. ACS (n = 8,636) and HF (n = 27,566) episodes were defined using primary diagnostic ICD-10 codes. ACS and HF admissions decreased during the first wave (IRR = 0.66, 95%CI: 0.58-0.76 and IRR = 0.61, 95% CI: 0.55-0.68, respectively) and during the second wave (IRR = 0.80, 95%CI: 0.72-0.88 and IRR = 0.76, 95%CI: 0.69-0.84, respectively); acute HF admissions also decreased in the period between waves (IRR: 0.81, 95%CI: 0.74-0.89). The impact was similar in all sex and socioeconomic subgroups and was higher in older patients with ACS. In-hospital mortality was higher than expected only during the first wave. ConclusionDuring the first wave of the COVID-19 pandemic, there was a marked decline in urgent cardiovascular hospital admissions that were attenuated during the second wave. Both the decline and the attenuation of the effect have been similar in all subgroups regardless of age, sex, or socioeconomic status. In-hospital mortality for ACS and HF episodes increased during the first wave, but not during the second wave