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.

Albumin replacement in patients with severe sepsis or septic shock.

BACKGROUND: Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. METHODS: In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. RESULTS: During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P=0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P=0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% confidence interval [CI], 0.87 to 1.14; P=0.94). At 90 days, 365 of 888 patients (41.1%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P=0.29). No significant differences in other secondary outcomes were observed between the two groups. CONCLUSIONS: In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS ClinicalTrials.gov number, NCT00707122.).

Sequential N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin Measurements During Albumin Replacement in Patients With Severe Sepsis or Septic Shock.

OBJECTIVES: Myocardial dysfunction is a frequent complication in patients with severe sepsis and can worsen the prognosis. We investigated whether circulating biomarkers related to myocardial function and injury predicted outcome and were associated with albumin replacement. DESIGN: A multicenter, randomized clinical trial about albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis trial). SETTING: Forty ICUs in Italy. PATIENTS: Nine hundred and ninety-five patients with severe sepsis or septic shock. INTERVENTIONS: Randomization to albumin and crystalloid solutions or crystalloid solutions alone. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of N- terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T were measured 1, 2, and 7 days after enrollment. We tested the relationship of single marker measurements or changes over time with clinical events, organ dysfunctions, albumin replacement, and ICU or 90-day mortality in the overall population and after stratification by shock. N-terminal pro-B-type natriuretic peptide levels were abnormal in 97.4% of the patients and high-sensitivity cardiac troponin T in 84.5%, with higher concentrations in those with shock. After extensive adjustments, N-terminal pro-B-type natriuretic peptide concentrations predicted ICU or 90-day mortality, better than high-sensitivity cardiac troponin T. Early changes in N-terminal pro-B-type natriuretic peptide or high-sensitivity cardiac troponin T concentrations were independently associated with subsequent mortality in patients with shock. Patients given albumin had significantly higher N-terminal pro-B-type natriuretic peptide levels; in addition, early rise in N-terminal pro-B-type natriuretic peptide was associated with a better outcome in this subgroup. CONCLUSIONS: Circulating N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T are frequently elevated in severe sepsis or septic shock and have relevant prognostic value, which may be important in monitoring the clinical efficacy of supporting therapy.

On the hypothetical universal use of statins in primary prevention: an observational analysis on low-risk patients and economic consequences of a potential wide prescription rate.

PURPOSE: Recent guidelines expand indications for statins. However, research on practical economic feasibility and cost-effectiveness in low-risk people is lacking. We aimed to describe the incidence of cardiovascular events (CVE), their total direct costs and the hypothetical effects of wide provision of statins on those rates and expenditures. METHODS: We conducted a population-based cohort study using administrative data among low risk individuals. Estimators of effects of statins were taken from Cholesterol Treatment trialist metaanalysis and from Heart Protection Study trial. Two statin prices were used for analyses: National Italian Health System (€ 0.36) and the International Drug Price Indicator (€ 0.021). RESULTS: Overall, 920,067 persons at low risk were identified and 14,849 CVE were registered (incidence rate 27.3 per 10,000 person-years). Direct costs for hospitalizations for CVE were 143 M €. Universal provision of statins would result in a significant decrease in CVE rates, from 27.3 to 17.5 per 10,000 person-years (PY) (95% confidence interval (CI): 15.8-19.4). Universal prescription of simvastatin 20 mg would cost 802 M €. Otherwise, provision of simvastatin at International Drug Price Indicator's prices would be both clinically effective and cost saving in men older than age 44 (observed expenditures 120 M €, expected 97.4 M €) but not in women (observed expenditures 22.7 M €, expected 36.5 M €). CONCLUSIONS: Among a low-risk population, hypothetical universal provision of low-cost simvastatin to men over 44 years could be both clinically effective and a cost-saving strategy.

Patient's adherence on pharmacological therapy for benign prostatic hyperplasia (BPH)-associated lower urinary tract symptoms (LUTS) is different: is combination therapy better than monotherapy?

BACKGROUND: Recent studies showed that the non-adherence to the pharmacological therapy of patients affected by BPH-associated LUTS increased the risk of clinical progression of BPH. We examined the patients adherence to pharmacological therapy and its clinical consequences in men with BPH-associated LUTS looking at the differences between drug classes comparing mono vs combination therapy. METHODS: A retrospective, population-based cohort study, using prescription administrative database and hospital discharge codes from a total of 1.5 million Italian men. Patients ≥ 40 years, administered alpha-blockers (AB) and 5alpha-reductase inhibitors (5ARIs), alone or in combination (CT), for BPH-associated LUTS were analyzed. The 1-year and long term adherence together with the analyses of hospitalization rates for BPH and BPH-related surgery were examined using multivariable Cox proportional hazards regression model and Pearson chi square test. RESULTS: Patients exposed to at least 6 months of therapy had a 1-year overall adherence of 29 % (monotherapy AB 35 %, monotherapy 5ARI 18 %, CT 9 %). Patient adherence progressively declined to 15 %, 8 % and 3 % for AB, 5ARI, and CT, respectively at the fifth year of follow up. Patients on CT had a higher discontinuation rate along all the follow-up compared to those under monotherapy with ABs or 5ARIs (all p < 0.0001). Moreover, CT was associated with a reduced risk of hospitalization for BPH-related surgery (HR 0.94; p < 0.0001) compared to AB monotherapy. CONCLUSIONS: Adherence to pharmacological therapy of BPH-associated LUTS is low and varies depending on drugs class. Patients under CT have a higher likelihood of discontinuing treatment for a number of reasons that should be better investigated. Our study suggests that new strategies aiming to increase patient's adherence to the prescribed treatment are necessary in order to prevent BPH progression.

Presepsin (soluble CD14 subtype) and procalcitonin levels for mortality prediction in sepsis: data from the Albumin Italian Outcome Sepsis trial.

INTRODUCTION: Sepsis, a leading cause of death in critically ill patients, is the result of complex interactions between the infecting microorganisms and the host responses that influence clinical outcomes. We evaluated the prognostic value of presepsin (sCD14-ST), a novel biomarker of bacterial infection, and compared it with procalcitonin (PCT). METHODS: This is a retrospective, case-control study of a multicenter, randomized clinical trial enrolling patients with severe sepsis or septic shock in ICUs in Italy. We selected 50 survivors and 50 non-survivors at ICU discharge, matched for age, sex and time from sepsis diagnosis to enrollment. Plasma samples were collected 1, 2 and 7 days after enrollment to assay presepsin and PCT. Outcome was assessed 28 and 90 days after enrollment. RESULTS: Early presepsin (day 1) was higher in decedents (2,269 pg/ml, median (Q1 to Q3), 1,171 to 4,300 pg/ml) than in survivors (1,184 pg/ml (median, 875 to 2,113); P = 0.002), whereas PCT was not different (18.5 µg/L (median 3.4 to 45.2) and 10.8 µg/L (2.7 to 41.9); P = 0.31). The evolution of presepsin levels over time was significantly different in survivors compared to decedents (P for time-survival interaction = 0.03), whereas PCT decreased similarly in the two groups (P = 0.13). Presepsin was the only variable independently associated with ICU and 28-day mortality in Cox models adjusted for clinical characteristics. It showed better prognostic accuracy than PCT in the range of Sequential Organ Failure Assessment score (area under the curve (AUC) from 0.64 to 0.75 vs. AUC 0.53 to 0.65). CONCLUSIONS: In this multicenter clinical trial, we provide the first evidence that presepsin measurements may have useful prognostic information for patients with severe sepsis or septic shock. These preliminary findings suggest that presepsin may be of clinical importance for early risk stratification.

The effects of dutasteride and finasteride on BPH-related hospitalization, surgery and prostate cancer diagnosis: a record-linkage analysis.

PURPOSE: To investigate differences in the risk of benign prostatic hyperplasia (BPH)-related hospitalization, for surgical and non-surgical reasons, and of new prostate cancer (PCa) diagnosis between patients using finasteride or dutasteride. METHODS: A retrospective cohort study was conducted using data from record linkage of administrative databases (pharmaceutical prescription data, hospital discharge records, Italian population registry). Men aged ≥ 40 years old who had received a prescription for at least 10 packs/year between January 1, 2004 and December 31, 2004 were included and followed for 5 years. The association of the outcomes was assessed using a multiple Cox proportional hazard model. Propensity score-matched analysis and a 5-1, greedy 1:1 matching algorithm were performed. RESULTS: 8,132 patients were identified. Overall incidence rates of BPH hospitalization and BPH-related surgery were 21.05 (95 % CI 19.52-22.71) and 20.97 (95 % CI 19.45-22.61) per 1,000 person-years, respectively. In the dutasteride group compared with finasteride group, the incidence rate of both events was statistically significant lower: 16.07 versus 21.76 for BPH hospitalization and 15.91 versus 21.69 for BPH-related surgery. The incidence rate of new PCa was also lower for the dutasteride group [8.34 (95 % CI 5.96-11.68) vs. 10.25 (95 % CI 9.15-11.49)]. Dutasteride was associated with a reduction in BPH-related hospitalizations (HR 0.75, 95 % CI 0.58-0.98 and 0.58-0.98 for surgical and non-surgical reasons). The matched analysis confirmed the risk reduction with dutasteride for BPH-related surgery. CONCLUSIONS: These findings suggest that the clinical effects of dutasteride and finasteride might be different. Patients treated with dutasteride seem to be less likely to experience BPH-related hospitalization. Comparative studies are needed to confirm these results.

Temporal trends of the gaps in post-myocardial infarction secondary prevention strategies of co-morbid and elderly populations vs. younger counterparts: an analysis of three successive cohorts between 2003 and 2008.

Aims Epidemiological studies reported two contrasting trends: on one hand, a significant improvement in the use of evidence-based treatments of patients discharged with a myocardial infarction (MI). On the other hand, the increasing number of elderly and co-morbid patients who are usually less treated. The aim of this study is to examine whether improvements in the treatment of MI are homogeneously distributed throughout all subgroups of patients. Methods and results Based on record linkage of administrative registers, 21 423 patients discharged with MI in three different periods (2003, 2005, and 2007), were identified and followed up for major clinical events up to 1 year. Using as a reference temporal category those patients discharged in 2003 (odds ratios, 95% confidence intervals) and as a demographic category male patients aged ≤75 years (1.00), the study identified: in-hospital mortality significantly decreased in all periods and in all groups of patients; out-of-hospital mortality decreased only in younger patients and not in older patients; prescription of evidence-based treatments increased in all periods for all patients; however, the magnitude of improvement was mostly concentrated in younger patients. Conclusion Although there was a mean improvement in the treatment and outcome of patients discharged from an MI, most of these benefits were strongly concentrated in younger, healthier patients. Old and co-morbid populations-although representing a substantial proportion of the burden of disease-received significant less attention and barely improved their survival.

Clinical effects and economical impact of dutasteride and finasteride therapy in Italian men with LUTS.

OBJECTIVES: To investigate differences in the risk of benign prostatic hyperplasia (BPH)- related hospitalization, for surgical and non-surgical reasons, and of new prostate cancer (PCa) diagnosis between patients under dutasteride or finasteride treatment. MATERIAL AND METHODS: A retrospective cohort study was conducted using data from record-linkage of administrative databases. Men aged ≥ 40 years old who had received a prescription for at least 10 boxes/year (index years: 2004-06) were included. The association of the outcomes was assessed using a multiple Cox proportional hazard model. Propensity score matched analysis and a 5-to-1, greedy 1:1 matching algorithm were performed. The budget impact analysis of dutasteride vs finasteride in BPH-treated patient was performed. RESULTS: From an initial cohort of about 1.5 million of Italian men, 19620 were selected. The overall hospitalization for BPH-non surgical reasons, for BPH-related surgery and for new detection of PCa incidence rates (IRs) were 8.20 (95% CI, 7.62-8.23), 18.0 (95% CI, 17.12-18.93) and 8.62 (95% CI, 8.03-9.26) per 1000 person-years, respectively. The multivariate analysis after the propensity score-matching showed that dutasteride was associated with an independent reduced likelihood of hospitalization for BPH-related surgery (HR 0.82; 95% CI 0.73-0.93; p = 0.0025) and of newly detected PCa (HR: 0.76,95% CI, 0.65-0.85; p = 0.0116). The IR for BPH-non surgical reasons was 8.07 (95% CI, 7.10-9.17) and 9.25 (95% CI, 8.19-10.44) per 1000 person-years, respectively. The IR for BPH-related surgery was 18.28 (95% CI, 17.17-20.32) and 21.28 (95% CI, 19.24-23.06) per 1000 person-years among patients under dutasteride compared with those under finasteride, respectively. For new-onset PCa, the IR was 8.01 (95% CI, 7.07-9.08) and 9.38 (95% CI, 8.32-10.58) per 1000 person-years The pharmacoeconomical evaluation showed that the net budget impact of the use of dutasteride vs. finasteride in 1000 BPH-treated patient for 1 year induces a saving of 3933 €. CONCLUSIONS: The clinical effects of dutasteride and finasteride are slightly different. The likelihood of hospitalization for BPH-related surgery and of newly detected PCa seems to be in favor of dutasteride. The budget impact analyses showed a slightly benefit for dutasteride. Comparative prospective studies are necessary to confirm these results.

[ProMoFIA_Oncologic: monitoring project of the innovative oncology drugs in Abruzzo]. / ProMoFIA_Oncologici: Progetto di Monitoraggio dei Farmaci Oncologici Innovativi in Abruzzo.

INTRODUCTION: The unmet therapeutic needs lead to accelerated registration of new oncology drugs, even with incomplete information of the benefit-risk ratio. METHODS: In Italy the Onco-AIFA Register was established to monitor oncology drugs when used according to authorized indications and to assure their appropriate use in clinical practice. In the Abruzzo region, an observational longitudinal study (ProMoFIA_Oncologici) was performed to evaluate in standard clinical practice all patients treated with these new oncology drugs for any indication. RESULTS: During the period 2008-2011, 3435 patients were observed: in 62.2% of patients, the use of these drugs was eligible also for the Onco-AIFA Register; in 22.7% it was in-label but not monitored in the Onco-AIFA; in 15.1% the use was off-label. DISCUSSION: The study findings showed a widespread use of the new oncology drugs beyond the Onco-AIFA indications, as well as their off-label use.

Previous prescription of ß-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis.

OBJECTIVES: Results from basic science and narrative reviews suggest a potential role of ß-blockers in patients with sepsis. Although the hypothesis is physiologically appealing, it could be seen as clinically counterintuitive. We sought to assess whether patients previously prescribed chronic ß-blocker therapy had a different mortality rate than those who did not receive treatment. SETTING: Record linkage of administrative databases of Italian patients hospitalized for sepsis during years 2003-2008 were identified and followed up for all-cause mortality at 28 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 9,465 patients aged≥40 yrs who were hospitalized in critical care units for sepsis. Of these, 1,061 patients were on chronic prescription with ß-blockers and 8404 were not previously treated. Despite a higher risk profile, patients previously prescribed with ß-blockers had lower mortality at 28 days (188/1061 [17.7%]) than those previously untreated (1857/8404 [22.1%]) (odds ratio 0.78; 95% confidence interval 0.66-0.93; p=.005 for unadjusted analysis, and odds ratio 0.81; 95% confidence interval 0.68-0.97; p=.025 for adjusted analyses). Sensitivity and pair-matched results confirm the primary findings. CONCLUSIONS: As far as we are aware, this pharmacoepidemiologic assessment is the largest to examine the potential association of previous ß-blocker prescription and mortality in patients with sepsis. Chronic prescription of ß-blockers may confer a survival advantage to patients who subsequently develop sepsis with organ dysfunction and who are admitted to an intensive care unit. Prospective randomized clinical trials should formally test this hypothesis.

A plea for a more epidemiological and patient-oriented pharmacovigilance.

The present work has the main objective of summarizing the history of pharmacovigilance and the associated methods and legislation and of showing how it could/should be reformulated in terms of a transition from a drug-centered to a patient/population-centered approach. The recurrent emergencies associated with new drug molecules raise many questions about the efficacy and efficiency of methodological tools as well as the role of regulatory systems. Drugs cannot be considered as an independent variable: the evaluation of all their effects must take into account the real contexts in which they are used and which affect not only their efficacy but also their tolerability and safety. Specific emphasis is given to recent and promising developments focused on the participation of patients and populations as key actors in producing knowledge that could technically integrate what has been produced so far and allow the evolution of surveillance from a role of controlling severe adverse reactions attributable to individual molecules to one of promoting a comprehensive assessment of the benefit/risk profile of drugs as they are utilized in society.

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.

[Memorandum for the management of clinical trials]. / Pro-memoria per la gestione della sperimentazione clinica.

A critical appraisal of the recent legislation on clinical trials is proposed, together with some reflections on the implications on the practice and principles of clinical experimentation. The possible role and contribution of Ethical Committees is discussed.

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.

Antidepressants and cardiovascular outcomes in patients without known cardiovascular risk.

PURPOSE: To identify a cohort of subjects without treatment for any cardiovascular risk and analyze the potential causative role of treatment for depression on the development of major cardiovascular outcomes during 2 years of follow-up. METHODS: We carried out a record-linkage analysis of hospital discharge records, prescription databases and vital statistics for all consecutive patients aged 30 years or older in one Italian region during a 4-year period. Depression was defined in terms of exposure to at least three prescriptions of antidepressant drugs within 1 year. Patients had no history of treatment with cardiovascular or antidiabetic agents and had not been hospitalized with a diagnosis of any cardiovascular condition in the preceding year. Follow-up was extended up to 2 years or to time to occurrence of major outcomes defined as either all-cause mortality, hospitalization for any cardiovascular cause or chronic exposure to cardiovascular drugs (antihypertensive, statins, antidiabetics). The results are expressed hazard ratios (HRs) and 95% confidence intervals (CIs) within age categories (30-49, 50-59, > or = 60 years). RESULTS: A total of 105,573 persons without treated cardiovascular risk at baseline were identified, among whom 1,129 (1.1%) had been chronically exposed to antidepressant treatment. Treated depression determined an increased risk of all cause-mortality (HR 1.88, 95% CI 1.33-2.66, p < 0.001) and of subsequent treatment with antidiabetic agents (HR 0.89, 95% CI 1.34-2.66, p < 0.001), statins (HR 1.87, 95% CI 1.53-2.29, p < 0.001) and antihypertensive drugs (HR 1.25, 95% CI 1.07-1.47, p = 0.006). CONCLUSION: Among the general population without treated cardiovascular risk, pharmacologic treatment for depression was associated with an increase in all-cause mortality and major cardiovascular outcomes.

[The ECAD_O project: clinical caring epidemiology of pain in the hospital: the nurses' contribution]. / Il modello di sorveglianza ECAD_O-Epidemiologia Clinico-Assistenziale del Dolore in Ospedale: il contributo degli infermieri.

AIMS: ECAD_O is a project aimed to establish a surveillance of pain treatment--as part of routine care and as a hospital pharmacovigilance activity--with the following objectives: to assess in each participant ward prevalence of patients exposed to analgesics; to describe the pharmacological management schedules; to document the perception of health-care professionals on the effectiveness of treatment administered; to identify groups of patients whose pain is undertreated, through the activation of a collaborative protocol. METHODS: A multicentre (48 hospitals) and multidisciplinary (nurses, clinicians, pharmacists) cross-sectional survey was conducted in 6 index-days. Epidemiological, clinical and therapeutic data were collected and heath-care professionals (nurses or clinicians) were asked about their perception on the effectiveness of treatment administered and the reasons of non-effectiveness. RESULTS: In the 164 participant wards (61 surgery, 46 medicine, 28 oncology, 22 orthopaedics, 7 other) 3854 patients (20.9% of inpatients) were exposed to analgesics. The majority of patients (84.3%) received analgesics around-the-clock. Opioid analgesics were administered around-the-clock (64.7%; 2103/3250) as well as only as needed (27.1%; 164/604). According to health-care professionals, analgesic therapy administered was not effective in 516 patients (13.4% of sample). Inspite of this evaluation, 288 patients did not receive rescue therapy, because it was not prescribed (180 patients) or not administered even if prescribed (108 patients). CONCLUSIONS: The establishment of a surveillance scheme which could be adopted in the routine conditions of care to monitor the quality of pain control has been successfully tested on the basis of multidisciplinary teams where the nurse personnel plays a key role.

Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial.

BACKGROUND: Strongyloides stercoralis infection is a neglected condition that places people who are immunocompromised at risk of hyperinfection and death. Ivermectin is the drug of choice for the treatment of S stercoralis infection, but there is no definitive evidence on the optimal dose. This trial aimed to assess whether multiple doses of ivermectin were superior to a single dose for the treatment of non-disseminated strongyloidiasis. METHODS: Our study was designed as a multicentre, open-label, phase 3, randomised controlled superiority trial. Participants were enrolled in four centres in Italy, three in Spain, and two in the UK, and recruiting sites were predominantly hospitals. Eligible patients were older than 5 years, weighed more than 15 kg, were residents in an area not endemic for S stercoralis, and either were positive for S stercoralis in faecal tests and on serology (any titre) or had a positive serological test with high titres, irrespective of the result of faecal tests. Patients were randomly assigned (1:1) using a computer-generated, blinded allocation sequence (with randomly mixed block sizes of six, eight, and ten participants) to receive either one dose of ivermectin 200 µg/kg or four doses of ivermectin 200 µg/kg (given on days 1, 2, 15, and 16). The primary endpoint was the proportion of participants with clearance of S stercoralis infection at 12 months, which was assessed in all randomly assigned participants who were not lost to follow-up (modified full-analysis set) and in participants in the modified full-analysis set who did not deviate from the assigned treatment regimen (per-protocol set). All participants were included in the safety analysis. The trial was registered with ClinicalTrials.gov, NCT01570504, and is now closed for recruitment. FINDINGS: Of the 351 patients assessed for eligibility, 309 recruited between March 26, 2013, and May 3, 2017, were randomly assigned to one dose (n=155) or four doses (n=154) of ivermectin. At 12 months in the modified full-analysis set, 86% (95% CI 79 to 91; 102 of 118 participants) had responded to treatment in the single-dose group compared with 85% (77 to 90; 96 of 113 participants) in the four-dose group (risk difference 1·48%, 95% CI -7·55 to 10·52; p=0·75); similar results were observed in the per-protocol set. Adverse events were generally of mild intensity and more frequent in the multiple-dose than in the single-dose group. The trial was terminated early due to futility. INTERPRETATION: Multiple doses of ivermectin did not show higher efficacy and was tolerated less than a single dose. A single dose should therefore be preferred for the treatment of non-disseminated strongyloidiasis. FUNDING: There was no funding source for this study.

Depression worsens outcomes in elderly patients with heart failure: an analysis of 48,117 patients in a community setting.

AIMS: To assess the relationship between depression and clinical outcomes among elderly patients with heart failure (HF) in a community setting. METHODS AND RESULTS: To identify patients with HF and depression we used record linkage analysis of hospital discharge records, prescription databases and vital statistics. All consecutive patients aged>or=60 years in 6 Local Health Authorities in Italy were included. HF was defined as either: 1) hospital discharge with HF diagnosis (ICD-9: 428) and/or 2) chronic treatment for HF identified as concomitant (within 45 days) prescription of any combination of ACE inhibitors, digoxin, furosemide, bisoprolol, carvedilol, spironolactone, ARB-blockers. Depression was identified from exposure to psychotropic drugs before HF diagnosis. Cox proportional hazards models adjusted for major confounders were used. To adjust for potential residual known confounders, a propensity score analysis was performed. Sensitivity and subgroup analysis were used to demonstrate the consistency or robustness of the results. 48,117 patients with HF were identified. Of these, 3328 (6.9%) were treated for depression. Among patients with HF, those with depression were significantly older, and more likely to be women with a previous stroke. Depression significantly worsened major outcomes including all cause mortality [HR (95%CI); 1.20 (1.08-1.33)] and the composite of stroke/TIA/AMI [1.23 (1.13-1.34)]. Patients with depression had no increased risk of rehospitalisation for HF. Propensity scores and subgroup analysis confirmed these findings. CONCLUSION: Among elderly patients with HF, depression was independently associated with poor clinical outcomes mostly due to an increase in vascular events.

Persistence of Central Venous Oxygen Desaturation During Early Sepsis Is Associated With Higher Mortality: A Retrospective Analysis of the ALBIOS Trial.

BACKGROUND: Relevance of low (< 70%) central venous oxygen saturation (Scvo2) during early sepsis has been recently questioned by three negative trials (Protocol-Based Care for Early Septic Shock, Australasian Resuscitation in Sepsis Evaluation, and Protocolized Management in Sepsis) on early goal-directed therapy; however, subjects included in those trials had Scvo2 at enrollment as high as 71 ± 13%, 73 ± 11%, and 70 ± 12%. Here we assess the association between Scvo2 < 70% at 6 h and 90-day mortality in subjects enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial, focusing on those with initial Scvo2 < 70%. METHODS: Regardless of treatment assignment (to receive albumin or not), all subjects enrolled in the ALBIOS trial received early goal-directed therapy aiming for Scvo2 ≥ 70% at 6 h. Using multivariable logistic regression analyses, we tested the association between Scvo2 < 70% at 6 h and 90-day mortality in those with initial Scvo2 < 70% (n = 514) or ≥ 70% (n = 961). RESULTS: Scvo2 < 70% at 6 h was independently associated with higher 90-day mortality in subjects with initial Scvo2 < 70% (OR, 1.84; 95% CI, 1.19-2.85; P = .007) but not in those with initial Scvo2 ≥ 70% (OR, 1.25; 95% CI, 0.79-1.95; P = .357). Scvo2 < 70% at enrollment and at 6 h was associated with history and/or signs of cardiac dysfunction but not with greater severity of disease or more aggressive resuscitation (required per protocol). CONCLUSIONS: In the ALBIOS trial, persistence of low Scvo2 was associated with higher 90-day mortality, possibly because it reflected underlying cardiac dysfunction. Subjects with Scvo2 < 70% may benefit most from individually tailored interventions aimed at normalizing the balance between systemic oxygen delivery and consumption. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00707122; URL: www.clinicaltrials.gov.