Safety and immunogenicity of a 4-component GMMA-based Shigella vaccine in healthy European adults: Stage 1 of a randomized, controlled phase I/II clinical trial.

BACKGROUND: We report data from Stage 1 of an ongoing two-staged, phase I/II randomized clinical trial (NCT05073003) with a 4-component Generalized Modules for Membrane Antigens-based vaccine against Shigella sonnei and S. flexneri 1b, 2a and 3a (altSonflex1-2-3, GSK). METHODS: 18-50-year-old Europeans (N=102) were randomized (2:1) to receive two injections of altSonflex1-2-3 or placebo at 3- or 6-month interval. Safety and immunogenicity were assessed at pre-specified timepoints. RESULTS: The most common solicited administration-site event (until 7 days post-each injection) and unsolicited adverse event (until 28 days post-each injection) were pain (altSonflex1-2-3: 97.1%; Placebo: 58.8%) and headache (32.4%; 23.5%), respectively. All serotype-specific functional IgG antibodies peaked 14-28 days post-injection 1 and remained substantially higher than pre-vaccination at 3 or 6 months post-vaccination; the second injection did not boost but restored the initial immune response. The highest seroresponse rates (≥4-fold increase in titers over baseline) were obtained against S. flexneri 2a (ELISA: post-injection 1: 91.0%; post-injection 2 [Day {D}113; D197]: 100%; 97.0%; serum bactericidal activity (SBA): post-injection 1: 94.4%; post-injection 2: 85.7%; 88.9%) followed by S. sonnei (ELISA: post-injection 1: 77.6%; post-injection 2: 84.6%; 78.8%; SBA: post-injection 1: 83.3%; post-injection 2: 71.4%; 88.9%). Immune responses against S. flexneri 1b and S. flexneri 3a, as measured by both ELISA and SBA, were numerically lower compared to those against S. sonnei and S. flexneri 2a. CONCLUSIONS: No safety signals or concerns were identified. altSonflex1-2-3 induced functional serotype-specific immune responses, allowing further clinical development in the target population.

What is the context? Shigella bacteria cause severe and often bloody diarrhea, called shigellosis, that affects mostly young children and can be life-threatening. Shigellosis is particularly common in low- and middle-income countries due to inadequate sanitation and limited access to healthcare. Since the immune response to Shigella is serotype-specific, an ideal vaccine should include multiple Shigella serotypes to ensure broad protection. What is new? We developed a novel vaccine against Shigella that includes Shigella sonnei and three prevalent Shigella flexneri serotypes. In Stage 1 (phase I) of the study, healthy European adults received two vaccine injections given 3 or 6 months apart. We found that: The vaccine was well tolerated, and no safety signals or concerns were identified.Regardless of the interval between injections, specific antibodies were elicited against all four Shigella serotypes, with highest levels against Shigella flexneri 2a and Shigella sonnei.Functional antibody levels peaked after the first injection, remaining higher than the baseline up to 6 months. A second injection did not boost responses but restored functional antibody levels to those after the first injection. What is the impact? The vaccine can now be tested in Stage 2 (phase II) of the study in Africa, a region highly affected by shigellosis.

Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.

Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4ß7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.

Age-dependent acquisition of IgG antibodies to Shigella serotypes-a retrospective analysis of seroprevalence in Kenyan children with implications for infant vaccination.

Background: Shigellosis mainly affects children under 5 years of age living in low- and middle-income countries, who are the target population for vaccination. There are, however, limited data available to define the appropriate timing for vaccine administration in this age group. Information on antibody responses following natural infection, proxy for exposure, could help guide vaccination strategies. Methods: We undertook a retrospective analysis of antibodies to five of the most prevalent Shigella serotypes among children aged <5 years in Kenya. Serum samples from a cross-sectional serosurvey in three Kenyan sites (Nairobi, Siaya, and Kilifi) were analyzed by standardized ELISA to measure IgG against Shigella sonnei and Shigella flexneri 1b, 2a, 3a, and 6. We identified factors associated with seropositivity to each Shigella serotype, including seropositivity to other Shigella serotypes. Results: A total of 474 samples, one for each participant, were analyzed: Nairobi (n = 169), Siaya (n = 185), and Kilifi (n = 120). The median age of the participants was 13.4 months (IQR 7.0-35.6), and the male:female ratio was 1:1. Geometric mean concentrations (GMCs) for each serotype increased with age, mostly in the second year of life. The overall seroprevalence of IgG antibodies increased with age except for S. flexneri 6 which was high across all age subgroups. In the second year of life, there was a statistically significant increase of antibody GMCs against all five serotypes (p = 0.01-0.0001) and a significant increase of seroprevalence for S. flexneri 2a (p = 0.006), S. flexneri 3a (p = 0.006), and S. sonnei (p = 0.05) compared with the second part of the first year of life. Among all possible pairwise comparisons of antibody seropositivity, there was a significant association between S. flexneri 1b and 2a (OR = 6.75, 95% CI 3-14, p < 0.001) and between S. flexneri 1b and 3a (OR = 23.85, 95% CI 11-54, p < 0.001). Conclusion: Children living in low- and middle-income settings such as Kenya are exposed to Shigella infection starting from the first year of life and acquire serotype-specific antibodies against multiple serotypes. The data from this study suggest that Shigella vaccination should be targeted to infants, ideally at 6 or at least 9 months of age, to ensure children are protected in the second year of life when exposure significantly increases.

Complement-mediated serum bactericidal activity of antibodies elicited by the Shigella sonnei GMMA vaccine in adults from a shigellosis-endemic country: Exploratory analysis of a Phase 2a randomized study.

Shigella is associated with a significant burden of disease worldwide among individuals of all ages and is the major cause of moderate and severe diarrhea in children under five years of age in low- and middle-income countries. Several candidate vaccines against Shigella species are currently under clinical development. The investigational 1790GAHB vaccine against Shigella sonnei is based on GMMA (Generalized Modules for Membrane Antigens) technology. The vaccine was well tolerated and induced high antibody levels in early-phase clinical trials in both Shigella-endemic and non-endemic settings. The present analysis assessed the bactericidal activity of antibodies induced by 1790GAHB in healthy Kenyan adults during a phase 2a, controlled, randomized study (NCT02676895). Participants received two doses of 1790GAHB 4 weeks apart containing either 1.5/25 µg or 6/100 µg O antigen/protein, or active comparator vaccines (Control). Serum bactericidal activity (SBA) against S. sonnei was assessed at pre-vaccination (D1), 28 days post-first dose (D29) and 28 days post-second dose (D57), using a luminescence-based assay. Most participants had SBA titers above the lower limit of quantification of the assay at D1. SBA geometric mean titers increased 3.4-fold in the 1.5/25 µg group and 6.3-fold in the 6/100 µg group by D29 and were maintained at D57. There was no increase in SBA geometric mean titers in the Control group. A strong correlation was observed between SBA titers and anti-S. sonnei lipopolysaccharide serum immunoglobulin G antibody concentrations (Pearson correlation coefficient = 0.918), indicating that SBA can effectively complement enzyme-linked immunosorbent assay data by indicating the functionality of 1790GAHB-induced antibodies.

GMMA Technology for the Development of Safe Vaccines: Meta-Analysis of Individual Patient Data to Assess the Safety Profile of Shigella sonnei 1790GAHB Vaccine in Healthy Adults, with Special Focus on Neutropenia.

INTRODUCTION: Shigellosis is a major health concern among children < 5 years of age from developing countries, and there are no widely available vaccines to prevent it. The GMMA-based 1790GAHB investigational vaccine against Shigella sonnei was well tolerated and immunogenic in phase 1 and 2 studies conducted in healthy adults from Shigella endemic and non-endemic populations. Based on pooled data of five individual trials, we assessed the association between vaccine administration and the risk of neutropenia as well as the overall safety profile of 1790GAHB. METHODS: The risk ratio (RR) of neutropenia was evaluated between participants receiving 1790GAHB (vaccinees) and active comparator/placebo (controls) using different ethnicity-specific absolute neutrophil count (ANC) thresholds established to define neutropenia. Safety was assessed in terms of solicited, unsolicited, and serious adverse events (AEs). RESULTS: Of the 279 participants, 11 (5.5%) vaccinees and 4 (5.0%) controls had ANC below the appropriate threshold within 7 days post-vaccination. RR was 0.96 [95% confidence interval (CI) 0.54-1.70]. When neutrophil counts of participants of African descent were measured against an ethnicity non-specific threshold, they resulted in neutropenia episodes in 30 (37.0%) vaccinees and 16 (30.2%) controls, while only 2 (2.5%) vaccinees and 1 (1.9%) control had neutropenia when the ethnicity-specific threshold was applied. RRs were 0.98 (95% CI 0.75-1.28) and 1.30 (95% CI 0.1-17.6), respectively. Solicited and unsolicited AEs were slightly more frequent among vaccinees than controls. No serious AEs, other than neutropenia cases, were recorded in the vaccine group. CONCLUSION: By applying the appropriate threshold, no increased risk of neutropenia was identified in vaccinees compared with the controls. The frequency of neutropenia events varied drastically when ethnicity-appropriate thresholds were applied. This observation highlights the importance of selecting appropriate cut-off values according to the correct population reference. Overall, the 1790GAHB vaccine demonstrated an acceptable safety profile.

The Pitfalls of Abnormal Laboratory Value Interpretation in Vaccine Clinical Trials: The Example of Asymptomatic Transient Neutropenia.

Hematological and clinical chemistry measurements are an integral part of vaccine safety monitoring. While adopting a conservative approach is important to exclude potential risks for patients, the rationale and methodology underlying the assessment of given adverse events have to be well grounded to avoid raising unfounded concerns. Using asymptomatic transient neutropenia as an example, this paper aims to address the complexity of interpreting abnormal hematological values in vaccine clinical trials and to evaluate the validity of using neutrophil count cut-off points to assess neutropenia in the context of safety monitoring. The validity of the neutrophil count cut-off point methodology was assessed in terms of content validity (i.e., the extent to which a single neutrophil count below the cut-off point corresponds to a clinically significant adverse event), criterion validity (i.e., the extent to which a neutrophil count below a given cut-off point correlates with another manifestation of neutropenia, namely bacteremia), and construct validity (i.e., the exactness of the assumption that a neutrophil count below a given cut-off point corresponds to a reactogenic event caused by the vaccination). We argue that, because of within-individual physiological fluctuations, variations according to population demographics, and poor predictive potential with regard to neutropenia-associated infection, the application of the cut-off point methodology to neutropenia safety monitoring presents major limitations. Based on this assessment, we conclude that hematological laboratory values must be evaluated on a case-by-case basis by investigators to determine their clinical significance.

Efficacy, safety, and immunogenicity of the Shigella sonnei 1790GAHB GMMA candidate vaccine: Results from a phase 2b randomized, placebo-controlled challenge study in adults.

BACKGROUND: Shigellosis accounts for substantial morbidity and mortality worldwide and is the second most common cause of moderate and severe diarrhoea in children. METHODS: This phase 2b study (NCT03527173), conducted between August 2018 and November 2019, evaluated vaccine efficacy (VE), safety, and immunogenicity of a Shigella sonnei GMMA candidate vaccine (1790GAHB) in adults, using a S. sonnei 53 G controlled human infection model. Participants (randomized 1:1) received two doses of 1790GAHB or placebo (GAHB-Placebo), at day (D) 1 and D29, and an oral challenge of S. sonnei 53 G at D57. VE was evaluated using several endpoints, reflecting different case definitions of shigellosis. For the primary endpoint, the success criterion was a lower limit of the 90% confidence interval >0. FINDINGS: Thirty-six and 35 participants received 1790GAHB or placebo, respectively; 33 and 29 were challenged, 15 and 12 developed shigellosis. VE was not demonstrated for any endpoint. Adverse events were more frequent in 1790GAHB versus placebo recipients post-vaccination. Anti-S. sonnei lipopolysaccharide (LPS) IgG responses increased at D29 and remained stable through D57 in group 1790GAHB; no increase was shown in placebo recipients. INTERPRETATION: 1790GAHB had an acceptable safety profile and induced anti-LPS IgG responses but did not demonstrate clinical efficacy against shigellosis. Baseline/pre-challenge antibody levels were higher in participants who did not develop shigellosis post-challenge, suggesting a role of anti-LPS IgG antibodies in clinical protection, although not fully elucidated in this study. For further vaccine development an increased S. sonnei O-antigen content is likely needed to enhance anti-LPS immune responses. FUNDING: GlaxoSmithKline Biologicals SA, Bill and Melinda Gates Foundation.

Antibodies Elicited by the Shigella sonnei GMMA Vaccine in Adults Trigger Complement-Mediated Serum Bactericidal Activity: Results From a Phase 1 Dose Escalation Trial Followed by a Booster Extension.

Shigella is the second most deadly diarrheal disease among children under five years of age, after rotavirus, with high morbidity and mortality in developing countries. Currently, no vaccine is widely available, and the increasing levels of multidrug resistance make Shigella a high priority for vaccine development. The single-component candidate vaccine against Shigella sonnei (1790GAHB), developed using the GMMA technology, contains the O antigen (OAg) portion of lipopolysaccharide (LPS) as active moiety. The vaccine was well tolerated and immunogenic in early-phase clinical trials. In a phase 1 placebo-controlled dose escalation trial in France (NCT02017899), three doses of five different vaccine formulations (0.06/1, 0.3/5, 1.5/25, 3/50, 6/100 µg of OAg/protein) were administered to healthy adults. In the phase 1 extension trial (NCT03089879), conducted 2-3 years following the parent study, primed individuals who had undetectable antibody levels before the primary series received a 1790GAHB booster dose (1.5/25 µg OAg/protein). Controls were unprimed participants immunized with one 1790GAHB dose. The current analysis assessed the functionality of sera collected from both studies using a high-throughput luminescence-based serum bactericidal activity (SBA) assay optimized for testing human sera. Antibodies with complement-mediated bactericidal activity were detected in vaccinees but not in placebo recipients. SBA titers increased with OAg dose, with a persistent response up to six months after the primary vaccination with at least 1.5/25 µg of OAg/protein. The booster dose induced a strong increase of SBA titers in most primed participants. Correlation between SBA titers and anti-S. sonnei LPS serum immunoglobulin G levels was observed. Results suggest that GMMA is a promising OAg delivery system for the generation of functional antibody responses and persistent immunological memory.

One-year follow up of asthmatic patients newly initiated on treatment with medium- or high-dose inhaled corticosteroid-long-acting ß2-agonist in UK primary care settings.

INTRODUCTION: Global Initiative for Asthma (GINA) recommends medium- or high-dose inhaled corticosteroid-long-acting ß2-agonist (ICS-LABA) as preferred treatments for patients with moderate-to-severe asthma. Limited data is available on how step 4/5 patients respond to ICS-LABA and how they step up/down in clinical practice. METHODS: This retrospective cohort study assessed the characteristics, control status, treatment pathways, and healthcare resource utilization in patients with asthma during one year after initiating medium- or high-dose ICS-LABA. Data from the United Kingdom Clinical Practice Research Datalink were analysed between January 01, 2006 and February 28, 2016. RESULTS: Overall, 29,229 and 16,575 patients initiated medium- and high-dose ICS-LABA, and 35.1% and 45.7% of patients, respectively, remained uncontrolled. The proportions of patients who were adherent to treatment (Medication Possession Ratio ≥80%) were 37.8% and 49.1% in the medium- and high-dose ICS-LABA cohorts, respectively. Among these adherent patients, 63.8% in the medium- and 70% in the high-dose cohorts remained uncontrolled. In patients who stepped up therapy in the medium-dose cohort (19.0%), the common step-up choices were add-on leukotriene receptor antagonist (LTRA) (42.2%), long-acting muscarinic antagonist (LAMA) (23.3%), and increase in ICS dose (22.9%). In patients who stepped up therapy in the high-dose cohort (26.1%), the common step-up choices were add-on LAMA (43.8%) and LTRA (42.1%). Healthcare resource utilization was higher in uncontrolled patients, regardless of the ICS-LABA dose. CONCLUSIONS: Many patients remain uncontrolled on both medium- or high-dose ICS-LABA, highlighting the need for timely assessment of asthma control to increase treatment intensity, following evidence-based treatment pathways.

Differences in COPD Exacerbation Risk Between Women and Men: Analysis From the UK Clinical Practice Research Datalink Data.

BACKGROUND: Historically, COPD has been considered to affect mostly older men with a history of smoking; however, in recent times, its prevalence and mortality rates have steadily increased among women. OBJECTIVES: The goal of this study was to systematically assess differences in COPD expression between women and men in UK primary care clinics who were newly diagnosed with COPD. METHODS: This retrospective cohort study compared women and men with an incident diagnosis of COPD by using electronic medical records data from the Clinical Practice Research Datalink and linked Hospital Episode Statistics data. The overall study period was between January 1, 2006, and February 28, 2016; patients with an incident diagnosis of COPD between January 1, 2010, and February 28, 2015, were analyzed. RESULTS: A cohort of 22,429 patients were identified as incident patients and included in the study; 48% of patients with COPD were women. The risk of first moderate or severe exacerbation was 17% greater in women than in men (hazard ratio, 1.17; 95% CI, 1.12-1.23), with a median time to first exacerbation of 504 days for women and 637 days for men. These differences were more prominent in the younger age group (≥ 40 years to < 65 years), as well as in Global Initiative for Chronic Obstructive Lung Disease 2016 groups B, C, and D and in individuals with moderate to severe airflow obstruction. The annual rate of moderate or severe exacerbations was higher in women compared with men in the first, second, and third year of follow-up. CONCLUSIONS: These results highlight the unmet need for appropriate identification and management of women with COPD in clinical practice.

Booster Vaccination With GVGH Shigella sonnei 1790GAHB GMMA Vaccine Compared to Single Vaccination in Unvaccinated Healthy European Adults: Results From a Phase 1 Clinical Trial.

The investigational Shigella sonnei vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti-S. sonnei lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2-3 years earlier (boosted group), compared to one dose in 28 vaccine-naïve individuals (vaccine-naïve group). Anti-S. sonnei LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day [D]1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naïve group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naïve groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naïve group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naïve participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naïve individuals. Vaccination was well tolerated.

Adherence to tobramycin inhaled powder vs inhaled solution in patients with cystic fibrosis: analysis of US insurance claims data.

PURPOSE: Tobramycin inhalation powder (TIP), the first dry-powder inhaled antibiotic for pulmonary Pseudomonas aeruginosa infection, is associated with reduced treatment burden, increased patient satisfaction, and higher self-reported adherence for cystic fibrosis (CF) patients. We compared adherence in CF patients newly treated with TIP with those newly treated with the traditional tobramycin inhalation solution (TIS), using US insurance claims data. PATIENTS AND METHODS: From the Truven MarketScan® database, we identified CF patients chronically infected with P. aeruginosa who had been prescribed TIP between May 1, 2013 to December 31, 2014, or TIS between September 1, 2010 to April 30, 2012 with at least 12 months of continuous medical and pharmacy benefits prior to and following prescription. TIP and TIS adherence levels were assessed. RESULTS: A total of 145 eligible patients were identified for the TIP cohort and 306 for the TIS cohort. Significant differences in age distribution (25.0 vs 21.9 years for TIP vs TIS, respectively, P=0.017), type of health plan (P=0.014), employment status (72.4% vs 63.4% of TIP vs TIS patients in full-time employment, P=0.008), and some comorbidities were observed between the two cohorts. Although a univariate analysis found no significant differences between TIP and TIS (odds ratio [OR] 1.411, 95% confidence interval [CI] 0.949-2.098), TIP was moderately associated with higher adherence levels compared with TIS in a multivariable analysis, once various demographic and clinical characteristics were adjusted for. These included geographic location (OR: 1.566, CI: 1.016-2.413) and certain comorbidities. CONCLUSION: This study of US patient data supports previous findings that TIP is associated with better adherence compared with TIS; however, further studies will be required to fully elucidate differences in adherence between TIP and TIS.

Cardiovascular safety of tiotropium Respimat vs HandiHaler in the routine clinical practice: A population-based cohort study.

The cardiovascular safety of tiotropium Respimat formulation in the routine clinical practice is still an open issue. Our aim was to compare the risk of acute myocardial infarction and heart rhythm disorders in incident users of either tiotropium Respimat or HandiHaler. The study population comprises patients aged ≥45 years, resident in two Italian regions with a first prescription of tiotropium (HandiHaler or Respimat) between 01/07/2011-30/11/2013. The cohort was identified through the database of prescriptions reimbursed by the Italian National Health Service. Comorbidities and clinical outcomes were obtained from hospital records. The primary outcome was the first hospitalization for acute myocardial infarction and/or for heart rhythm disorders during the exposure period. Hazard ratios were estimated in the propensity score-matched groups through Cox regression. After matching, 31,334 patients with incident prescription of tiotropium were included. The two groups were balanced with regard to baseline characteristics. Similar incidence rates of the primary outcome between Respimat and HandiHaler users were identified (adjusted hazard ratio 1.02, 95% CI 0.82-1.28). No risk difference between Respimat and HandiHaler emerged when considering clinical events separately. This large cohort study showed a comparable acute cardiovascular safety profile of the two tiotropium formulations.

Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions.

AIM: Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. METHODS: Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant. RESULTS: We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. CONCLUSIONS: As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred.

Paroxysmal Sympathetic Hyperactivity in Pediatric Rehabilitation: Pathological Features and Scheduled Pharmacological Therapies.

OBJECTIVE: Information on course and treatment of paroxysmal sympathetic hyperactivity (PSH) during rehabilitation and in pediatric patients is lacking. To increase knowledge on the course and treatment of PSH in pediatric patients during rehabilitation, we retrospectively analyzed 23 pediatric patients with PSH, describing the course of PSH and administered drugs, and explored the association of PSH remission with drug doses. SETTING: Neurorehabilitation unit of IRCCS Eugenio Medea, Bosisio Parini (LC), Italy. PARTICIPANTS: Twenty-three pediatric patients with postacute acquired brain injury, who remitted from PSH. DESIGN: Retrospective cohort study. MAIN MEASURES: Description of features and course of PSH, description of drug therapies, and analysis of covariance of their doses. Correlations between remission and drug doses/clinical variables. Estimation of the odds ratios of remission. RESULTS: At admittance patients displayed at least 3 features of PSH with an overall score of 9, which diminished progressively during remission. Therapies with propranolol, baclofen, niaprazine, and diazepam were progressively uptitrated, indicating potential usefulness. When testing possible predictors of remission, we found positive effects of propranolol and diazepam and of traumatic etiology and a negative effect of maximum PSH severity. CONCLUSIONS: Results should be interpreted carefully regarding causal relationships and drug doses and combinations, but they encourage further studies on the use of propranolol and diazepam to favor PSH remission.

Acute renal failure in patients treated with dronedarone or amiodarone: a large population-based cohort study in Italy.

PURPOSE: Causes of ARF are numerous including drugs. In 2012, spontaneous reporting showed a possible association between dronedarone and ARF. To further investigate such association, a retrospective cohort study on health-service claim databases was performed taking amiodarone as comparison. METHODS: All patients receiving new prescription of amiodarone or dronedarone between September 2010 and December 2012 were selected. Cox regression models to estimate the hazard ratios (HRs), with 95 % confidence intervals (CIs), for dronedarone versus amiodarone were performed. HRs were calculated: (i) for the entire cohort; (ii) for matched cohorts using propensity score; (iii) and high-dimensional propensity score. RESULTS: New users without previous episodes of ARF were 56,739 and 1761 on dronedarone and 54,978 on amiodarone. After 1:1 matching for propensity score, new users with dronedarone and amiodarone were 1467 and 1467, respectively. The cumulative incidence rate of ARF was 1.6 % (95 % CI 0.7-3.6 %) among dronedarone group and 2.3 % (1.0-5.1 %) among amiodarone group (p from log rank test = 0.4884). The unadjusted HR of ARF was 0.34 (0.18-0.64) in dronedarone new users compared to amiodarone; in propensity score matched cohort, it was 0.75 (0.26-2.16), and in high-dimensional propensity score, it was 0.83 (0.25-2.73). CONCLUSIONS: This large community-based study did not confirm the signal of an increased nephrotoxicity from dronedarone compared to amiodarone. Nevertheless, given the increasing number of reports collected from pharmacovigilance databases worldwide on this association, it is advisable for clinicians and patients to be aware of the possible kidney damage due to dronedarone in order to improve clinical outcomes with early intervention.

Antipsychotic drug exposure and risk of pulmonary embolism: a population-based, nested case-control study.

BACKGROUND: Only three observational studies investigated whether exposure to antipsychotics is associated with an increased risk of pulmonary embolism, with conflicting results. This study was therefore carried out to establish the risk of pulmonary embolism associated with antipsychotic drugs, and to ascertain the risk associated with first- and second-generation antipsychotic drugs, and with exposure to individual drugs. METHODS: We identified 84,253 adult individuals who began antipsychotic treatment in a large Italian health care system. Cases were all cohort members who were hospitalized for non-fatal or fatal pulmonary embolism during follow-up. Up to 20 controls for each case were extracted from the study cohort using incidence density sampling and matched by age at cohort entry and gender. Each individual was classified as current, recent or past antipsychotic user. The occurrence non-fatal or fatal pulmonary embolism was the outcome of interest. RESULTS: Compared to past use, current antipsychotic use more than double the risk of pulmonary embolism (odds ratio 2.31, 95% confidence interval 1.16 to 4.59), while recent use did not increase the risk. Both conventional and atypical antipsychotic exposure was associated with an increase in risk, and the concomitant use of both classes increased the risk of four times (odds ratio 4.21, 95% confidence interval 1.53 to 11.59). CONCLUSIONS: Adding the results of this case-control study to a recent meta-analysis of three observational studies substantially changed the overall estimate, which now indicates that antipsychotic exposure significantly increases the risk of pulmonary embolism.