Search

Summary Background Myocardial injury after non-cardiac surgery (MINS) increases the risk of cardiovascular events and deaths, which anticoagulation therapy could prevent. Dabigatran prevents perioperative venous thromboembolism, but whether this drug can prevent a broader range of vascular complications in patients with MINS is unknown. The MANAGE trial assessed the potential of dabigatran to prevent major vascular complications among such patients. Methods In this international, randomised, placebo-controlled trial, we recruited patients from 84 hospitals in 19 countries. Eligible patients were aged at least 45 years, had undergone non-cardiac surgery, and were within 35 days of MINS. Patients were randomly assigned (1:1) to receive dabigatran 110 mg orally twice daily or matched placebo for a maximum of 2 years or until termination of the trial and, using a partial 2-by-2 factorial design, patients not taking a proton-pump inhibitor were also randomly assigned (1:1) to omeprazole 20 mg once daily, for which results will be reported elsewhere, or matched placebo to measure its effect on major upper gastrointestinal complications. Research personnel randomised patients through a central 24 h computerised randomisation system using block randomisation, stratified by centre. Patients, health-care providers, data collectors, and outcome adjudicators were masked to treatment allocation. The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding. Analyses were done according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT01661101. Findings Between Jan 10, 2013, and July 17, 2017, we randomly assigned 1754 patients to receive dabigatran (n=877) or placebo (n=877); 556 patients were also randomised in the omeprazole partial factorial component. Study drug was permanently discontinued in 401 (46%) of 877 patients allocated to dabigatran and 380 (43%) of 877 patients allocated to placebo. The composite primary efficacy outcome occurred in fewer patients randomised to dabigatran than placebo (97 [11%] of 877 patients assigned to dabigatran vs 133 [15%] of 877 patients assigned to placebo; hazard ratio [HR] 0·72, 95% CI 0·55–0·93; p=0·0115). The primary safety composite outcome occurred in 29 patients (3%) randomised to dabigatran and 31 patients (4%) randomised to placebo (HR 0·92, 95% CI 0·55–1·53; p=0·76). Interpretation Among patients who had MINS, dabigatran 110 mg twice daily lowered the risk of major vascular complications, with no significant increase in major bleeding. Patients with MINS have a poor prognosis; dabigatran 110 mg twice daily has the potential to help many of the 8 million adults globally who have MINS to reduce their risk of a major vascular complication. Funding Boehringer Ingelheim and Canadian Institutes of Health Research.

We examine how the U.S. Food and Drug Administration Amendments Act (FDAAA) of 2007, which requires additional disclosures regarding clinical trial results, impacts information asymmetry between the disclosing pharmaceutical firm and capital market participants, the general public, academics, and practitioners. We document a reduction in information asymmetry in capital markets. We also document an increase in adverse event and product problem complaint reports filed against the pharmaceutical firms to the FDA and a higher number of drug and medical device recalls for affected firms after the FDAAA enactment. Finally, cross-sectional analyses suggest that the increase in FDA complaint reports and recalls after the FDAAA enactment was more prominent in firms with a higher bid-ask spread decrease. Taken together, our results suggest that the FDAAA has some benefits for both investors and consumers.

Diabetes mellitus (DM), and its micro and macrovascular complications, is one of the biggest challenges for world public health. Despite overall improvement in prevention, diagnosis and treatment, its incidence is expected to continue increasing over the next years. Nowadays, finding therapies to prevent or retard the progression of diabetic complications remains an unmet need due to the complexity of mechanisms involved, which include inflammation, oxidative stress and angiogenesis, among others. Flavonoids are natural antioxidant compounds that have been shown to possess anti-diabetic properties. Moreover, increasing scientific evidence has demonstrated their potential anti-inflammatory and anti-oxidant effects. Consequently, the use of these compounds as anti-diabetic drugs has generated growing interest, as is reflected in the numerous in vitro and in vivo studies related to this field. Therefore, the aim of this review is to assess the recent pre-clinical and clinical research about the potential effect of flavonoids in the amelioration of diabetic complications. In brief, we provide updated information concerning the discrepancy between the numerous experimental studies supporting the eficacy of flavonoids on diabetic complications and the lack of appropriate and well-designed clinical trials. Due to the well-described beneficial effects on different mechanisms involved in diabetic complications, the excellent tolerability and low cost, future randomized controlled studies with compounds that have adequate bioavailability should be evaluated as add-on therapy on well-established anti-diabetic drugs, This paper was not funded. The authors work has been supported by FEDER-ISCIII Funds (PI17/00130, PI17/01495), Spanish Ministry of Economy and Competitiveness (RTI2018-098788-B-100, DTS17/00203, DTS19/00093, RYC-2017-22369), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN) and Spanish Society of Atherosclerosis (SEA). TCO is an employee of FAES Pharma. The authors (except JAM) have an ongoing research project in common with FAES Pharma on Flavonoids in diabetic complications under the auspices of the joint-RETOS Collaborations Project 2017 (RTC-2017-6089-1), program supported by Spanish Ministry of Economy and Competitiveness.

IntroductionThe IMPACT study focuses on chronic low back pain (CLBP) and depression symptoms, a prevalent and complex problem that represents a challenge for health professionals. Acceptance and Commitment Therapy (ACT) and Brief Behavioural Activation Treatment for Depression (BATD) are effective treatments for patients with persistent pain and depression, respectively. The objectives of this 12 month, multicentre, randomised, controlled trial (RCT) are (i) to examine the efficacy and cost-utility of adding a group-based form of ACT or BATD to treatment-as-usual (TAU) for patients with CLBP and moderate to severe levels of depressive symptoms; (ii) identify pre–post differences in levels of some physiological variables and (iii) analyse the role of polymorphisms in the FKBP5 gene, psychological process measures and physiological variables as mediators or moderators of long-term clinical changes.Methods and analysisParticipants will be 225 patients with CLBP and moderate to severe depression symptoms recruited at Parc Sanitari Sant Joan de Déu (St. Boi de Llobregat, Spain) and Hospital del Mar (Barcelona, Spain), randomly allocated to one of the three study arms: TAU vs TAU+ACT versus TAU+BATD. A comprehensive assessment to collect clinical variables and costs will be conducted pretreatment, post-treatment and at 12 months follow-up, being pain interference the primary outcome measure. The following physiological variables will be considered at pretreatment and post-treatment assessments in 50% of the sample: immune-inflammatory markers, hair cortisol and cortisone, serum cortisol, corticosteroid-binding globulin and vitamin D. Polymorphisms in the FKBP5 gene (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916) will be analysed at baseline assessment. Moreover, we will include mobile-technology-based ecological momentary assessment, through the Pain Monitor app, to track ongoing clinical status during ACT and BATD treatments. Linear mixed-effects models using restricted maximum likelihood, and a full economic evaluation applying bootstrapping techniques, acceptability curves and sensitivity analyses will be computed.Ethics and disseminationThis study has been approved by the Ethics Committee of the Fundació Sant Joan de Déu and Hospital del Mar. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media and various community engagement activities.Trial registration numberNCT04140838

Cellular therapies have been increasingly applied to diverse human diseases. Intracoronary infusion of bone marrow-derived mononuclear cells (BMMNC) has demonstrated to improve ventricular function after acute myocardial infarction. However, less information is available about the role of BMMNC therapy for the treatment of dilated myocardiopathies (DCs) of non-ischemic origin. This article presents the methodological description of a study aimed at investigating the efficacy of intracoronary injection of autologous BMMNCs in the improvement of the ventricular function of patients with DC. This randomised, placebo-controlled, double-blinded phase IIb clinical trial compares the improvement on ventricular function (measured by the changes on the ejection fraction) of patients receiving the conventional treatment for DC in combination with a single dose of an intracoronary infusion of BMMNCs, with the functional recovery of patients receiving placebo plus conventional treatment. Patients assigned to both treatment groups are monitored for 24 months. This clinical trial is powered enough to detect a change in Left Ventricular Ejection Fraction (LVEF) equal to or greater than 9%, although an interim analysis is planned to re-calculate sample size. The study protocol was approved by the Andalusian Coordinating Ethics Committee for Biomedical Research (Comite Coordinador de Etica en Investigacion Biomedica de Andalucia), the Spanish Medicines and Medical Devices Agency (Agencia Espanola de Medicamentos y Productos Sanitarios), and is registered at the EU Clinical Trials Register (EudraCT: 2013–002015-98). The publication of the trial results in scientific journals will be performed in accordance with the applicable regulations and guidelines to clinical trials. ClinicalTrials.gov Identifier NCT02033278 (First Posted January 10, 2014): https://clinicaltrials.gov/ct2/show/NCT02033278 ; EudraCT number: 2013–002015-98, EU CT Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002015-98 . Trial results will also be published according to the CONSORT statement at conferences and reported peer-reviewed journals.

We examine whether a firm’s decision to disclose non-financial proprietary information depends on peer disclosures of similar information. Using a sample of 5,035 unique clinical trials by U.S. pharmaceutical firms over the 2007-2014 period, we find that the firm is less likely to disclose its own clinical trial results if peers have published clinical trial results pertaining to the same medical condition. Conditional on disclosing clinical trial results, the firm is also less likely to disclose the trial results on time when peers have disclosed their clinical trial results. Our cross-sectional tests suggest that proprietary costs of disclosure play an important role in the relation between peer disclosures and the firm’s own disclosure. In particular, the negative relation is more pronounced when proprietary costs of disclosure are higher. Taken together, our findings provide new evidence on the interplay between peer and own disclosures of non-financial proprietary information.

The purpose of the present paper was to evaluate the effects of an 8-week multimodal program focused on core stability exercises and recovery massage with DVD support for a 6-month period in physical and psychological outcomes in breast cancer survivors. A randomized controlled clinical trial was performed. Seventy-eight (n=78) breast cancer survivors were assigned to experimental (core stability exercises plus massage-myofascial release) and control (usual health care) groups. The intervention period was 8 weeks. Mood state, fatigue, trunk curl endurance, and leg strength were determined at baseline, after the last treatment session, and at 6 months of followup. Immediately after treatment and at 6 months, fatigue, mood state, trunk curl endurance, and leg strength exhibited greater improvement within the experimental group compared to placebo group. This paper showed that a multimodal program focused on core stability exercises and massage reduced fatigue, tension, depression, and improved vigor and muscle strength after intervention and 6 months after discharge.