Digital tools for trial recruitment and retention - Plenty of tools but rigorous evaluation is in short supply

Peer reviewedPublisher PD

Statins: pleiotropic, but less than previously thought

This editorial refers to ‘Effect of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evi-dence from randomized trials’, by K. Rahimi et al., doi:10.1093/eurheartj/ehs005 Statins are undoubtedly the mainstay in the treatment of hyperlip-idaemia. They are used in primary and secondary prevention of cardiovascular disease.1,2 It is therefore not surprising that statins rank very high among the most successful drugs in the history of medicine. For example, atorvastatin has raked in around US$130 billion for Pfizer during its 14 years on the market, making it cur-rently the world’s bestselling drug.3 Recent studies show that statins possess powerful pleiotropic effects that are independent of their effects on lipids and lipoproteins.4 The pleiotropic effects of statins are credite

Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required

Substitutes of Structural and Non-Structural Autologous Bone Grafts in Hindfoot Arthrodeses and Osteotomies: A Systematic Review

Background: Structural and non-structural substitutes of autologous bone grafts are frequently used in hindfoot arthrodeses and osteotomies. However, their efficacy is unclear. The primary goal of this systematic review was to compare autologous bone grafts with structural and non-structural substitutes regarding the odds of union in hindfoot arthrodeses and osteotomies. Methods: The Medline and EMBASE and Cochrane databases were searched for relevant randomized and non-randomized prospective studies as well as retrospective comparative chart reviews. Results: 10 studies which comprised 928 hindfoot arthrodeses and osteotomies met the inclusion criteria for this systematic review. The quality of the retrieved studies was low due to small samples sizes and confounding variables. The pooled random effect odds for union were 12.8 (95% CI 12.7 to 12.9) for structural allografts, 5.7 (95% CI 5.5 to 6.0) for cortical autologous grafts, 7.3 (95% CI 6.0 to 8.6) for cancellous allografts and 6.0 (95% CI 5.7 to 6.4) for cancellous autologous grafts. In individual studies, the odds of union in hindfoot arthrodeses achieved with cancellous autologous grafts was similar to those achieved with demineralised bone matrix or platelet derived growth factor augmented ceramic granules. Conclusion: Our results suggest an equivalent incorporation of structural allografts as compared to autologous grafts in hindfoot arthrodeses and osteotomies. There is a need for prospective randomized trials to further clarify the role of substitutes of autologous bone grafts in hindfoot surgery

Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients

Aims Statin therapy is associated with important benefits for patients at risk of, and with, established cardiovascular disease. There is widespread interest in whether intensive dosing of statins yields larger treatment effects. We aimed to determine if intensive dosing is clinically important using a meta-analysis of randomized clinical trials (RCTs). Methods We conducted comprehensive searches of electronic databases from inception to December 2010. We included any RCT evaluating a larger dose with a clinically common dose. Two reviewers independently extracted data, in duplicate. We performed random-effects meta-analysis and a trial sequential analysis. Results We identified 10 RCTs enrolling a total of 41 778 participants. Trials followed patients for a mean of 2.5 years. We did not find statistically significant effects on all-cause mortality [relative risk (RR) 0.92, 95% confidence interval (CI), 0.83-1.03, P = 0.14, I2 = 38%] or cardiovascular disease (CVD) deaths (RR 0.89, 95% CI, 0.78-1.01, P = 0.07, I2 = 34%). When we pooled the composite endpoint of coronary heart disease (CHD) death plus non-fatal myocardial infarction (MI), we found a significant protective effect of intensive statin dosing (RR 0.90, 95% CI, 0.84-0.96, P ≤ 0.0001, I2 = 0%). We also found a significant effect on non-fatal MIs (RR 0.82, 95% CI, 0.76-0.89, P ≤ 0.0001, I2 = 0%) and a significant reduction in the composite of fatal and non-fatal strokes (excluding transient ischaemic attacks) reported in 10 RCTs (RR 0.86, 95% CI, 0.77-0.96, P = 0.006, I2 = 0%). A subgroup analysis of three trials examining acute coronary syndrome patients found significant effects on all-cause (RR 0.75, 95% CI, 0.61-0.91, P = 0.005, I2 = 0%) and CVD mortality (RR 0.74, 95% CI, 0.59-0.94, P = 0.013, I2 = 0%) with intensive dosing. Applying an analysis of optimal information size on the primary analysis, we found that the evidence for CHD death plus non-fatal MIs is conclusive. The evidence for CVD deaths alone is not yet conclusive. Conclusions Available evidence suggests that intensive statin therapy reduces the risk of non-fatal events and may have a role in reducing mortalit

Investigational medicinal products, related costs and hospital pharmacy services for investigator-initiated trials: A mixed-methods study.

BACKGROUND Conducting high quality investigator-initiated trials (IITs) is challenging and costly. The costs of investigational medicinal products (IMPs) in IITs and the role of hospital pharmacies in the planning of IITs are unclear. We conducted a mixed-methods study to compare planned and actual costs of IMPs in Swiss IITs, to examine potential reasons for differences, and to gather stakeholder views about hospital services for IITs. METHODS We included all IITs with IMP services from the Basel hospital pharmacy invoiced between January 2014 and June 2020 (n = 24). We documented trial and IMP characteristics including planned and actual IMP costs. Our working definition for a substantial cost difference was that the actual IMP costs were more than 10% higher than the planned IMP costs in a trial. We conducted semi-structured interviews with investigators, clinical trials unit and hospital pharmacy staff, and qualitatively analyzed transcribed interviews. RESULTS For 13 IITs we observed no differences between planned and actual costs of IMPs (median, 11'000 US$; interquartile range [IQR], 8'882-16'302 US$), but for 11 IITs we found cost increases from a median of 11'000 US$(IQR, 8'922-36'166 US$) to a median over 28'000 US$(IQR, 13'004-49'777 US$). All multicenter trials and 10 of 11 IITs with patients experienced substantial cost differences. From the interviews we identified four main themes: 1) Patient recruitment and organizational problems were identified as main reasons for cost differences, 2) higher actual IMP costs were bearable for most investigators, 3) IMP services for IITs were not a priority for the hospital pharmacy, and 4) closer collaboration between clinical trial unit and hospital pharmacy staff, and sufficient staff for IITs at the hospital pharmacy could improve IMP services. CONCLUSIONS Multicenter IITs enrolling patients are particularly at risk for higher IMP costs than planned. These trials are more difficult to plan and logistically challenging, which leads to delays and expiring IMP shelf-lives. IMP services of hospital pharmacies are important for IITs in Switzerland, but need to be further developed

The natriuretic peptide MR-proANP predicts all-cause mortality and adverse outcome in community patients: a 10-year follow-up study

The precursor peptide of atrial natriuretic peptide (MR-proANP) has a physiological role in fluid homeostasis and is associated with mortality and adverse clinical outcomes in heart failure patients. Little is known about the prognostic potential of this peptide for long-term mortality prediction in community-dwelling patients. We evaluated associations of MR-proANP levels with 10-year all-cause mortality in patients visiting their general practitioner for a respiratory tract infection.; In this post-hoc analysis including 359 patients (78.5%) of the original trial, we calculated cox regression models and area under the receiver operating characteristic curve (AUC) to assess associations of MR-proANP blood levels with mortality and adverse outcome including death, pulmonary embolism, and major adverse cardiac or cerebrovascular events.; After a median follow-up of 10.0 years, 9.8% of included patients died. Median admission MR-proANP levels were significantly elevated in non-survivors compared to survivors (80.5 pmol/L, IQR 58.6-126.0; vs. 45.6 pmol/L, IQR 34.2-68.3; p<0.001) and associated with 10-year all-cause mortality (age-adjusted HR 2.0 [95% CI 1.3-3.1, p=0.002]; AUC 0.79). Results were similar for day 7 blood levels and also for the prediction of other adverse outcomes.; Increased MR-proANP levels were associated with 10-year all-cause mortality and adverse clinical outcome in a sample of community-dwelling patients. If diagnosis-specific cut-offs are confirmed in future studies, this marker may help to direct preventive measures in primary care

Protocol for a mixed methods feasibility and implementation study of a community-based integrated care model for home-dwelling older adults: The INSPIRE project

Evaluations of integrated care models for home-dwelling frail older adults have shown inconclusive results on health and service outcomes. However, limited research has focused on the implementation of integrated care models. Applying implementation science methods may facilitate uptake of integrated care models, thus generating positive outcomes e.g., reduced hospital admissions. This paper describes the protocol to assess the feasibility of an integrated care model (featuring a four-step comprehensive geriatric assessment: screening, a multi-dimensional assessment, a coordinated individualized care plan and follow-up) designed for a new community-based center for home-dwelling older adults in Switzerland. The study includes the following objectives: 1) to assess implementation by a) monitoring respondents to the outreach strategies and describing the Center's visitors; b) assessing implementation outcomes related to the care model (i.e., adoption, acceptability, feasibility, fidelity) and implementation processes related to collaboration; and 2) assessing implementation costs.; For objective 1a, we will use a descriptive design to assess respondents to the outreach strategies and describe the Center's visitors. We will use a parallel convergent mixed methods design for objective 1b. Implementation outcomes data will be collected from meetings with the Center's staff, interviews with older adults and their informal caregivers, and reviewing older adults' health records at the Center. Implementation processes related to collaboration will be assessed through a questionnaire to external collaborators (e.g., GPs) towards the end of the study. For objective 2, implementation costs will be calculated using time-driven activity-based costing methods. Data collection is anticipated to occur over approximately six months.; This study of a contextually adapted integrated care model will inform adaptations to the outreach strategies, care model and implementation strategies in one community center, prior to evaluating the care model effectiveness and potentially scaling out the intervention.; Feasibility study registration ID with clinicaltrials.gov: NCT05302310; registration ID with BMC: ISRCTN12324618

Copeptin predicts 10-year all-cause mortality in community patients: a 10-year prospective cohort study

Copeptin, the C-terminal part of the arginine vasopressin (AVP) precursor peptide, is secreted in response to stress and correlates with adverse clinical outcomes in the acute-care hospital setting. There are no comprehensive data regarding its prognostic value in the community. We evaluated associations of copeptin levels with 10-year mortality in patients visiting their general practitioner (GP) for a respiratory infection included in a previous trial.; This is a post hoc analysis including data from 359 patients included in the PARTI trial. Copeptin was measured in batch-analysis on admission and after 7 days. We calculated Cox regression models and area under the receiver operating characteristic curve (AUC) to assess an association of copeptin with mortality and adverse outcome. Follow-up data were collected by GP, patient and relative tracing through phone interviews 10 years after trial inclusion.; After a median follow-up of 10.0 years, mortality was 9.8%. Median admission copeptin levels (pmol/L) were significantly elevated in non-survivors compared to survivors (13.8, IQR 5.9-27.8; vs. 6.3 IQR 4.1-11.5; p>0.001). Admission copeptin levels were associated with 10-year all-cause mortality [age-adjusted hazard ratio 1.7 (95% CI, 1.2-2.5); p>0.001, AUC 0.68]. Results were similar for discharge copeptin levels. Copeptin also predicted adverse outcomes defined as death, pulmonary embolism and major adverse cardiac and cerebrovascular events.; In a sample of community-dwelling patients visiting their GP for a respiratory infection, copeptin levels were associated with 10-year all-cause mortality. In conjunction with traditional risk factors, this marker may help to better direct preventive measures in this population

The reporting of studies using routinely collected health data was often insufficient.

OBJECTIVES: To assess reporting quality of studies using routinely collected health data (RCD) to inform the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) guideline development. STUDY DESIGN AND SETTING: PubMed search for observational studies using RCD on any epidemiologic or clinical topic. Sample of studies published in 2012. Evaluation of five items based on the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guideline and eight newly developed items for RCD studies. RESULTS: Of 124 included studies, 39 (31.5%) clearly described its design in title or abstract. Complete information to frame a focused research question, that is, on the population, intervention/exposure, and outcome, was provided for 51 studies (41.1%). In 44 studies where definitions of codes or classification algorithms would be necessary to operationalize such a research question, only nine (20.5%) reported all items adequately. In 81 studies describing multivariable analyses, 54 (66.7%) reported all variables used for modeling and 34 (42.0%) reported basic details required for replication. Database linkage was reported adequately in 12 of 41 studies (29.3%). Statements about data sharing/availability were rare (5/124; 4%). CONCLUSION: Most RCD studies are insufficiently reported. Specific reporting guidelines and more awareness and education on their use are urgently needed