Pragmatic Trial Research Articles

Diuretic dosing and outcomes with torsemide and furosemide following hospitalization for heart failure: the TRANSFORM-HF trial

Abstract Background The TRANSFORM-HF trial found no significant difference in all-cause mortality and all-cause hospitalization following hospitalization for heart failure (HF) with a diuretic strategy of torsemide versus furosemide. However, the impact of diuretic dosing on the trial results and whether the relationship between dosing and outcomes differs between torsemide and furosemide is unclear. Purpose To assess and compare the associations between diuretic dosing and outcomes with torsemide and furosemide. Methods TRANSFORM-HF was an open-label, pragmatic trial that randomized 2859 patients hospitalized for HF in the United States to a diuretic strategy of torsemide versus furosemide after discharge. These post-hoc analyses categorized patients according to investigator-selected discharge dose tertile of torsemide and furosemide, i.e. tertile 1) ≤40 mg, 2) >40-80 mg and 3) >80 mg of furosemide equivalents using a 2:1 conversion with torsemide. Study endpoints were all-cause mortality, all-cause hospitalization, composite all-cause mortality or hospitalization, and change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS). Results Dosing data were available for 2379 (83%) of patients with median age 65 years (IQR: 56, 75), 883 (37.1%) were women, and 812 (34.2%) were Black. When categorized by discharge dose, a total of 1136 (47.8%) patients were included in dose tertile 1, 696 (29.2%) in tertile 2 and 547 (23.0%) in tertile 3. For all-cause mortality, furosemide showed adjusted hazard ratios (aHR) of 1.21 (95% CI: 0.91, 1.59) for tertile 2 and 1.40 (95% CI: 1.04, 1.88) for tertile 3 compared with tertile 1. For torsemide aHR for all-cause mortality were 1.74 (95% CI: 1.32, 2.30) for tertile 2 and 1.58 (95% CI: 1.14, 2.19) for tertile 3 compared with tertile 1 (Table 1). The risk of adverse events increased similarly with dose for both diuretics and no statistically significant interaction between loop diuretic and dose was observed (Pinteraction=0.17). Likewise, for the endpoints of all-cause hospitalization and the composite of all-cause mortality and hospitalization, higher doses of furosemide and torsemide aligned with higher risk of both endpoints, and interaction p-values that did not demonstrate statistical significance by loop diuretic (all-cause hospitalization: Pinteraction= 0.28, all-cause mortality and hospitalization: Pinteraction=0.38) (Table 1). Changes in KCCQ-CSS were similar across the range of dose tertiles from baseline to month 12 for both furosemide and torsemide (Table 2). Conclusions Following hospitalization for HF, no clinical differences were observed across the dosing spectrum in all-cause mortality, all-cause hospitalization, or KCCQ-CSS at 12-mornths between torsemide and furosemide. Irrespective of diuretic agent used, increasing dose of loop diuretics correlates with worse clinical outcomes.

Sex-specific clinical outcomes and healthcare resource utilization in the 5 years following hospitalization for heart failure

Abstract Background Heart failure (HF) a leading cause of hospitalization, and sex differences in care have been described. Purpose We assessed sex-specific clinical outcomes and healthcare resource utilization following hospitalization for HF. Methods This was an exploratory analysis of patients hospitalized for HF across 10 Canadian hospitals enrolled in the Patient-Centred Care Transitions in HF pragmatic cluster-randomized trial. Primary outcome was all-cause mortality. Secondary outcomes included all-cause readmissions, HF readmissions, emergency department (ED) visits, and healthcare resource utilization. Outcomes were obtained via linkages with administrative datasets. Results The 4441 patients (50.7% female) had high event rates. At 5 years of follow-up, 63.6% male and 65.5% of male and female patients, respectively, had died (p=0.19); 85.4% and 84.4% of male and female patients, respectively, were readmitted with no sex differences in mean [SD] all-cause readmissions (males, 2.8 [7.8] and females, 3.0 [8.4], p=0.54) or HF readmissions (males, 0.9 [3.6] and females, 0.9 [4.5], p=0.80) per person. The mean (SD) annual total healthcare costs per patient was $80334 (116762) for males and $81010 (112625) for females, with no sex difference (p=0.90); however, there were sex differences in cost breakdown: males incurred greater costs from specialist, hemodialysis, and day surgical care, and females incurred greater costs from home visits and long-term care. Conclusions Males and females were at similarly high risk of mortality and readmissions, and had similar total healthcare costs following hospitalized for HF. Notwithstanding similar risks, males received relatively more specialist and invasive care, and females received relatively more supportive care.

Electronic nudge letters to increase influenza vaccination uptake in younger and middle-aged individuals with diabetes: a prespecified analysis of the NUDGE-FLU-CHRONIC trial

Abstract Background Despite evidence demonstrating that influenza vaccination is associated with reduced risk of adverse cardiovascular events and all-cause mortality, influenza vaccine uptake remains suboptimal in persons with diabetes mellitus (DM). Purpose In this prespecified analysis of the NUDGE-FLU-CHRONIC trial we assessed the effectiveness of electronically delivered nudges on influenza vaccine uptake according to DM status. Methods NUDGE-FLU-CHRONIC was a nationwide, randomized, pragmatic implementation trial among younger and middle-aged (18-64 years) Danish citizens with chronic disease during the 2023/2024 influenza season. All trial participants were eligible for a free influenza vaccination through the Danish governmental vaccine program. Participants were randomized in a 2.45:1:1:1:1:1:1 ratio to usual care (no electronic letter) or one of 6 different electronic nudge letters delivered on Sep 26, 2023. Baseline and outcome data were obtained using the Danish nationwide registries. The endpoint was receipt of a seasonal influenza vaccine on or before Jan 1, 2024. Results Of 299,881 NUDGE-FLU-CHRONIC participants, 57,666 (19.2%) had DM at baseline. Participants with DM had a median age of 51.6 years, 43.0% were female, median Hba1c of 53 mmol/mol, median DM duration of 10.0 years, and 51.2% were insulin dependent. During follow-up, 43.0% of those with DM vs. 34.6% of those without DM received the seasonal influenza vaccine (p<0.001). Any electronic letter vs. usual care was highly effective in increasing vaccine uptake in participants with DM at baseline (45.6% vs. 36.5%, difference: +9.1 percentage points [99.29%CI: 7.9-10.3], relative risk ratio [RR]: 1.42, 99.29%CI: [1.39-1.44]). However, DM status modified the effect of any electronic letter such that participants without DM at baseline experienced a slightly greater effect than those with DM (37.3% vs. 25.9%, difference: +12.3 percentage points [11.7-12.8], RR: 1.47 [1.45-1.50]; p-interaction <0.001). For each individual electronic nudge letter, the effect of the intervention was slightly lower in participants with DM compared to those without (Figure 1; all p-interaction < 0.015). When assessing DM subgroups, the effect of any electronic letter vs. usual care was greater in participants with DM and concomitant cardiovascular disease than in those without, greater in non-insulin treated than in insulin-treated individuals, and greater in those with shorter diabetes duration. Effectiveness of nudges were consistent across all other DM subgroups including HbA1c level (Figure 2). Conclusions Electronic nudge letters significantly boosted vaccine uptake in a broad range of individuals with DM, but the effect was slightly lower compared to those without DM. Future studies should test whether behaviorally designed nudges may positively influence other health behaviors in people with diabetes.

Relative effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against hospitalizations and mortality according to frailty score: a post-hoc analysis of the DANFLU-1 trial

Abstract Background Frailty is a major risk factor for adverse cardiovascular events. Influenza vaccination has been shown to protect against cardiovascular fatal and nonfatal events. However, limited data exist on the added benefit of high-dose versus standard-dose influenza vaccination according to frailty status. Purpose We sought to assess the relative effectiveness of high-dose (QIV-HD) versus standard-dose (QIV-SD) quadrivalent influenza vaccination according to frailty status in elderly individuals. Methods This is a post-hoc analysis of the randomized controlled feasibility trial of QIV-HD versus QIV-SD conducted during the 2021–2022 influenza season in adults aged 65–79 years. We assessed the following prespecified outcomes: hospitalizations for pneumonia or influenza, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations and all-cause mortality. Level of frailty was defined according to the Hospital Frailty Risk Score based on ICD-10 codes for relevant comorbidities any time prior to vaccination. We divided the participants into two categories according to Frailty Score (FS): low frailty (0-4 points) and intermediate or high frailty (≥5 points). We analyzed outcomes as time to first event using Cox proportional hazards regression. Results Among 12,473 randomly assigned participants to QIV-HD versus QIV-SD (mean age 71.7 years, 47.1% female), 10,711 (85.9%) were categorized as having low frailty and 1,762 (14.1%) had intermediate or high frailty. In total, 38 individuals were hospitalized for pneumonia or influenza during follow-up, 219 were hospitalized for cardiorespiratory illness, 1055 were hospitalized due to any cause and 62 died during follow-up. FS significantly modified the effect of QIV-HD versus QIV-SD for all-cause mortality (P for interaction 0.02). In participants with low frailty, QIV-HD was associated with a lower risk of all-cause mortality (Figure 1: HR 0.26, 95% CI 0.13 to 0.55), whereas there was no evidence of effect among those with intermediate or high frailty (HR 1.68, 95% CI 0.66 to 4.26). QIV-HD versus QIV-SD was associated with a lower incidence of hospitalizations for pneumonia and influenza, this effect was consistent regardless of frailty status (P for interaction 0.88). QIV-HD was not associated with a significantly lower incidence of hospitalizations due to cardiovascular, cardiorespiratory or respiratory disease or any cause regardless of frailty status. Conclusions In this post-hoc analysis of a large-scale pragmatic trial, QIV-HD was similarly associated with a lower incidence of hospitalizations for pneumonia and influenza among older adults irrespective of frailty status. The potential benefit of QIV-HD versus QIV-SD may therefore be applicable regardless of frailty status. However, our results suggest that QIV-HD is associated with a lower risk of all-cause mortality among adults with low frailty only.Figure 1.

My virtual escape from patient life: a feasibility study on the experiences and benefits of individualized virtual reality for inpatients in palliative cancer care

BackgroundCancer patients benefit from Virtual Reality (VR) in burdensome situations, but evidence is scarce for palliative situations. Based on earlier work in palliative care, individualized VR interventions like seeing the patient’s home may address a patient’s wish to be at home and thus have a greater effect compared to standard VR content. Yet, some patients and relatives may be concerned about their privacy. Also, patient stakeholders raised concerns about triggering depressed mood or homesickness.AimTo test the feasibility and safety of individualized vs. standard 360°video VR interventions in palliative cancer inpatients.MethodsProspective observational study with patient-reported outcome measurement using validated instruments of well-being (MDBF), symptoms and psychosocial burden (IPOS), cybersickness (SSQ), presence experience (SPES), subjective benefit (2 items), content analysis of interviews, and field notes. Individualized VR content was recorded with action camcorder-technology to protect the patients’ privacy.ResultsSeventeen patients participated, median age 65 years (range 20–82), 9 women (53%), 8 single or widowed (47%), 4 childless (23.5%), 4 academics (23.5%), with a median length of stay of 9 days (1–75) in the hematology (10), palliative care (3), or radiotherapy (2) unit of a German university hospital. Eight patients (53.3%) chose their own home environments or family for individualized VR-content. All participants enjoyed the intervention. Compared to standard VR content the individualized VR tended to have a stronger effect on well-being and emotional touch. It was not inferior in terms of psychosocial burden and cybersickness. No subjective and relevant side effects occurred. The patients well tolerated the assessments. However, most patients demanded a lighter headset and a desire for more interactivity.ConclusionsIndividualization of VR content shows potential for enhancement of immersion, which improves the VR experience and does not harm in terms of depressed mood or worsening of symptoms. The patients’ and family desire for privacy is feasible with the support of family members who recorded the individualized videos, which is easily manageable today. We suggest a pragmatic randomized clinical trial to compare the effects of individualized vs. standard VR-content.Trial registrationRegistered at German Clinical Trials Register (Deutsches Register Klinischer Studien; DRKS); registration number: DRKS00032172; registration date: 11/07/2023.

Standard HIPAA Authorization Forms Decreased Response Rates for a Multi-site Pragmatic Trial.

The Health Insurance Portability and Accountability Act (HIPAA) aims to safeguard patient information; however, complex legal language may lead to confusion and mistrust, and hinder enrollment in clinical trials. To evaluate the effect of a standard HIPAA authorization included in mailed survey packets on study enrollment for a multi-site pragmatic trial. This study is nested within an advance care planning pragmatic trial at 50 primary care clinics across three University of California (UC) Health Systems. We included English and Spanish-speaking seriously ill patients. One third of eligible patients received and 2/3 did not receive the HIPAA authorization in their enrollment packet. We compared enrollment rates at 3months and assessed the readability, understandability, and actionability of the standard HIPAA form using the Federal Plain Language Guidelines Checklist for Plain Language, the Automatic Readability Checker consensus calculator (grade 8 is the average reading level for US adults), and the Patient Education Materials Assessment Tool for Printable Materials (PEMAT-P, 0-100%, 70% considered the minimum). Of 4632 eligible patients (mean age 71, 48% women, 11% Spanish-speaking, 40% racial/ethnic minority); 1543 received a mailed enrollment packet with a HIPAA form and 3089 did not. Patients mailed the HIPAA form were less likely to enroll (10.2% vs. 14.8%, p < 0.001). The standard HIPAA form scored at the 12th grade reading level, had a PEMAT-P Understandability score of 42%, had an Actionability score of 40%, and only met 50% of Federal Plain Language Guideline Checklist items. The inclusion of a standard HIPAA authorization in mailed enrollment packets for a large pragmatic trial led to lower rates of study enrollment. This study informs how HIPAA authorization forms should be redesigned to be more accessible to patients to prevent unnecessary barriers to research enrollment.

High-Risk Medications in Persons Living With Dementia

Individuals with Alzheimer disease (AD) and Alzheimer disease-related dementias (ADRD) may be at increased risk for adverse outcomes relating to inappropriate prescribing of certain high-risk medications, including antipsychotics, sedative-hypnotics, and strong anticholinergic agents. To evaluate the effect of a patient/caregiver and prescriber-mailed educational intervention on potentially inappropriate prescribing to patients with AD or ADRD. This prospective, open-label, pragmatic randomized clinical trial, embedded in 2 large national health plans, was conducted from April 2022 to June 2023. The trial included patients with AD or ADRD and use of any of 3 drug classes targeted for deprescribing (antipsychotics, sedative-hypnotics, or strong anticholinergics). Patients were randomized to 1 of 3 arms: (1) a mailing of educational materials specific to the medication targeted for deprescribing to both the patient and their prescribing clinician; (2) a mailing to the prescribing clinician only; or (3) a usual care arm. Analysis was performed using a modified intention-to-treat approach. The primary study outcome was the dispensing of the medication targeted for deprescribing during a 6-month study observation period. Secondary outcomes included changes in medication-specific mean daily dose and health service utilization. Among 12 787 patients included in the modified intention-to-treat analysis, 8742 (68.4%) were female, and the mean (SD) age was 77.3 (9.4) years. The cumulative incidence of being dispensed a medication targeted for deprescribing was 76.7% (95% CI, 75.4-78.0) in the patient and prescriber mailing group, 77.9% (95% CI, 76.5-79.1) in the prescriber mailing only group, and 77.5% (95% CI, 76.2-78.8) in the usual care group. Hazard ratios were 0.99 (95% CI, 0.94-1.04) for the patient and prescriber group and 1.00 (95% CI, 0.96-1.06) for the prescriber only group compared with the usual care group. There were no differences between the groups for secondary outcomes. These findings suggest medication-specific educational mailings targeting patients with AD or ADRD and their clinicians are not effective in reducing the use of high-risk medications. ClinicalTrials.gov Identifier: NCT05147428.

Approaches to Deprescribing Proton Pump Inhibitors in Clinical Practice: A Systematic Review.

Background: Proton pump inhibitors (PPIs) are some of the most frequently prescribed medications, but they are often used inappropriately, either being prescribed without a clear indication or continued for longer than necessary. In such cases, deprescribing is recommended. However, despite its proven effectiveness, the implementation of deprescribing in clinical practice remains inconsistent and varied, making it challenging to identify the most effective strategies. The goal is to provide a comprehensive outline of deprescribing interventions for PPI therapy implemented across various settings and by different healthcare professionals. Methods: The study is designed to be a systematic review of the published literature. PubMed, Embase, and Web of Science databases were searched from 1 January 1989 (the first PPI on the market) to 30 September 2024 for articles assessing PPI deprescribing in adult patients, focusing on the implementation rate (primary outcome) or effects on symptoms (secondary outcome). Results: After screening, 66 studies were included, predominantly pragmatic trials (N = 32) or randomized controlled trials (N = 25). We found a variety of interventions promoting PPI deprescription. Collaborative efforts involving multiple healthcare professionals, the use of algorithms for clinical decision-making, and patient involvement have proven to be key elements in the most effective strategies. Discontinuing therapy may not be advisable in cases of recurrent symptoms, suggesting that on-demand therapy could be a recommended approach. Deprescribing is particularly relevant for individuals with mild illnesses and symptoms, where tapering can effectively mitigate the rebound symptoms often associated with abrupt discontinuation. Conclusions: Given the current prevalence of inappropriate PPI prescribing, it is imperative to raise awareness among both physicians and patients about the importance of the deprescribing process, which should be tailored to the specific needs of each patient, considering his/her medical history, current health status, and personal preferences.

Racial differences in the quality of care interactions among nursing home residents with dementia

ABSTRACT Objective The resident population in nursing homes is increasingly racially diverse. The purpose of this study was to assess racial differences in the quality of care interactions among nursing home residents with dementia. Design The study utilized baseline data from the Testing the Evidence Integration Triangle for Behavioral and Psychological Symptoms of Dementia (EIT-4-BPSD), a randomized controlled pragmatic trial. The Quality of Interaction Scale (QuIS) was used to measure quality of staff-resident care interactions. The sample included 531 residents. An analysis of covariance was conducted to address the aim. Results The majority of interactions were positive social (42%) or positive care (37%). Black residents living with dementia had higher QuIS scores (M = 5.98, SD = 1.66) than White residents with dementia (M = 5.40, SD = 1.75), whereas higher QuIS scores indicating more positive interactions. However, the results of the analysis of covariance indicated that there was not a significant difference in QuIS scores between Black versus White residents living with dementia (p =.203). Conclusion The findings suggest that care interactions in nursing homes are consistent between Black residents and White residents. Future research should evaluate the impact of staff race on the quality of care interaction among nursing home residents.

The effects of neighborhood perceptions on response to a technology-assisted parenting intervention for adolescent substance use: protocol of a diversity supplement to parent SMART (Substance Misuse in Adolescents in Residential Treatment)

BackgroundIt is well established that an adolescent’s neighborhood is associated with their likelihood of developing a substance use disorder. The availability of drugs, lack of access to resources, and exposure to violence are all associated with greater substance use among young people, leading to more pronounced health inequities. Technology assisted interventions (TAIs) have been touted to enhance the reach of substance use treatment and improve outcomes for high-need families living in underserved neighborhoods. A key question is whether neighborhood characteristics impact the effectiveness of TAIs, given these interventions are embedded within an adolescent’s natural environment. This National Institute on Drug Abuse-funded Diversity Supplement will examine the role of perceived neighborhood characteristics on response to Parent SMART, a TAI for parents of adolescents in residential substance use treatment (R37DA052918; PI: Becker). Aim 1 will use both adolescent and parent self-report of multiple neighborhood dimensions (e.g., physical environment, social disorder, satisfaction with community resources) to identify indicators predictive of treatment response. Aim 2 will then explore the indirect relationship between neighborhood context and response to Parent SMART, via engagement.MethodsParticipants include adolescent and parent dyads enrolled in an effectiveness trial evaluating Parent SMART, a TAI for parents of adolescents in residential substance youth treatment. Participants will complete self-report measures of neighborhood physical environment, social disorder, and satisfaction with community resources at baseline to predict parenting and youth substance outcomes at 6-, 12-, and 24-weeks post discharge.DiscussionTo date, few studies have explicitly tested how neighborhood affects response to TAIs for adolescent substance use. Assessing adolescent and parent perceptions of neighborhood characteristics holds potential to pinpoint key contextual factors that affect TAI response and to promote consideration of multi-level health equity determinants in substance use research. Understanding neighborhood influences can advance public health by helping tailor TAIs to address the unique needs of adolescents living in underserved communities.Trial registrationThis study extends the measurement and analysis plan of a pragmatic effectiveness trial. The pragmatic effectiveness trial is registered at ClinicalTrials.gov NCT05169385; https://clinicaltrials.gov/ct2/show/NCT05169385

A non-randomized pragmatic historically controlled trial evaluating the effectiveness and safety of a bedaquiline or a linezolid-based short regimen for rifampicin-resistant tuberculosis

Short all-oral regimens for Rifampicin-resistant tuberculosis (ShORRT) have been a turning point in the treatment of drug-resistant tuberculosis. Despite this, access to drugs, stockouts, or adverse effects may limit the use of the recommended regimens. Pragmatic non-randomized trial evaluating the efficacy and safety of a ShORRT strategy for the treatment of rifampicin-resistant Tuberculosis (RR-TB) at the Hospital Nossa Senhora da Paz (Angola). The strategy assigned participants to receive a bedaquiline (BDQ) or a linezolid-based (LZF) regimen supplemented with levofloxacin, clofazimine, and cycloserine for up to 9 months. One hundred and twenty-one participants with pulmonary RR-TB were treated with the ShORRT strategy; 69 received the bedaquiline- and 52 the linezolid-based regimen. Overall, 98 (81%) participants had successful treatment outcomes, which was significantly higher compared to a 20-month historical injectable-based regimen (successful outcome rate including cure and treatment completed: 53.7%) (p<0.001). No significant differences between treatment success rates (85.5% vs. 75.0%), treatment failure (0.0% vs. 1.9%), death (5.8% vs. 13.5%), or lost to follow-up (LTFU) (8.7% vs. 9.6%) were seen between the BDQ and the LZF-based regimen. Globally, 72 adverse events (AE) occurred in 36 (29.7%) participants. Eighteen (14.9%) of these were grade ≥3 and were more frequently observed in those receiving the LZD-based regimen (p=0.02). The ShORRT strategy with a nine-month BDQ- or LZD-based regimen supports the efficacy of shorter all-oral regimens for the treatment of RR-TB and presents real-world data from schemes without bedaquiline, nitroimidazole, or injectables.

Preparing for responsive management versus preparing for renal dialysis in multimorbid older people with advanced chronic kidney disease (Prepare for Kidney Care): Study protocol for a randomised controlled trial.

BackgroundChronic kidney disease (CKD) prevalence is steadily increasing, in part due to increased multimorbidity in our aging global population. When progression to kidney failure cannot be avoided, people need unbiased information to inform decisions about whether to start dialysis, if or when indicated, or continue with holistic person-centred care without dialysis (conservative kidney management). Comparisons suggest that while there may be some survival benefit from dialysis over conservative kidney management, in people aged 80 years and over, or with multiple health problems or frailty, this may be at the expense of quality of life, hospitalisations, symptom burden and preferred place of death. Prepare for Kidney Care aims to compare preparation for a renal dialysis pathway with preparation for a conservative kidney management pathway, in relation to quantity and quality of life in multimorbid, frail, older people with advanced CKD.MethodsThis is a two-arm, superiority, parallel group, non-blinded, individual-level, multi-centre, pragmatic trial, set in United Kingdom National Health Service (NHS) kidney units. Patients with advanced CKD (estimated glomerular filtration rate < 15 mL/min/1.73 m2, not due to acute kidney injury) who are (a) 80 years of age and over regardless of frailty or multimorbidity, or (b) 65–79 years of age if they are frail or multimorbid, are randomised 1:1 to ‘prepare for responsive management’, a protocolised form of conservative kidney management, or ‘prepare for renal dialysis’. An integrated QuinteT Recruitment Intervention is included. The primary outcome is mean total number of quality-adjusted life years during an average follow-up of 3 years. The primary analysis is a modified intention-to-treat including all participants contributing at least one quality of life measurement. Secondary outcomes include survival, patient-reported outcomes, physical functioning, relative/carer reported outcomes and qualitative assessments of treatment arm acceptability. Cost-effectiveness is estimated from (i) NHS and personal social services and (ii) societal perspectives.DiscussionThis randomised study is designed to provide high-quality evidence for frail, multimorbid, older patients with advanced CKD choosing between preparing for dialysis or conservative kidney management, and healthcare professionals and policy makers planning the related services.Trial registrationISRCTN, ISRCTN17133653 (https://doi.org/10.1186/ISRCTN17133653). Registered 31 May 2017.

Moving psychedelic-assisted therapies from promising research into routine clinical practice: Lessons from the field of implementation science.

Psychedelics (e.g., 3,4-Methylenedioxymethamphetamine [MDMA], lysergic acid diethylamide [LSD], psilocybin) are molecules that have the potential to produce rapid therapeutic effects when paired with psychotherapy. Randomized clinical trials of psychedelic-assisted psychotherapy (PAT) have shown promising results for post-traumatic stress disorder (PTSD), depression, and substance use disorders. The U.S. Food and Drug Administration has acknowledged the promise of PAT, signaling potential approval of psilocybin-assisted therapy for depression by 2026. Given this timeline, implementation scientists must engage with PAT researchers, policymakers, and practitioners to think critically about bringing these promising new treatments into routine practice settings while maintaining quality and safety. This commentary aims to initiate a dialogue between implementation scientists and PAT researchers and practitioners on addressing these questions with a lens toward equity. Specifically, we discuss how the field of implementation science can support PAT stakeholders to accelerate the translational process from research into practice, focusing specifically on safety-net settings (i.e., Federally Qualified Health Centers and Veterans Affairs health systems) that serve historically marginalized populations. We use the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework to illustrate five critical areas where implementation science can help move PAT from research into real-world practice. For each RE-AIM dimension, we highlight ways the field of implementation science can contribute tools (e.g., implementation strategies), methodologies (e.g., pragmatic hybrid implementation-effectiveness trials), and approaches (community-based participatory research) for establishing the safety, effectiveness, and accessibility of PAT for historically underserved communities.

MA10.07 Understanding Symptom Burden in Young Adults with Lung Cancer Based on an Analysis from the E2C2 Pragmatic Clinical Trial

MA10.07 Understanding Symptom Burden in Young Adults with Lung Cancer Based on an Analysis from the E2C2 Pragmatic Clinical Trial

Population-level effects on crime of recovering firearms from armed prohibited persons: intention-to-treat analysis of a pragmatic cluster-randomised trial in California cities

Population-level effects on crime of recovering firearms from armed prohibited persons: intention-to-treat analysis of a pragmatic cluster-randomised trial in California cities

Clinical Trial Design Considerations for Hospitalised Patients With Ulcerative Colitis Flares and Application to Study Hyperbaric Oxygen Therapy in the NIDDK HBOT-UC Consortium.

Patients with ulcerative colitis (UC) who are hospitalised for acute severe flares represent a high-risk orphan population. To provide guidance for clinical trial design methodology in these patients. We created a multi-centre consortium to design and conduct a clinical trial for a novel therapeutic intervention (hyperbaric oxygen therapy) in patients with UC hospitalised for moderate-severe flares. During planning, we identified and addressed specific gaps for inclusion/exclusion criteria; disease activity measures; pragmatic trial design considerations within care pathways for hospitalised patients; standardisation of care delivery; primary and secondary outcomes; and sample size and statistical analysis approaches. The Truelove-Witt criteria should not be used in isolation. Endoscopy is critical for defining eligible populations. Patient-reported outcomes should include rectal bleeding and stool frequency, with secondary measurement of urgency and nocturnal bowel movements. Trial design needs to be tailored to care pathways, with early intervention focused on replacing and/or optimising responsiveness to steroids and later interventions focused on testing novel rescue agents or strategies. The PRECIS-2 framework offers a means of tailoring to local populations. We provide standardisation of baseline testing, venous thromboprophylaxis, steroid dosing, discharge criteria and post-discharge follow-up to avoid confounding by usual care variability. Statistical considerations are provided given the small clinical trial nature of this population. We provide an outline for framework decisions made for the hyperbaric oxygen trial in patients hospitalised for UC flares. Future research should focus on the remaining gaps identified.

The Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer (CISTO) study: Lessons learned about management and patient enrollment in a large, pragmatic, patient-centered trial.

The growth of patient and public involvement in clinical research highlights the paucity of literature on operational practices that ensure the success of large, patient-centered outcomes trials. The authors' objective was to identify tools launched by the Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer (CISTO) study team to determine their effectiveness in maximizing patient enrollment in this observational, pragmatic trial. The primary outcomes for this study were patient screening and enrollment across 36 CISTO study sites. The operational strategies included CISTOquestion email correspondence and All Sites Meetings, specifically poll performance data from meetings, and a nonanonymized feedback survey about the CISTO study's management practices. Effectiveness was measured using correlation analysis with patient cohort data, including screenings, enrollments, post-hoc exclusions, and the post-hoc exclusion rate. Average screenings and enrollment rose after the implementation of CISTOquestion in April 2021, with the average number of screenings rising from 7.42 to 26.8 patients per month and enrollment rising from 3.76 to 16 patients per month. Use of CISTOquestion was correlated strongly with increased patient screenings and enrollment across all study sites. Eighty-three percent of sites with above-average post-hoc exclusion rates (≥0.092) sent below the average number of CISTOquestion inquiries. Poll performance and survey data revealed that all survey respondents who used CISTOquestion found that it was a valuable and accessible resource. Of the several operational tools implemented within the CISTO study that aimed to improve patient enrollment, CISTOquestion, a centralized email for addressing eligibility questions, was most beneficial to overall patient accrual.

Predictors of recurrent venous thromboembolism and major bleeding in patients with cancer: A secondary analysis of the CANVAS trial

IntroductionPatients with cancer have an increased risk of developing venous thromboembolism (VTE) but also have an increased risk of both recurrent VTE and bleeding with anticoagulation compared to anticoagulated patients without cancer. CANVAS, a randomized pragmatic effectiveness trial, compared the direct oral anticoagulants a class to low molecular weight heparin for treatment of a new VTE in patients with cancer. The aim of this prespecified secondary analysis of the CANVAS trial is to identify predictors of both recurrent VTE and major bleeding in patients with cancer and new VTE. MethodsData from the 671 participants in the analysis population were used to identify predictors of recurrent VTE and bleeding during the 6-month treatment period. Significant predictors identified in the univariable models were carried forward in the multivariable models to identify independent predictors of both risks. ResultsIndependent predictors of recurrent VTE include ECOG performance status ≥2 (HR, 3.19 [95 % CI, 1.45–7.02]; P < .005), presence of metastatic disease (HR, 2.57 [95 % CI, 1.14–5.80]; P = .023), treatment with bevacizumab (HR, 2.50 [95 % CI, 1.04–5.99]; P = .041), and deep vein thrombosis without pulmonary embolus as index VTE (HR, 1.86 [95 % CI, 1.04–3.33]; P = .037). Independent predictors of major bleeding include serum albumin <3.5 g/dL (HR 1.97 [95 % CI, 1.02–3.79]; P = .044) and metastatic disease (HR 2.80 [95 % CI, 1.08–7.22]; P = .034). ConclusionFindings from this pre-specified analysis of the CANVAS trial identified risk factors for recurrent VTE and major bleeding in a population of participants with cancer and new VTE that reflect current oncology clinical practice. Results can be used to identify at risk patients in practice and inform new risk prediction models to improve the care of these patients.

Health dialogue intervention versus opportunistic screening in primary care for type 2 diabetes and cardiovascular disease prevention in settings with low socioeconomic status (DETECT): study protocol for a pragmatic cluster-randomized trial

BackgroundMeta-analyses of randomized trials suggest that health checks and health promotion interventions targeting behavior change in primary care do not prevent cardiovascular morbidity and mortality in the general population. However, whether such interventions are more effective in high-risk populations, such as people living in low socioeconomic settings, remains unclear, as they have been poorly represented in previous trials. Therefore, we aim to evaluate the effectiveness, cost-effectiveness, and implementation of systematic screening followed by an individually oriented, lifestyle-focused, health dialogue intervention for prevention of type 2 diabetes and cardiovascular disease, as compared to opportunistic screening, in primary care in socioeconomically disadvantaged areas.MethodsUsing an overall pragmatic approach and a cluster-randomized design with two arms, we aim to enroll 3000 participants aged 50–59 years from 30 primary care centers (PCCs) with an above-average level of Care Need Index in Stockholm Region, Sweden. PCCs will be randomized (1:1) either to a health dialogue intervention, which includes inviting enlisted patients to a systematic screening of risk factors followed by an individually oriented lifestyle-focused health dialogue, or to opportunistic screening, which includes screening patients for a smaller set of risk factors during an appointment at their PCC taking place for other reasons. The main outcome will be change in systolic blood pressure during 6- and 12-month follow-ups. Additional short-term outcomes will be changes in other biological risk factors, health-related quality-of-life, and lifestyle habits, as well as process and implementation outcomes, and unintended side effects. The long-term effect on type 2 diabetes and cardiovascular disease incidence and mortality will be examined using regional and nationwide registers. Changes in systolic blood pressure and other health outcomes will be analyzed using mixed-effect generalized linear modeling and mixed-effect Cox regression to capture variability between and within PCCs. A health economic evaluation will assess resource use and costs in the short- and long-term.DiscussionThis trial of lifestyle-focused health dialogues and opportunistic screening in primary care in socioeconomically disadvantaged areas in the largest region of Sweden has the potential to yield valuable insights that could support evidence-based policymaking.Trial registrationClinicalTrials.gov (NCT06067178). Prospectively registered September 27, 2023.

Electronic Nudges to Increase Influenza Vaccination in Patients With Chronic Diseases

Despite strong worldwide guideline recommendations, influenza vaccination rates remain suboptimal among young and middle-aged patients with chronic diseases. Effective scalable strategies to increase vaccination are needed. To investigate whether electronically delivered letter-based nudges informed by behavioral science could increase influenza vaccination uptake among patients aged 18 to 64 years with chronic diseases. Nationwide pragmatic registry-based randomized clinical implementation trial conducted between September 24, 2023, and May 31, 2024, enrolling all Danish citizens aged 18 to 64 years who met criteria for free-of-charge influenza vaccination in light of preexisting chronic disease. All trial data were sourced from nationwide administrative health registries. Randomized in 2.45:1:1:1:1:1:1 ratio to no letter (usual care) or 6 different behaviorally informed electronic letters. The primary end point was receipt of influenza vaccination on or before January 1, 2024, assessed in 7 prespecified coprimary comparisons (all intervention groups pooled vs usual care and each individual intervention group vs usual care). Absolute risk difference in proportions and a crude relative risk were calculated for each comparison. A total of 299 881 participants (53.2% [159 454] female, median age, 52.0 [IQR, 39.8-59.0] years) were randomized. Compared with usual care, influenza vaccination rates were higher among those receiving any intervention letter (any intervention letter, 39.6% vs usual care, 27.9%; difference, 11.7 percentage points; 99.29% CI, 11.2-12.2 percentage points; P < .001). Each individual letter type significantly increased influenza vaccination with the largest effect sizes observed with a repeated letter sent 10 days after the initial letter (repeated letter, 41.8% vs usual care, 27.9%; difference, 13.9 percentage points; 99.29% CI, 13.1-14.7 percentage points; P < .001) and a letter emphasizing potential cardiovascular benefits of vaccination (cardiovascular gain, 39.8% vs usual care, 27.9%; difference, 11.9 percentage points; 99.29% CI, 11.1-12.7 percentage points; P < .001). Vaccination rates were improved across major subgroups. In a nationwide randomized clinical implementation trial, electronically delivered letter-based nudges markedly increased influenza vaccination compared with usual care among young and middle-aged patients with chronic diseases. The results of this study suggest that simple, scalable, and cost-efficient electronic letter strategies may have substantial public health implications. ClinicalTrials.gov Identifier: NCT06030739.