Primary Effectiveness Outcome Research Articles

Very brief intervention for physical activity behaviour change in cardiac rehabilitation: protocol for the ‘Measure It!’ effectiveness–implementation hybrid trial

IntroductionPhysical inactivity is a risk factor for repeat cardiac events and all-cause mortality in coronary heart disease (CHD). Cardiac rehabilitation, a secondary prevention programme, aims to increase physical activity levels...

Effectiveness and safety of 99Tc-methylene diphosphonate as a disease-modifying anti-rheumatic drug (DMARD) in combination with conventional synthetic (cs) DMARDs in the treatment of rheumatoid arthritis: A systematic review and meta-analysis of 34 randomized controlled trials

BackgroundTechnetium [99Tc] methylene diphosphonate injection (99Tc-MDP) is widely used for the treatment of rheumatoid arthritis (RA), but there is still insufficient evidence for its application. Through the utilization of meta-analysis and systematic reviews, this study aimed to evaluate the effectiveness and safety of 99 TC-MDP in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for RA. MethodsThis study was registered on PROSPERO in advance (CRD42021220780). A systematic search was conducted in PubMed, Embase, the Cochrane Library, and multiple international public databases from their inception to April 2023 to identify clinical randomized controlled trials exploring the use of 99Tc-MDP combined with csDMARDs in the treatment of RA. Each outcome was subjected to meta-analysis, and the quality of evidence was assessed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The American College of Rheumatology's 50 %/70 % response criteria scores (ACR50/70) scores were utilized as the primary effectiveness outcomes, and risks were measured by assessing the rates of AEs. Moreover, secondary efficacy outcomes were evaluated, including the Disease Activity Score 28 (DAS28) and bone mineral density (BMD) as joint function indicators and the erythrocyte sedimentation rate (ESR) and interleukin-17 (IL-17) as inflammatory indicators. ResultsIn this meta-analysis, a total of 34 studies (2296 patients) were included out of 1149 retrieved studies. The summarized results showed that the treatment group treated with the combination of 99Tc-MDP and csDMARDs had significantly higher ACR50 (RR = 1.32, 95 % CI: 1.13–1.55, P = 0.0004) and ACR70 (RR = 1.40, 95 % CI: 1.07–1.82, P = 0.01) scores than the control group receiving csDMARDs alone. In addition, the overall incidence of AEs was lower with the combination of 99Tc-MDP and csDMARDs than with csDMARDs alone (RR = 0.75, 95 % CI: 0.60–0.93, P = 0.009), but the possibility of phlebitis was higher in the treatment group (RR = 4.15, 95 % CI: 1.04–16.50, P = 0.04). In addition, the combination of 99Tc-MDP and csDMARDs had advantages over csDMARDs alone in improving DAS28 (WMD = 1.56, 95 % CI: 0.86–2.25, P < 0.0001), BMD (SMD = 1.12, 95 % CI 0.46–1.78, P = 0.0008), ESR (SMD = 0.71, 95 % CI 0.45–0.97, P < 0.00001), and IL-17 (WMD = 5.82, 95 % CI 3.86–7.77, P < 0.00001). However, the above results might have been influenced by the 99Tc-MDP dosage, csDMARD category, and treatment duration. Combining methotrexate and leflunomide, administering continuous treatment for 24 weeks, or using 3 sets of 99Tc-MDP doses (16.5 mg) may be the optimal 99Tc-MDP treatment plan for RA. ConclusionCompared with csDMARD therapy alone, the combination therapy with 99Tc-MDP is more effective for RA patients and is associated with a lower overall incidence of adverse events, although the possibility of phlebitis was higher. However, due to the inherent limitations of the included RCTs, high-quality clinical trials are still needed to further assess the effectiveness and safety of this combination therapy.

Piloting an ICU follow-up clinic to improve health-related quality of life in ICU survivors after a prolonged intensive care stay (PINA): feasibility of a pragmatic randomised controlled trial

BackgroundICU survivors often suffer from prolonged physical and mental impairments resulting in the so called “Post-Intensive Care Syndrome” (PICS). The aftercare of former ICU patients affected by PICS in particular has not been addressed sufficiently in Germany so far. The aim of this study was to evaluate the feasibility of a pragmatic randomised trial (RCT) comparing an intensive care unit (ICU) follow-up clinic intervention to usual care.MethodsThis pilot study in a German university hospital evaluated the feasibility of a pragmatic RCT. Patients were assigned in a 1:1 ratio to an ICU follow-up clinic intervention or to usual care. The concept of this follow-up clinic was previously developed in a participatory process with patients, next of kin, health care professionals and researchers. We performed a process evaluation and determined acceptability, fidelity, completeness of measurement instruments and practicality as feasibility outcomes. The RCT’s primary outcome (health-related quality of life) was assessed six months after ICU discharge by means of the physical component scale of the Short-Form-12 self-report questionnaire.ResultsThe pilot study was conducted from June 2020 to May 2021 with 21 and 20 participants in the intervention and control group. Principal findings related to feasibility were 85% consent rate (N = 48), 62% fidelity rate, 34% attrition rate (N = 41) and 77% completeness of outcome measurements. The primary effectiveness outcome (health-related quality of life) could be measured in 93% of participants who completed the study (N = 27). The majority of participants (85%) needed assistance with follow-up questionnaires (practicality). Median length of ICU stay was 13 days and 85% (N = 41) received mechanical ventilation, median Sequential Organ Failure Assessment Score was nine. Six-month follow-up assessment was planned for all study participants and performed for 66% (N = 41) of the participants after 197 days (median).ConclusionThe participatory developed intervention of an ICU follow-up clinic and the pragmatic pilot RCT both seem to be feasible. We recommend to start a pragmatic RCT on the effectiveness of the ICU follow-up clinic.Trial registrationClinicalTrials.gov US NLM, NCT04186468, Submission: 02/12/2019, Registration: 04/12/2019, https://clinicaltrials.gov/ct2/show/NCT04186468

Sustained Effect of Clinical Decision Support for Heart Failure: A Natural Experiment Using Implementation Science.

In a randomized controlled trial, we found that applying implementation science (IS) methods and best practices in clinical decision support (CDS) design to create a locally customized, "enhanced" CDS significantly improved evidence-based prescribing of β blockers (BB) for heart failure compared with an unmodified commercially available CDS. At trial conclusion, the enhanced CDS was expanded to all sites. The purpose of this study was to evaluate the real-world sustained effect of the enhanced CDS compared with the commercial CDS. In this natural experiment of 28 primary care clinics, we compared clinics exposed to the commercial CDS (preperiod) to clinics exposed to the enhanced CDS (both periods). The primary effectiveness outcome was the proportion of alerts resulting in a BB prescription. Secondary outcomes included patient reach and clinician adoption (dismissals). There were 367 alerts for 183 unique patients and 171 unique clinicians (pre: March 2019-August 2019; post: October 2019-March 2020). The enhanced CDS increased prescribing by 26.1% compared with the commercial (95% confidence interval [CI]: 17.0-35.1%), which is consistent with the 24% increase in the previous study. The odds of adopting the enhanced CDS was 81% compared with 29% with the commercial (odds ratio: 4.17, 95% CI: 1.96-8.85). The enhanced CDS adoption and effectiveness rates were 62 and 14% in the preperiod and 92 and 10% in the postperiod. Applying IS methods with CDS best practices was associated with improved and sustained clinician adoption and effectiveness compared with a commercially available CDS tool.

Comparisons of Effectiveness and Safety between On-label Dosing, Off-label Underdosing and Off-label Overdosing in Asian and Non-Asian Atrial Fibrillation Patients Treated with Rivaroxaban: A Systematic Review and Meta-analysis of Observational Studies.

Limited real-world data show that rivaroxaban following dosage criteria from either ROCKET AF (20mg/day or 15mg/day if creatinine clearance [CrCl]<50ml/min) or J-ROCKET AF (15mg/day or 10mg/day if CrCl<50ml/min) are associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We are aimed to study whether these observations differ between Asian and non-Asian subjects. A systematic review and meta-analysis with random effects was conducted to estimate the aggregate hazard ratio (HR) and 95% confidence interval (CI) using PubMed and MEDLINE databases from September 8, 2011 to December 31, 2022 searched for adjusted observational studies that reported relevant clinical outcomes of NVAF patients receiving rivaroxaban 10mg/day if CrCl>50ml/min, on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and rivaroxaban 20mg/day if CrCl<50ml/min. Effectiveness and safety endpoints were compared between ROCKET AF and J-ROCKET AF dosing regimen in Asian and non-Asian subjects, separately. Also, risks of events of rivaroxaban 10mg/day despite of CrCl>50ml/min and rivaroxaban 20mg/day despite of CrCl<50ml/min were compared to that of "ROCKET AF/J-ROCKET AF dosing". Sensitivity analyses were performed by sequential elimination of each study from the pool. The meta-regression analysis was performed to explore the influence of potential factors on the effectiveness and safety outcomes. Eighteen studies involving 67,571 Asian and 54,882 non-Asian patients were included. Rivaroxaban following J-ROCKET AF criteria was associated with comparable risks of thromboembolism in the Asian subgroup, whereas rivaroxaban following J-ROCKET AF criteria was associated with higher risks of all-cause mortality (HR:1.30; 95%CI:1.05-1.60) compared with that of ROCKET AF criteria in the non-Asian population. There were no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF versus ROCKET AF criteria either in the Asian or non-Asian population. Use of rivaroxaban 10mg despite of CrCl>50ml/min was associated with a higher risk of thromboembolism (HR:1.64; 95%CI:1.28-2.11) but lower risk of major bleeding (HR:0.72; 95%CI:0.57-0.90) compared with eligible dosage criteria. Use of rivaroxaban 20mg despite of CrCl<50ml/min was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.32; 95%CI:1.09-1.59), mortality (HR:1.33; 95%CI:1.10-1.59) and major bleeding (HR:1.26; 95%CI:1.03-1.53) compared with eligible dosage criteria. The pooled results were generally in line with the primary effectiveness and safety outcomes by removing a single study at one time. Meta-regression analyses failed to detect the bias in most potential patient characteristics associated with the clinical outcomes. Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET-AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favorable for the non-Asian population. Use of rivaroxaban 10mg despite of CrCl>50ml/min was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while use of rivaroxaban 20mg despite of CrCl<50ml/min was associated with worse outcome in most clinical events.

Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease and Diabetes Mellitus: A Subgroup Analysis of the ADAPTABLE Trial.

Patients with diabetes mellitus (DM) and concomitant atherosclerotic cardiovascular disease (ASCVD) must be on the most effective dose of aspirin to mitigate risk of future adverse cardiovascular events. ADAPTABLE, an open-label, pragmatic study, randomized patients with stable, chronic ASCVD to 81 mg or 325 mg of daily aspirin. The effects of aspirin dosing was assessed on the primary effectiveness outcome, a composite of all-cause death, hospitalization for myocardial infarction, or hospitalization for stroke, and the primary safety outcome of hospitalization for major bleeding. In this prespecified analysis, we used Cox proportional hazards models to compare aspirin dosing in patients with and without DM for the primary effectiveness and safety outcome. Of 15,076 patients, 5,676 (39%) had DM of whom 2,820 (49.7%) were assigned to 81 mg aspirin and 2,856 (50.3%) to 325 mg aspirin. Patients with versus without DM had higher rates of the composite cardiovascular outcome (9.6% vs. 5.9%; P < 0.001) and bleeding events (0.78% vs. 0.50%; P < 0.001). When comparing 81 mg vs. 325 mg of aspirin, patients with DM had no difference in the primary effectiveness outcome (9.3% vs. 10.0%; hazard ratio [HR] 0.98 [95% CI 0.83-1.16]; P = 0.265) or safety outcome (0.87% vs. 0.69%; subdistribution HR 1.25 [95% CI 0.72-2.16]; P = 0.772). This study confirms the inherently higher risk of patients with DM irrespective of aspirin dosing. Our findings suggest that a higher dose of aspirin yields no added clinical benefit, even in a more vulnerable population.

Real-World Utilization of an Intrauterine, Vacuum-Induced, Hemorrhage-Control Device.

To assess the real-world effectiveness and safety of a U.S. Food and Drug Administration (FDA)-cleared intrauterine vacuum-induced-hemorrhage control device for postpartum hemorrhage (PPH) management. Sixteen centers in the United States participated in this observational, postmarket registry medical record review (October 2020 through March 2022). The primary effectiveness outcome was treatment success , defined as bleeding control after insertion with no treatment escalation or bleeding recurrence. Additional outcomes included blood loss, time to device insertion, indwelling time, bleeding recurrence, and time to bleeding control. Treatment success and severe maternal morbidity measures (transfusion of 4 or more units of red blood cell, intensive care unit admission, and hysterectomy) were evaluated by blood loss before insertion. To assess safety, serious adverse events (SAEs) and adverse device effects were collected. All outcomes were summarized by mode of delivery; treatment success was summarized by bleeding cause (all causes, any atony, isolated atony, nonatony). In total, 800 individuals (530 vaginal births, 270 cesarean births) were treated with the device; 94.3% had uterine atony (alone or in combination with other causes). Median total blood loss at device insertion was 1,050 mL in vaginal births and 1,600 mL in cesarean births. Across all bleeding causes, the treatment success rate was 92.5% for vaginal births and was 83.7% for cesarean births (95.8% [n=307] and 88.2% [n=220], respectively, in isolated atony). Median indwelling time was 3.1 hours and 4.6 hours, respectively. In vaginal births, 14 SAEs were reported among 13 individuals (2.5%). In cesarean births, 22 SAEs were reported among 21 individuals (7.8%). Three (0.4%) SAEs were deemed possibly related to the device or procedure. No uterine perforations or deaths were reported. For both vaginal and cesarean births in real-world settings, rapid and effective bleeding control was achieved with an FDA-cleared intrauterine vacuum-induced hemorrhage-control device. The safety profile was consistent with that observed in the registrational trial (NCT02883673), and SAEs or adverse device effects were of the nature and severity expected in the setting of PPH. This device is an important new tool for managing a life-threatening condition, and timely utilization may help to improve obstetric hemorrhage outcomes. ClinicalTrials.gov , NCT04995887.

A Hybrid Effectiveness-Implementation Study of Adherence to Long-Term Oxygen Therapy for COPD.

Interventions to promote adherence to long-term oxygen therapy (LTOT) in chronic obstructive pulmonary disease (COPD) are needed. Examine the real-world effectiveness of phone-based peer coaching on LTOT adherence and other outcomes in a pragmatic trial of patients with COPD. In a hybrid effectiveness-implementation pragmatic trial, patients were randomized to phone-based Proactive coaching (educational materials, five phone-based peer coaching sessions over 60 days), Reactive coaching (educational materials, peer coaching when requested), or usual care. Study staff collected baseline and outcome data via phone at 30, 60 and 90 days after randomization. Adherence to LTOT over 60 days, the primary effectiveness outcome, was defined as mean LTOT use ≥17.7 hours/day. LTOT use was calculated using information about home oxygen equipment use in worksheets completed by study participants. Comparisons of adherence to LTOT between each coaching group and the usual care group using multivariable logistic regression models were pre-specified as the primary analyses. Secondary effectiveness outcomes included Patient Reported Outcome Management Information System (PROMIS) measures for physical, emotional, and social health. We assessed early implementation domains in the RE-AIM framework (reach, adoption, implementation). In 444 participants, the proportion who were adherent to LTOT at 60 days was 74% in usual care, 84% in Reactive coaching , and 70% in Proactive coaching groups. Although reach, adoption by stakeholder partners, and intervention fidelity were acceptable, complete LTOT adherence data was available in only 73% of participants. Reactive coaching (adjusted odds ratio [aOR] 1.77, 97.5% confidence interval [CI] 0.80-3.90) and Proactive coaching (aOR 0.70, 97.5% CI 0.34-1.46) did not improve adherence to LTOT compared with usual care. However, Proactive coaching significantly reduced depressive symptoms and sleep disturbance compared with usual care and reduced depressive symptoms compared with Reactive coaching. Unexpectedly, LTOT adherence was significantly lower in Proactive compared with Reactive coaching group. The results were inconclusive about whether either phone-based peer coaching strategy changed LTOT adherence compared with usual care. Further studies are needed to confirm the potential benefits of Proactive peer coaching on secondary effectiveness outcomes and differences in LTOT adherence between Proactive and Reactive peer coaching. Clinical trial registered with ClinicalTrials.gov (NCT02098369).

Brief Cognitive-Behavioral Therapy for Depression in Community Clinics: A Hybrid Effectiveness-Implementation Trial.

The authors examined whether brief cognitive-behavioral therapy (bCBT) for depression, delivered by mental health providers in community-based outpatient clinics (CBOCs) of the Veterans Health Administration, improved depression outcomes and was feasible and acceptable in clinical settings. The authors used a type-2 hybrid effectiveness-implementation, patient-randomized trial to compare bCBT with enhanced usual care. Participants (N=189) with moderate symptoms of depression (Patient Health Questionnaire-9 [PHQ-9] score ≥10) were enrolled from CBOCs in the southern United States. bCBT (N=109) consisted of three to six sessions, delivered by mental health providers (N=17) as part of routine clinic practices. Providers received comprehensive training and support to facilitate bCBT delivery. Recipients of enhanced usual care (N=80) were given educational materials and encouraged to discuss treatment options with their primary care provider. The primary effectiveness outcome was PHQ-9-assessed depression symptoms posttreatment (4 months after baseline) and at 8- and 12-month follow-ups. Implementation outcomes focused on bCBT dose received, provider fidelity, and satisfaction with bCBT training and support. bCBT improved depression symptoms (Cohen's d=0.55, p<0.01) relative to enhanced usual care posttreatment, and the improvement was maintained at 8- and 12-month follow-ups (p=0.004). bCBT participants received a mean±SD of 3.7±2.7 sessions (range 0-9), and 64% completed treatment (≥3 sessions). Providers delivered bCBT with fidelity and reported that bCBT training and support were feasible and effective. bCBT had a modest treatment footprint of approximately four sessions, was acceptable to participants and providers, was feasible for delivery in CBOCs, and produced meaningful sustained improvements in depression.

Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes.

To evaluate the comparative cardiovascular effectiveness and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in older adults with type 2 diabetes (T2D) across different frailty strata. We performed three 1:1 propensity score-matched cohort studies, each stratified by three frailty strata, using data from Medicare beneficiaries (2013-2019) with T2D who initiated SGLT-2is, GLP-1RAs, or DPP-4is. In time-to-event analyses, we assessed the primary cardiovascular effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, and all-cause mortality. The primary safety outcome was a composite of severe adverse events that have been linked to SGLT-2i or GLP-1RA use. Compared with DPP-4is, the overall hazard ratio (HR) for the primary effectiveness outcome associated with SGLT-2is (n = 120,202 matched pairs) was 0.72 (95% CI 0.69-0.75), corresponding to an incidence rate difference (IRD) of -13.35 (95% CI -15.06 to -11.64). IRD ranged from -6.74 (95% CI -8.61 to -4.87) in nonfrail to -27.24 (95% CI -41.64 to -12.84) in frail people (P for interaction < 0.01). Consistent benefits were observed for GLP-1RAs compared with DPP-4is (n = 113,864), with an overall HR of 0.74 (95% CI 0.71-0.77) and an IRD of -15.49 (95% CI -17.46 to -13.52). IRD in the lowest frailty stratum was -7.02 (95% CI -9.23 to -4.81) and -25.88 (95% CI -38.30 to -13.46) in the highest (P for interaction < 0.01). Results for SGLT-2is versus GLP-1RAs (n = 89,865) were comparable. Severe adverse events were not more frequent with SGLT-2is or GLP-1RAs than DPP-4is. SGLT-2is and GLP-1RAs safely improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among frail people.

A user-centred implementation strategy for tuberculosis contact investigation in Uganda: protocol for a stepped-wedge, cluster-randomised trial

BackgroundTuberculosis(TB) is among the leading causes of infectious death worldwide. Contact investigation is an evidence-based, World Health Organisation-endorsed intervention for timely TB diagnosis, treatment, and prevention but has not been widely and effectively implemented.MethodsWe are conducting a stepped-wedge, cluster-randomised, hybrid Type III implementation-effectiveness trial comparing a user-centred to a standard strategy for implementing TB contact investigation in 12 healthcare facilities in Uganda. The user-centred strategy consists of several client-focused components including (1) a TB-education booklet, (2) a contact-identification algorithm, (3) an instructional sputum-collection video, and (4) a community-health-rider service to transport clients, CHWs, and sputum samples, along with several healthcare-worker-focused components, including (1) collaborative improvement meetings, (2) regular audit-and-feedback reports, and (3) a digital group-chat application designed to develop a community of practice. Sites will cross-over from the standard to the user-centred strategy in six, eight-week transition steps following a randomly determined site-pairing scheme and timeline. The primary implementation outcome is the proportion of symptomatic close contacts completing TB evaluation within 60 days of TB treatment initiation by the index person with TB. The primary clinical effectiveness outcomes are the proportion of contacts diagnosed with and initiating active TB disease treatment and the proportion initiating TB preventative therapy within 60 days. We will assess outcomes from routine source documents using intention-to-treat analyses. We will also conduct nested mixed-methods studies of implementation fidelity and context and perform cost-effectiveness and impact modelling. The Makerere School of Public Health IRB(#554), the Uganda National Council for Science and Technology(#HS1720ES), and the Yale Institutional Review Board(#2000023199) approved the study and waived informed consent for the main trial implementation-effectiveness outcomes. We will submit results for publication in peer-reviewed journals and disseminate findings to local policymakers and representatives of affected communities.DiscussionThis pragmatic, quasi-experimental implementation trial will inform efforts to find and prevent undiagnosed persons with TB in high-burden settings using contact investigation. It will also help assess the suitability of human-centred design and communities of practice for tailoring implementation strategies and sustaining evidence-based interventions in low-and-middle-income countries.Trial registrationThe trial was registered(ClinicalTrials.gov Identifier NCT05640648) on 16 November 2022, after the trial launch on 7 March 2022.

Safety and effectiveness comparison of a new cohesive ophthalmic viscosurgical device.

Evaluation of the safety and effectiveness of a new cohesive OVD (StableVisc) compared to a marketed cohesive OVD (ProVisc) in patients undergoing cataract surgery. 22 sites in the United States. Prospective, multicenter, controlled, double-masked, and randomized 1:1 (StableVisc:ProVisc; stratified by site, age group, and cataract severity). Adults (≥45 years) with age-related non-complicated cataract considered amenable to treatment with standard phacoemulsification cataract extraction and IOL implantation were included. Patients were randomized to receive either StableVisc or ProVisc during standard cataract surgery. Postoperative visits occurred at 6 hours, 24 hours, 7 days, 1 month, and 3 months. The primary effectiveness outcome was the change in endothelial cell density (ECD) from baseline to 3 months. The primary safety endpoint was the proportion of patients who experienced at least one IOP measurement ≥30 mmHg at any follow-up visit. Noninferiority between the devices was tested. Inflammation and adverse events were evaluated. 390 patients were randomized; 187 patients with StableVisc and 193 patients with ProVisc completed the study. StableVisc was noninferior to ProVisc in mean ECD loss from baseline to 3 months (17.5% and 16.9%, respectively). StableVisc was noninferior to ProVisc in the proportion of patients with postoperative IOP ≥30 mmHg at any follow-up visit (5.2% and 8.2%, respectively). StableVisc cohesive OVD, which provides both mechanical and chemical protection, is safe and effective when used in cataract surgery and provides surgeons with a new cohesive OVD.

Scaling and sustaining COVID-19 vaccination through meaningful community engagement and care coordination for underserved communities: hybrid type 3 effectiveness-implementation sequential multiple assignment randomized trial

BackgroundCOVID-19 inequities are abundant in low-income communities of color. Addressing COVID-19 vaccine hesitancy to promote equitable and sustained vaccination for underserved communities requires a multi-level, scalable, and sustainable approach. It is also essential that efforts acknowledge the broader healthcare needs of these communities including engagement in preventive services.MethodsThis is a hybrid type 3 effectiveness-implementation study that will include a multi-level, longitudinal, mixed-methods data collection approach designed to assess the sustained impact of a co-created multicomponent strategy relying on bidirectional learning, shared decision-making, and expertise by all team members. The study capitalizes on a combination of implementation strategies including mHealth outreach with culturally appropriate messaging, care coordination to increase engagement in high priority preventive services, and the co-design of these strategies using community advisory boards led by Community Weavers. Community Weavers are individuals with lived experience as members of an underserved community serving as cultural brokers between communities, public health systems, and researchers to co-create community-driven, culturally sensitive public health solutions. The study will use an adaptive implementation approach operationalized in a sequential multiple assignment randomized trial design of 300 participants from three sites in a Federally Qualified Health Center in Southern California. This design will allow examining the impact of various implementation strategy components and deliver more intensive support to those who benefit from it most. The primary effectiveness outcomes are COVID-19 vaccine completion, engagement in preventive services, and vaccine confidence. The primary implementation outcomes are reach, adoption, implementation, and maintenance of the multicomponent strategy over a 12-month follow-up period. Mixed-effects logistic regression models will be used to examine program impacts and will be triangulated with qualitative data from participants and implementers.DiscussionThis study capitalizes on community engagement, implementation science, health equity and communication, infectious disease, and public health perspectives to co-create a multicomponent strategy to promote the uptake of COVID-19 vaccination and preventive services for underserved communities in San Diego. The study design emphasizes broad engagement of our community and clinic partners leading to culturally sensitive and acceptable strategies to produce lasting and sustainable increases in vaccine equity and preventive services engagement.Trial registrationClinicalTrials.gov Identifier: NCT05841810 May 3, 2023

Safety and Effectiveness of As-Needed Formoterol in Asthma Patients Taking Inhaled Corticosteroid (ICS)-Formoterol or ICS-Salmeterol Maintenance Therapy.

As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting β2-agonists. To evaluate the safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study. RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 μg or salbutamol 200 μg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n= 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation. For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P= .0066 and P= .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P= .007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P= .35). As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol.

P-169 In vitro fertilization versus intrauterine insemination with ovarian stimulation for unexplained infertility: A Collaborative Meta-analysis with Individual Participant Data

Abstract Study question In couples with unexplained infertility, does IVF increase cumulative live birth rate and reduce multiple pregnancy rate compared to intrauterine insemination with ovarian stimulation (IUI-OS)? Summary answer There were no significant differences in cumulative live birth and multiple pregnancy rates between IVF and IUI-OS in couples with unexplained infertility. What is known already IVF and IUI-OS are widely used in managing unexplained infertility, especially in couples with a poor prognosis for natural conception. Although several randomized controlled trials (RCTs) have compared IVF versus IUI-OS, it remains inconclusive regarding which approach is more effective. Some of the RCTs did not define a time limit for follow up and others made the comparison on a per-cycle basis which provides a biased estimate in favour of IVF. Study design, size, duration We performed an individual participant data meta-analysis (IPD-MA) that synthesised available individual-level data comparing IVF and IUI-OS in unexplained infertility. We searched MEDLINE, EMBASE, CENTRAL, PsycINFO, CINAHL, and the Cochrane Gynaecology and Fertility Group Specialised Register of RCTs and included eligible RCTs that completed data collection before June 2021. We invited author groups of eligible studies to join the IPD-MA and share the deidentified IPD of their RCTs. Participants/materials, setting, methods RCTs that compared IVF/ICSI to IUI-OS in couples with unexplained infertility were included. The primary effectiveness outcome was cumulative live birth, defined by time to pregnancy leading to live birth. The primary safety outcome was the number of multiple pregnancies per participant. IPD were checked and standardised before synthesis. The quality of evidence was assessed using the Risk of Bias 2 tool. The analysis followed the intention-to-treat principle, and a two-stage IPD meta-analysis was performed. Main results and the role of chance Of eight potentially eligible RCTs, four shared individual-level data of 933 couples, of which 550 couples were allocated to IVF and 383 couples to IUI-OS. Two RCTs had a low risk of bias, one had some concerns, and one had a high risk of bias. Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (4 RCTs, 908 couples, 50.3% vs 43.2%, HR 1.10, 95% CI 0.54 to 2.21, I2 = 68.7%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than in IUI-OS (3 RCTs, 923 couples, 3.8% vs 5.2%, OR 0.78, 95% CI 0.41 to 1.50, I2 = 0.0%). Clinical pregnancy (4 RCTs, 933 couples, OR 1.09, 95% CI of 0.78 to 1.53, I2 = 14.3%) and pregnancy loss (3 RCTs, 760 couples, OR 0.97, 95% CI 0.55 to 1.72, I2 = 0.0%) were comparable between IVF and IUI-OS. There were no significant differences in neonatal outcomes between the two interventions on gestational age and birth weight. Limitations, reasons for caution Four RCTs did not share IPD which may introduce the risk of data availability bias. Only two included RCTs collected data on neonatal outcomes. Three of the included RCTs predominantly or only included couples with poor prognosis of natural conception which limits generalisability. Wider implications of the findings IVF and IUI-OS are both viable options in terms of effectiveness and safety for managing unexplained infertility, especially for those with a poor prognosis of natural conception. The associated costs of interventions and the preference of couples are important in clinical decision-making. Trial registration number not applicable

Protocol: Implementation evaluation of a combination intervention for sustainable blood pressure control in rural KwaZulu-Natal, South Africa (IMPACT BP): A three-arm, unblinded, parallel group individually randomized clinical trial

BackgroundHypertension is the primary risk factor for stroke and heart disease, which are leading causes of death in South Africa. Despite the availability of treatments, there is an implementation gap in how best to deliver hypertension care in this resource-limited region. MethodsWe describe a three-arm parallel group individually randomized control trial to evaluate the effectiveness and implementation of a technology-supported, community-based intervention to improve blood pressure control among people with hypertension in rural KwaZulu-Natal. The study will compare three strategies: 1) standard of care (SOC arm) clinic-based management, 2) home-based blood pressure management supported by community blood pressure monitors (CBPM arm) and a mobile health application to record blood pressure readings and enable clinic-based nurses to remotely manage care, and 3) an identical strategy to the CBPM arm, except that participants will use a cellular blood pressure cuff, which automatically transmits completed readings over cellular networks directly to clinic-based nurses (eCBPM+ arm). The primary effectiveness outcome is change in blood pressure from enrollment to 6 months. The secondary effectiveness outcome is the proportion of participants with blood pressure control at 6 months. Acceptability, fidelity, sustainability, and cost-effectiveness of the interventions will also be assessed. ConclusionsIn this protocol, we report the development of interventions in partnership with the South Africa Department of Health, a description of the technology-enhanced interventions, and details of the study design so that our intervention and evaluation can inform similar efforts in rural, resource-limited settings.Protocol: Version 3 November 9th, 2022.Clinicaltrials.gov Trial Registration: NCT05492955SAHPRA Trial Number: N20211201.SANCTR Number: DOH-27-112,022-4895.

Comparison of the effectiveness and safety of 2 aspirin doses in secondary prevention of cardiovascular outcomes in patients with chronic kidney disease: A subgroup analysis of ADAPTABLE

Among patients with established cardiovascular disease, the ADAPTABLE trial found no significant differences in cardiovascular events and bleeding rates between 81 mg and 325 mg of aspirin (ASA) daily. In this secondary analysis from the ADAPTABLE trial, we studied the effectiveness and safety of ASA dosing in patients with a history of chronic kidney disease (CKD). ADAPTABLE participants were stratified based on the presence or absence of CKD, defined using ICD-9/10-CM codes. Within the CKD group, we compared outcomes between patients taking ASA 81 mg and 325 mg. The primary effectiveness outcome was defined as a composite of all cause death, myocardial infarction, or stroke and the primary safety outcome was hospitalization for major bleeding. Adjusted Cox proportional hazard models were utilized to report differences between the groups. After excluding 414 (2.7%) patients due to missing medical history, a total of 14,662 patients were included from the ADAPTABLE cohort, of whom 2,648 (18%) patients had CKD. Patients with CKD were older (median age 69.4 vs 67.1 years; P < .0001) and less likely to be white (71.5% vs 81.7%; P < .0001) when compared to those without CKD. At a median follow-up of 26.2 months, CKD was associated with an increased risk of both the primary effectiveness outcome (adjusted HR 1.79 [1.57, 2.05] P < .001 and the primary safety outcome (adjusted HR 4.64 (2.98, 7.21), P < .001 and P < .05, respectively) regardless of ASA dose. There was no significant difference in effectiveness (adjusted HR 1.01 95% CI 0.82, 1.23; P=.95) or safety (adjusted HR 0.93; 95% CI 0.52, 1.64; P=.79) between ASA groups. Patients with CKD were more likely than those without CKD to have adverse cardiovascular events or death and were also more likely to have major bleeding requiring hospitalization. However, there was no association between ASA dose and study outcomes among these patients with CKD.

0570 Use of the ExVent Accessory with the O2Vent Optima Oral Appliance for the Treatment of Obstructive Sleep Apnea – A Clinical Trial

Abstract Introduction The ExVent is an optional accessory to the O2Vent Optima mandibular advancement device (MAD) and provides oral Expiratory Positive Airway Pressure (EPAP). Oral EPAP with the ExVent is designed to provide upper airway support via similar mechanisms of action of nasal EPAP devices in commercial distribution, e.g., passive dilatation of the airway, which reduces flow limitation. Nasal EPAP devices are in commercial distribution as stand-alone therapies for the treatment of OSA. The oral EPAP provided by the ExVent accessory is designed to augment the OSA therapy provided by the O2Vent Optima. Methods This is a prospective, open-label, single-arm study conducted at 3 sites. Subjects who have been diagnosed with mild to moderate OSA (i.e., AHI ≥ 5 and ≤ 30) were included. Screening Phase The subjects completed a PSG study to obtain the baseline AHI and confirm a diagnosis of mild to moderate OSA Home Use Phase Subjects used the O2Vent Optima + ExVent for up to 3 months and logged usage hours. Subsequent to the Home Use Phase subjects underwent an in-lab PSG sleep night while using the O2Vent Optima + ExVent. Primary Effectiveness Outcome Measure: Change in AHI between baseline and the AHI measured during the in-lab PSG sleep night using O2Vent Optima + ExVent. Safety Outcome Measure: Adverse events will be summarized descriptively in terms of type and frequency Results Patients with mild to moderate OSA were treated with Optima MAD and ExVent for 3 months at 3 different sites in North America. Preliminary data analysis demonstrated that treatment with Optima MAD and ExVent reduced AHI from 13.5±6.4/hr to 6.6±4.5/hr (p&amp;lt; 0.05), average 58% reduction in AHI. The lowest oxygen during sleep increased from 84.6±2.7% to 88.6±2.9% (p&amp;lt; 0.05). Overall success rate (&amp;gt;50% reduction in AHI) with treatment was 80%. During the trial patients on treatment with Optima MAD and ExVent demonstrated no excessive adverse events or device malfunction. Conclusion The clinical trial confirmed successful treatment with combined use of O2Vent Optima MAD and oral Expiratory Positive Airway Pressure accessory - ExVent in patients with mild to moderate OSA. Treatment was well tolerated with no excessive adverse effects. Support (if any)

Study protocol: Type III hybrid effectiveness-implementation study implementing Age-Friendly evidence-based practices in the VA to improve outcomes in older adults

BackgroundUnmet care needs among older adults accelerate cognitive and functional decline and increase medical harms, leading to poorer quality of life, more frequent hospitalizations, and premature nursing home admission. The Department of Veterans Affairs (VA) is invested in becoming an “Age-Friendly Health System” to better address four tenets associated with reduced harm and improved outcomes among the 4 million Veterans aged 65 and over receiving VA care. These four tenets focus on “4Ms” that are fundamental to the care of older adults, including (1) what Matters (ensuring that care is consistent with each person’s goals and preferences); (2) Medications (only using necessary medications and ensuring that they do not interfere with what matters, mobility, or mentation); (3) Mentation (preventing, identifying, treating, and managing dementia, depression, and delirium); and (4) Mobility (promoting safe movement to maintain function and independence). The Safer Aging through Geriatrics-Informed Evidence-Based Practices (SAGE) Quality Enhancement Research Initiative (QUERI) seeks to implement four evidence-based practices (EBPs) that have shown efficacy in addressing these core tenets of an “Age-Friendly Health System,” leading to reduced harm and improved outcomes in older adults.MethodsWe will implement four EBPs in 9 VA medical centers and associated outpatient clinics using a type III hybrid effectiveness-implementation stepped-wedge trial design. We selected four EBPs that align with Age-Friendly Health System principles: Surgical Pause, EMPOWER (Eliminating Medications Through Patient Ownership of End Results), TAP (Tailored Activities Program), and CAPABLE (Community Aging in Place – Advancing Better Living for Elders). Guided by the Pragmatic Robust Implementation and Sustainability Model (PRISM), we are comparing implementation as usual vs. active facilitation. Reach is our primary implementation outcome, while “facility-free days” is our primary effectiveness outcome across evidence-based practice interventions.DiscussionTo our knowledge, this is the first large-scale randomized effort to implement “Age-Friendly” aligned evidence-based practices. Understanding the barriers and facilitators to implementing these evidence-based practices is essential to successfully help shift current healthcare systems to become Age-Friendly. Effective implementation of this project will improve the care and outcomes of older Veterans and help them age safely within their communities.Trial registrationRegistered 05 May 2021, at ISRCTN #60,657,985.Reporting guidelinesStandards for Reporting Implementation Studies (see attached).

Effectiveness of spinal manipulation and biopsychosocial self-management compared to medical care for low back pain: a randomized trial study protocol

BackgroundChronic low back pain (cLBP) is widespread, costly, and burdensome to patients and health systems. Little is known about non-pharmacological treatments for the secondary prevention of cLBP. There is some evidence that treatments addressing psychosocial factors in higher risk patients are more effective than usual care. However, most clinical trials on acute and subacute LBP have evaluated interventions irrespective of prognosis.MethodsWe have designed a phase 3 randomized trial with a 2 × 2 factorial design. The study is also a Hybrid type 1 trial with focus on intervention effectiveness while simultaneously considering plausible implementation strategies. Adults (n = 1000) with acute/subacute LBP at moderate to high risk of chronicity based on the STarT Back screening tool will be randomized in to 1 of 4 interventions lasting up to 8 weeks: supported self-management (SSM), spinal manipulation therapy (SMT), both SSM and SMT, or medical care. The primary objective is to assess intervention effectiveness; the secondary objective is to assess barriers and facilitators impacting future implementation. Primary effectiveness outcome measures are: (1) average pain intensity over 12 months post-randomization (pain, numerical rating scale); (2) average low back disability over 12 months post-randomization (Roland-Morris Disability Questionnaire); (3) prevention of cLBP that is impactful at 10–12 months follow-up (LBP impact from the PROMIS-29 Profile v2.0). Secondary outcomes include: recovery, PROMIS-29 Profile v2.0 measures to assess pain interference, physical function, anxiety, depression, fatigue, sleep disturbance, and ability to participate in social roles and activities. Other patient-reported measures include LBP frequency, medication use, healthcare utilization, productivity loss, STarT Back screening tool status, patient satisfaction, prevention of chronicity, adverse events, and dissemination measures. Objective measures include the Quebec Task Force Classification, Timed Up & Go Test, the Sit to Stand Test, and the Sock Test assessed by clinicians blinded to the patients’ intervention assignment.DiscussionBy targeting those subjects at higher risk this trial aims to fill an important gap in the scientific literature regarding the effectiveness of promising non-pharmacological treatments compared to medical care for the management of patients with an acute episode of LBP and the prevention of progression to a severe chronic back problem.Trial registrationClinicalTrials.gov Identifier: NCT03581123.