Real-world Effectiveness Trials Research Articles

Real-World Effectiveness in Hypertension and Hyperlipidemia Collaborative Management between Pharmacies and Primary Care in Portugal: A Multicenter Pragmatic Controlled Trial (USFarmácia®).

There is evidence of the efficacy of collaborative health interventions with pharmacies and primary care providers but little of its real-world effectiveness. We aimed to assess the effectiveness and discuss the design and challenges of hypertension and hyperlipidemia management between pharmacies and primary care providers using real-world data exchange between providers and experimental bundled payment. This was a pragmatic, quasi-experimental controlled trial. We collected patient-level data from primary care prescription claims and Electronic Medical Record databases, a pharmacy claims database, and patient telephone surveys at several time points. The primary outcomes were changes in blood pressure and total cholesterol. We used matched controls with difference-in-differences estimators in a Generalized Linear Model (GLM) and controlled interrupted time series (CITS). We collected additional data for economic and qualitative studies. A total of 6 Primary Care Units, 20 pharmacies, and 203 patients entered the study. We were not able to observe significant differences in the effect of intervention vs. control. We experienced challenges that required creative strategies. This real-world trial was not able to show effectiveness, likely due to limitations in the primary care technology which affected the sample size. It offers, however, valuable lessons on methods, strategies, and data sources, paving the way for more real-world effectiveness trials to advance value-based healthcare.

Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: A STAR*D analysis

IntroductionGuidance on Major Depressive Disorder (MDD) treatment in those with comorbid Alcohol Use Disorder (AUD) is limited. We performed a secondary analysis on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, examining the association between comorbid AUD and depression outcomes. MethodsSTAR*D was a real-world effectiveness trial starting with citalopram in level 1. Non-responding participants progressed through 3 other sequential treatment levels with different switch or augmentation options. Antidepressant outcomes were compared between MDD (n = 2826) and comorbid MDD and AUD (n = 864). Logistic regressions were performed to evaluate remission and response predictors in the total STAR*D sample and the AUD-comorbidity interaction. ResultsChi-squared tests showed no significant difference in response or remission rates from depression between groups across treatment levels. Higher Hamilton Rating Scale for Depression (HRSD) score was associated with overall lower odds of remission in treatment level 1 (OR = 0.93, p < 0.001) and 2 (OR = 0.95, p < 0.001), with no significant interaction with comorbid AUD. Higher baseline suicidality had overall lower odds of remission in level 1 (OR = 0.82, p < 0.001) and 2 (OR = 0.1, p < 0.001), but with comorbid AUD compared to no AUD, suicidality increased odds of level 1 remission (OR = 1.30, p = 0.012). In comorbid AUD in level 2, venlafaxine was associated with lower odds of remission (OR = 0.13, p = 0.013) and response (OR = 0.12, p = 0.006); bupropion with lower odds of response (OR = 0.22, p = 0.024). LimitationsOpen label study design and lack of alcohol use data. ConclusionsComorbid AUD may interact with predictors of antidepressant response in MDD and using venlafaxine or bupropion may be less effective. Addressing this comorbidity requires unique assessment and treatment approaches.

Effectiveness of a Smartphone App (MINISTOP 2.0) integrated in primary child health care to promote healthy diet and physical activity behaviors and prevent obesity in preschool-aged children: randomized controlled trial

BackgroundChildhood overweight and obesity is a public health priority. We have previously reported the efficacy of a parent-oriented mobile health (mHealth) app-based intervention (MINISTOP 1.0) which showed improvements in healthy lifestyle behaviors. However, the effectiveness of the MINISTOP app in real-world conditions needs to be established.ObjectiveTo evaluate the real-world effectiveness of a 6-month mHealth intervention (MINISTOP 2.0 app) on children’s intake of fruits, vegetables, sweet and savory treats, sweet drinks, moderate-to-vigorous physical activity, and screen time (primary outcomes), and on parental self-efficacy (PSE) for promoting healthy lifestyle behaviors, and children’s body mass index (BMI) (secondary outcomes).MethodsA hybrid type 1 effectiveness-implementation design was utilized. For the effectiveness outcomes, a two-arm, individually randomized controlled trial was conducted. Parents (n = 552) of 2.5-to-3-year-old children were recruited from 19 child health care centers across Sweden, and, randomized to either a control (standard care) or intervention group (MINISTOP 2.0 app). The 2.0 version was adapted and translated into English, Somali and Arabic to increase reach. All recruitment and data collection were conducted by the nurses. Outcomes were assessed at baseline and after six months, using standardized measures (BMI) and a questionnaire (health behaviors, PSE).ResultsAmong the participating parents (n = 552, age: 34.1 ± 5.0 years), 79% were mothers and 62% had a university degree. Twenty-four percent (n = 132) of children had two foreign-born parents. At follow-up, parents in the intervention group reported lower intakes of sweet and savory treats (-6.97 g/day; p = 0.001), sweet drinks (-31.52 g/day; p < 0.001), and screen time (-7.00 min/day; p = 0.012) in their children compared to the control group. The intervention group reported higher total PSE (0.91; p = 0.006), PSE for promoting healthy diet (0.34; p = 0.008) and PSE for promoting physical activity behaviors (0.31; p = 0.009) compared to controls. No statistically significant effect was observed for children’s BMI z-score. Overall, parents reported high satisfaction with the app, and 54% reported using the app at least once a week.ConclusionChildren in the intervention group had lower intakes of sweet and savory treats, sweet drinks, less screen time (primary outcomes) and their parents reported higher PSE for promoting healthy lifestyle behaviors. Our results from this real-world effectiveness trial support the implementation of the MINISTOP 2.0 app within Swedish child health care.Trial registrationClinicaltrials.gov NCT04147039; https://clinicaltrials.gov/ct2/show/NCT04147039

ADDRESSING THE MENTAL HEALTH NEEDS OF HOMEBOUND OLDER ADULTS IN AGING SERVICE SETTINGS

Abstract Despite significant and urgent mental health needs among low-income homebound older adults, the existing mental health service systems’ reach for these older adults is almost nonexistent. Given the current and projected geriatric mental health workforce shortages, innovative approaches are needed to better serve these underserved older adults. This presentation will focus on a series of randomized clinical trials that tested acceptable and feasible mental health service delivery models for homebound older adults who are served by aging service network agencies that provide hot meals and case management. Findings from the real-world effectiveness trials of tele-delivered behavioral activation treatment for depression and loneliness by bachelor’s-level lay counselors who are embedded in aging service agencies will be shared. Ways to promote a wider adoption of scalable and sustainable mental health service delivery models for homebound older adults will be discussed.

Appropriate controls for digital therapeutic clinical trials: A narrative review of control conditions in clinical trials of digital therapeutics (DTx) deploying psychosocial, cognitive, or behavioral content.

Digital therapeutics (DTx) are software programs that treat a disease or condition. Increasingly, DTx are part of medical care, and in the US healthcare system they are regulated by the FDA as Software as a Medical Device (SaMD). Randomized controlled trials (RCT) remain a key evidence generation step for most DTx. However, developing a unified approach to the design of appropriate control conditions has been a challenge for two main reasons: (1) inheriting control condition definitions from pharmacotherapy and medical device RCT that may not directly apply, and (2) challenges in establishing control conditions for psychosocial interventions that build the core of many DTx. In our critical review we summarize different approaches to control conditions and patient blinding in RCT evaluating DTx with psychosocial, cognitive or behavioral content. We identify control condition choices, ranging from very minimal digital controls to more complex and stringent digital applications that contain aspects of "fake" therapy, general wellness content or games. Our review of RCTs reveals room for improvement in describing and naming control conditions more consistently. We further discuss challenges in defining placebo controls for DTx and ways in which control choices may have a therapeutic effect. While no one-size-fits-all control conditions and study designs will apply to all DTx, we propose points to consider for defining appropriate digital control conditions. At the same time, given the rapid iterative development and optimization of DTx, treatments with low risk profile may be evaluated with minimal digital controls followed by extensive real-world effectiveness trials.

Impact of a Follow-up Telephone Call Program on 30-Day Readmissions (FUTR-30): A Pragmatic Randomized Controlled Real-world Effectiveness Trial.

Telephone call programs are a common intervention used to improve patients' transition to outpatient care after hospital discharge. To examine the impact of a follow-up telephone call program as a readmission reduction initiative. Pragmatic randomized controlled real-world effectiveness trial. We enrolled and randomized all patients discharged home from a hospital general medicine service to a follow-up telephone call program or usual care discharge. Patients discharged against medical advice were excluded. The intervention was a hospital program, delivering a semistructured follow-up telephone call from a nurse within 3-7 days of discharge, designed to assess understanding and provide education, and assistance to support discharge plan implementation. Our primary endpoint was hospital inpatient readmission within 30 days identified by the electronic health record. Secondary endpoints included observation readmission, emergency department revisit, and mortality within 30 days, and patient experience ratings. All 3054 patients discharged home were enrolled and randomized to the telephone call program (n=1534) or usual care discharge (n=1520). Using a prespecified intention-to-treat analysis, we found no evidence supporting differences in 30-day inpatient readmissions [14.9% vs. 15.3%; difference -0.4 (95% confidence interval, 95% CI), -2.9 to 2.1; P=0.76], observation readmissions [3.8% vs. 3.6%; difference 0.2 (95% CI, -1.1 to 1.6); P=0.74], emergency department revisits [6.1% vs. 5.4%; difference 0.7 (95% CI, -1.0 to 2.3); P=0.43], or mortality [4.4% vs. 4.9%; difference -0.5 (95% CI, -2.0 to 1.0); P=0.51] between telephone call and usual care groups. We found no evidence of an impact on 30-day readmissions or mortality due to the postdischarge telephone call program.

How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding.

The aim of this article is to discuss the validity of relapse prevention trials and the issue of withdrawal confounding in these trials. Recommendations for long-term antidepressant treatment are based almost exclusively on discontinuation trials. In these relapse prevention trials, participants with remitted depression are randomised either to have the antidepressant abruptly discontinued and replaced by inert placebo or to continue active treatment. The drug–placebo difference in relapse rates at the end of the maintenance phase is then interpreted as a prophylactic drug effect. These trials consistently produce remarkable benefits for maintenance treatment. However, the internal validity of this trial protocol is compromised, as research has shown that abruptly stopping antidepressants can cause severe withdrawal reactions that lead to (or manifest as) depression relapses. That is, there is substantial withdrawal confounding in discontinuation trials, which renders their findings uninterpretable. It is not clear to what degree the drug–placebo separation in relapse prevention (discontinuation) trials is due to withdrawal reactions, but various estimations suggest that it is presumably the majority. A review of findings based on other methodologies, including real-world long-term effectiveness trials like STAR*D and various naturalistic cohort studies, do not indicate that antidepressants have considerable prophylactic effects. As absence of evidence does not imply evidence of absence, no definitive conclusions can be drawn from the literature. To enable a thorough risk–benefit evaluation, real-world effectiveness trials should not only focus on relapse prevention, but also assess antidepressants’ long-term effects on social functioning and quality of life. Thus far, reliable long-term data on these outcome domains are lacking.

Validity and generalizability of findings of randomized controlled trials on arthroscopic partial meniscectomy of the knee.

The validity and generalizability of evidence from trials on arthroscopic partial meniscectomy (APM) for a ruptured meniscus of the knee has been debated in scientific journals. The aim of this paper was to assess the validity and generalizability of evidence for trials on effectiveness of APM by a novel Benchmarking method; to compare this assessment with established assessment methods; and to make an overall assessment of the current evidence on validity and generalizability of findings. Literature search was undertaken to find all randomized controlled trials. The benchmarking method, the Cochrane method for the assessment of validity of RCTs, and CONSORT method for the assessment of generalizability of findings were used. The data were extracted and checked for accuracy twice. Seven RCTs were found, of which 2 were double blinded. The benchmarking method indicated that only one trial, assessing real-world effectiveness, had recruited patients comprehensively from the catchment area and showed clinically important effectiveness for APM. All trials had deficiencies in reporting of baseline characteristics and adherence to interventions. In 5 trials, the crossover to surgery from conservative treatment arm was between 19 and 36 percent. The benchmarking method indicates that APM may be an effective treatment for meticulously selected patients, or when APM is targeted to those patients who do not respond to the conservative treatment. There is a need for more sham-controlled and real-world effectiveness trials reporting comprehensively patient characteristics and adherence to interventions, preferably in a representative sample of patients living in the recruitment area.

ERJPodcast February 2018: Effectivenessversusefficacy

As part of the February issue, the European Respiratory Journal presents the latest in its series of podcasts. Chief editor Martin Kolb interviews the Jørgen Vestbo (The University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK) about the important difference between standard efficacy trials and real-world effectiveness trials such as the Salford Lung Study.

The Effectiveness of a Large-Scale Language and Preliteracy Intervention: The SPELL Randomized Controlled Trial in Denmark.

The present article reports results of a real-world effectiveness trial conducted in Denmark with six thousand four hundred eighty-three 3- to 6-year-olds designed to improve children's language and preliteracy skills. Children in 144 child cares were assigned to a control condition or one of three planned variations of a 20-week storybook-based intervention: a base intervention and two enhanced versions featuring extended professional development for educators or a home-based program for parents. Pre- to posttest comparisons revealed a significant impact of all three interventions for preliteracy skills (=.21-.27) but not language skills (d=.04-.16), with little differentiation among the three variations. Fidelity, indexed by number of lessons delivered, was a significant predictor of most outcomes. Implications for real-world research and practice are considered.

Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder.

Current pharmacotherapies for major depressive disorder (MDD) have a distinct lag of onset that can prolong distress and impairment for patients, and real-world effectiveness trials further suggest that antidepressant efficacy is limited in many patients. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or antagonists with varying affinities for serotonin, norepinephrine, or dopamine. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, as well as in the development of novel therapeutics for this disorder. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD. These have been associated with relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics with increased potential in clinical practice (for instance, oral administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX-13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that have yet to be studied clinically, are also briefly discussed; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists.

Implementing Family-Centered Prevention in Rural African American Communities: a Randomized Effectiveness Trial of the Strong African American Families Program.

Efforts to disseminate evidence-based prevention programs are hampered by a lack of real-world effectiveness trials undertaken with community providers. The Strong African American Families (SAAF) program is an empirically validated intervention designed to prevent problem behavior among rural African American youth. To evaluate the effectiveness of SAAF and its implementation protocols when delivered by a community provider, we conducted a randomized, wait-list-controlled trial with outcome measurements assessed longitudinally at baseline and 6 months after baseline. A total of 465 African American youth and their parents were recruited randomly from public school lists of fifth- and sixth-grade students in eight rural counties in south Georgia. Youth and parents assessed targeted outcomes in their homes. The main outcome, problem behavior vulnerability, was operationalized as a latent construct comprising three indicators: tolerance for deviance, intentions to engage in risky behavior, and affiliations with risk-taking peers. SAAF was implemented with uniformly high levels of adherence (85.5%; SD = 10.8) and attendance (M = 4.1, SD = 2.9, range = 0-7). Intent-to-treat and complier average causal effect analyses revealed significant program effects on intervention-targeted parenting practices, youth self-regulatory processes, and problem behavior vulnerability. SAAF influenced problem behavior vulnerability indirectly via effects on targeted parenting and youth processes. This study supported the effectiveness of SAAF in a community setting when a systematic implementation model supports participant engagement and intervention adherence.

Ketamine for depression: evidence, challenges and promise.

Major depressive disorder and bipolar depression are among the most prevalent and disabling mental disorders worldwide. Real-world effectiveness trials in major depressive disorder have underscored that most pharmacological options target monoamines, which are involved in a minority (15-20%) of synaptic contacts in the mammalian brain. Most synapses (∼50%) use the amino acid glutamate as their primary neurotransmitter, and preclinical models of depression have implicated aberrant glutamatergic neurotransmission for 25 years (1). More recently, the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine was shown to produce rapid and robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression (2–7).

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review.

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Predictors of Treatment Engagement to the Parenting Intervention Mom Power Among Caucasian and African American Mothers

ABSTRACT. It has been well documented that early-intervention programs focused on young children hold the greatest promise to mediating mental, emotional, and behavioral disorders. Parenting programs with young children have yielded favorable outcomes; however, engaging and retaining participants has typically been a challenge. Predictors of treatment engagement, or factors influencing participants’ attendance rates and/or retention in a program, have been routinely studied with outcomes yielding differing results. The present study aims to extend this research by presenting engagement data on 150 mothers and their young children (ages 0–6 years old) in an attachment-based parenting and self-care skills intervention called Mom Power (MP). This study examines the impact of sociodemographic data, and mental and physical health factors on attendance rates of the entire mother–child sample and also compares rates for Caucasian and African American mothers separately. Results show that employment status and physical health impacted attendance for the entire sample and continued to be main predictors among African American mothers. This study has implications for future research specifically pertaining to ethnic and physical health predictors of participants’ retention in intervention programs. Recommendations for engagement and retention strategies are discussed, as are considerations for next steps to test the MP model in a real-world effectiveness trial.

Web-Based SBIRT Skills Training for Health Professional Students and Primary Care Providers

ABSTRACT The authors have developed and assessed 2 innovative, case-based, interactive training programs on substance abuse, one for health professional students on alcohol and one for primary care providers on screening, brief intervention, and referral to treatment (SBIRT). Both programs build skills in substance abuse SBIRT. Real-world effectiveness trials involving medical students (n = 10) and nursing students (n = 60) were completed; trials involving primary care providers (n = 65) are in progress during 2011. Medical students and nursing students had similarly low baseline scores on assessments that benefited from training: knowledge, confidence, and clinical performance measured via an online standardized patient case and encounter note all improved post-training. Preliminary results indicate that practicing providers improved on knowledge, attitude, and brief intervention skill performance after a similar training. Results suggest that SBIRT skills can be improved with this model for case-based interactive training programs, and thus, that this training has the potential to impact patient outcomes.

Daily skin cleansing with chlorhexidine did not reduce the rate of central-line associated bloodstream infection in a surgical intensive care unit

Cleansing the skin of intensive care unit (ICU) patients daily with chlorhexidine gluconate (CHG) has been associated with beneficial effects, including a reduction in central-line-associated bacteremias (CLABSIs). Most studies have been done in medical ICUs. In this study, we evaluated the effectiveness of daily chlorhexidine skin cleansing on CLABSI rates in a surgical ICU. In Fall 2005, the 30-bed surgical ICU at Rush University Medical Center discontinued daily soap-and-water bathing of patients and substituted skin cleansing with no-rinse, 2% CHG-impregnated cloths. This change was made without research investigator input or oversight. Using administrative, microbiological and infection control practitioner databases, we compared rates of CLABSIs and blood culture contamination during soap-and-water bathing (September 2004-October 2005) and CHG cleansing (November 2005-October 2006) periods. Rates of other nosocomial infections that were not expected to be affected by CHG bathing (secondary bacteremia, Clostridium difficile-associated diarrhea, ventilator-associated pneumonia, urinary tract infection) were included as control variables. There was no significant difference in the CLABSI rate between soap-and-water and CHG bathing periods (3.81/1,000 central line days vs. 4.6/1,000 central line days; p = 0.57). Blood culture contamination declined during CHG bathing (5.97/1,000 to 2.41/1,000 patient days; p = 0.003). Rates of other nosocomial infections did not change significantly. In this real-world effectiveness trial, daily cleansing of surgical ICU patients' skin with CHG had no effect on CLABSI rates, but was associated with half the rate of blood culture contamination. Controlled trials in surgical ICUs are needed to determine whether CHG bathing can prevent infections in this setting.

Psychopharmacologic approaches to the management of posttraumatic stress disorders in the acute care medical sector.

This pharmacotherapy chapter outlines a series of recommendations regarding the delivery of medications for patients who present with posttraumatic stress disorders (PTSD) and related behavioral and emotional disturbances in the acute care medical setting. These recommendations integrate information previously articulated in PTSD treatment guidelines with clinical experiences derived from real world effectiveness trials. Information from clinical trials suggests that there are patient, provider, and system level considerations that serve to influence the delivery of pharmacotherapeutic interventions targeting PTSD in acute care. The current pharmacotherapy recommendations also integrate considerations regarding the delivery of psychotherapeutic interventions targeting PTSD among injured trauma survivors.