Grand Rounds Archive

Grand Rounds October 24, 2025: Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation: The PARACHUTE-HF Trial (Renato Lopes MD, PhD)

Posted on by Sophia Ramirez

Speaker

Renato Lopes MD, PhD
Professor of Medicine, Division of Cardiology
Duke University Medical Center
Duke Clinical Research Institute

Keywords

Heart Failure; Chagas Disease; Underserved Population

Key Points

  • Chagas disease is a condition caused by the parasite Trypanosoma cruzi. One of the complications of Chagas is heart failure (HF). Though Latin America has historically borne the brunt of Chagas-related HF, incidence is increasing globally.
  • Chagas-related HF has unique characteristics, with lower prevalence of hypertension and diabetes, worse health-related quality of life, and higher hospitalization and mortality rates when compared to other types of HF. In short, though patients with Chagas-related HF are less likely to have classic HF risk factors, their event rates are higher. Furthermore, there’s a lack of clinical evidence to guide their treatment.
  • Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation (PARACHUTE-HF) was a prospective randomized trial evaluating the effect of sacubitril/valsartan compared with enalapril in improving a hierarchical composite endpoint including cardiovascular (CV) death, HF hospitalization, and reduction in NT-proBNP levels – in that order, on the basis of clinical importance.
  • The study population consisted of 922 patients from 83 sites in 4 Latin American countries: Argentina, Brazil, Colombia, and Mexico. Participants had HF with reduced ejection fraction (HFrEF) and a confirmed diagnosis of Chagas disease.
  • After 12 weeks, the study team found that sacubitril/valsartan was superior to enalapril with respect to the hierarchical composite endpoint. These results were primarily driven by a 32% reduction in average NT-proBNP levels.
  • There were some limitations, including COVID-19-related changes in clinical practice that may have affected HF hospitalization rates and the observed treatment effect.
  • PARACHUTE-HF was the first major randomized trial studying HF treatment in HFrEF patients with Chagas disease. While sacubitril/valsartan has extensive clinical and real-world data supporting its effectiveness for HFrEF, this trial further supports its use in treating this specific population.
  • There is a need for rigorously conducted clinical trials in Chagas disease to better define the cardiovascular benefit/risk profile of new treatment options for this neglected and high-risk population. This trial provides a model for international collaboration among cardiologists and infectious disease physicians with a shared goal.

Discussion Themes

The pathophysiology of Chagas is complex. It includes chronic, low-intensity myocarditis, which can lead to changes in coagulation pathways and thrombotic events; a neurological tropism, which can cause sudden arrythmias; and an autoimmune component.

Dr. Lopes emphasized the impact that an intentional and informed coordinating center; carefully selected sites; deeply invested PIs; and a strong Data and Safety Monitoring Board (DSMB) had on the success of PARACHUTE-HF.

Grand Rounds October 17, 2025: Making Effective Use of Data Infrastructure in PCORnet® (Charles Bailey, MD, PhD; Keith Marsolo, PhD)

Posted on by Sophia Ramirez

Speakers

Charles Bailey, MD, PhD
Department of Pediatrics
Perelman School of Medicine
University of Pennsylvania
Biomedical and Health Informatics
Children’s Hospital of Philadelphia

Keith Marsolo, PhD
Associate Professor
Department of Population Health Sciences
Duke Clinical Research Institute
Duke University School of Medicine

Keywords

PCORnet®; Data; Clinical Research Network; Patient-Centered Research; Common Data Model

Key Points

  • PCORnet® is a clinical research network that connects communities (namely providers; researchers; patients, caregivers, and advocates) and data (EHR, claims, and patient-reported). It functions as a learning health system to help researchers generate answers that advance health outcomes.
  • The network is made up of healthcare institutions, from large academic health centers to local community clinics. As of August 2025, PCORnet® had collated data from healthcare encounters in all 50 states, representing over 47 million people. There had been 57 PCORnet® studies and 991 publications supported by PCORnet® resources.
  • To be useful, data have to be standardized across systems. Frequent data curation and a single language enabled by the PCORnet® Common Data Model (CDM) facilitates this. Data that are in the CDM and currently available for use in research include demographics, diagnoses, and vital signs. Data that may or may not be in the CDM and require additional work for research include immunizations, social determinants of health, and patient-reported outcomes.
  • Quarterly, the PCORnet® team executes a data curation process. This includes a range of checks looking at data completeness; plausibility; persistence; and conformance to the PCORnet® CDM. Over the last decade, PCORnet® network performance has improved in terms of data mapping and latency.
  • Researchers can approach the PCORnet® Front Door with both simple univariate and bivariate statistical questions – i.e. how often a particular medication is used within the PCORnet® population – and with prep-to-research queries, which may identify an eligible population and generate some information about how that population behaves.
  • Once a team is running a PCORnet® study, they can submit queries for study-specific data extracts. This involves identifying a cohort and extracting patient-level data.
  • In the near future, PCORnet® will include additional data visualization options to increase the ease of navigating complex results. The team is also working on a Query Tools repository that will show what other people have already asked about a given set of data.
  • Because each study operates on specific variables and general characteristics do not predict specific characteristics, study-focused assessment of data fitness is critical.
  • The presenters walked attendees through 5 different PCORnet® studies and how they utilized this data infrastructure in their projects.

Discussion Themes

There is no charge for Front Door queries; they are part of the research engagement process. However, prep-to-research queries are limited to those that can be turned around in a reasonable period of time; they don’t extend to statistical modeling or requests that involve asking sites to get new kinds of data. At the pilot level, researchers can execute custom queries that provide a deeper look at the data.

Linkage partners will depend on the needs of a study. For example, PCORnet® Studies have linked to claims data from Centers for Medicare & Medicaid Services, registries that collect lived experience information, and commercial vendors that perform specialty lab or image testing.

An advantage of using PCORnet® for pragmatic and prospective trials is the connection with the health system, local investigators, and data experts. These can serve as valuable resources during the design, recruitment, and analysis stages.

Grand Rounds October 10, 2025: Integrating the BeatPain Study With PRaCTICe, a New Network Research Hub of the CARE for Health Initiative (Julie M. Fritz, PhD, PT, FAPTA; Sebastian Tong, MD, MPH)

Posted on by Sophia Ramirez

Speakers

Julie M. Fritz, PhD, PT, FAPTA
Distinguished Professor
Department of Physical Therapy & Athletic Training University of Utah

Sebastian Tong, MD, MPH
Associate Professor
University of Washington

Keywords

Engagement; Community-Engaged Research; Rural; Pain; Partnership

Key Points

  • In an assessment of 10 high-income nations, the United States ranked 10th in healthcare system performance despite maintaining a significant lead in terms of healthcare spending.
  • The capacity of clinical research to improve healthcare is limited by a lack of representation. Patients who are older; live in rural locations; are uninsured; have co-morbid conditions; belong to minority groups; and are more likely to receive non-standard treatment are all inadequately represented in trials.
  • The NIH CARE for Health Initiative seeks to address these interrelated challenges. It will develop infrastructure for a clinical research network focused on primary care (PC); establish a foundation for sustained engagement with underrepresented communities; implement innovative study designs; integrate research into routine PC without increasing the burden on providers; and facilitate the adoption of evidence-based research findings.
  • CARE for Health is based in 6 national research hubs. One is the Primary Care Rural and Frontier Clinical Trials Innovation Center (PRaCTICe), a research network partnering with 300 PC practices serving 7 underrepresented population across Oregon, Washington, Wyoming, Alaska, Montana, and Idaho.
  • PRaCTICe utilizes a continuum of community engagement, from outreach to shared leadership. Engagement strategies have included community needs assessment reviews, regional listening sessions, and a new study development process that involves co-designing studies with PRaCTICe partners.
  • In 2024, BeatPain – a pragmatic, decentralized, NIH Collaboratory Trial – was selected as 1 of 2 trials PRaCTICe would partner with during Year 1. By the presentation date, PRaCTICe had referred 165 patients to the BeatPain team, 95% of which were rural residents.
  • Rural populations simultaneously have higher incidence of chronic pain and are less likely to receive evidence-based, nonpharmacologic treatment for it. BeatPain seeks to serve this population by delivering physical therapy (PT) to federally qualified health center patients with lower back pain.
  • Over the course of their collaboration with PRaCTICe, BeatPain investigators have made strides in terms of localizing the study to partnering communities, building trust with referring providers and patients, and coordinating the end of the trial. Decentralized trial methods hold promise for engaging rural residents and clinics in clinical research.

Discussion Themes

Relationships between research staff and a variety of clinic staff were critical to effective engagement. In one example provided by Dr. Tong, staff helped identify which exercises were most effective when it came to getting providers interested in the referral process. Clinics were not passive recipients, but co-developers.

To deliver PT in a rural setting, the BeatPain team delivered a virtual intervention combining traditional PT, health coaching, motivational interviewing, and pain coping strategies. In some care processes, the hands-on component of PT is essential; less so for chronic pain. Strategic use of technology could expand access to nonpharmacologic care.

Research teams will need to be responsive to shifts in the capacity of rural hospitals and clinics due to funding cuts. This may look like designing interventions that don’t increase the burden on staff; supplying resources; and sharing strategies that clinics can use to be financially sustainable.

IT support proved central to the success of this partnered research. When clinic resources are constrained, the ability to help solve problems related to the electronic health record is essential.

Grand Rounds October 3, 2025: Multi-Domain Rehabilitation for Older Patients With Myocardial Infarction: The PIpELINe Trial (Elisabetta Tonet, MD)

Posted on by Sophia Ramirez

Speaker

Elisabetta Tonet, MD
Cardiology Consultant
Cardiology Unit
Azienda Ospedaliero–Universitaria di Ferrara, Italy

Keywords

Cardiovascular; Myocardial Infarction; Rehabilitation

Key Points

  • The standard of care in myocardial infarction (MI) management has evolved dramatically in the 20th century, shifting from absolute bed rest to early ambulation to the modern cardiac rehabilitation concept focused on physical activity. This typically includes inpatient mobilization, a 6 – 12 week outpatient program, and a maintenance phase.
  • Traditional cardiac rehabilitation programs have several limitations, including standardized activities, early withdrawal, high costs, and low enrollment of older adults. The latter factor is increasingly significant, as the contemporary MI patient has also changed; 2/3 of MI patients are over 65 years old.
  • Despite advancements in acute care, older patients presenting with MI are the highest risk population with the worst prognosis. Older adults also represent the least physically active group, often experiencing functional decline, frailty and disability after MI.
  • The research team sought to assess a physical activity model with both remote and supervised, in-person, monthly sessions. In the HULK pilot study, this intervention was seen to improve short physical performance battery values 6 months after acute coronary syndrome.
  • The Physical Activity Intervention in Elderly Patients with Myocardial Infarction (PIpELINe) trial evaluated whether an early, tailored, multi-domain rehabilitation intervention improved outcomes in older patients (65+ years old) admitted to the hospital for MI and with impaired physical performance.
  • PIpELINe was an investigator-initiated, multicenter, prospective, superiority randomized trial conducted across 7 centers in Italy. The intervention included metabolic risk factors management; diet counseling; and exercise training. The primary outcome was cardiovascular (CV) death or CV-related, unplanned hospitalization.
  • The research team found that the multi-domain cardiac rehabilitation program reduced CV death or CV-related, unplanned hospitalization in their target population by 8% compared to usual care.

Discussion Themes

One difficulty cited by similar projects is older adults’ reluctance to participate in clinical trials. In this case, the research team found that a monthly, sustained program that provided guidance following an MI was attractive to this population. The main barrier to enrollment was the pandemic.

The impact of the intervention on heart failure and unplanned hospitalization may be more pertinent to this population than CV death, as they pertain to functional decline and quality of life.

The monthly pace renders this intervention low-cost with high availability.

The multidimensionality of the trial makes it difficult to identify which factors drove the effectiveness of the intervention and to what extent. Dr. Tonet suspects that the physical activity component was the most impactful.

Grand Rounds September 26, 2025: Significance in ePCTs: P Values vs Decision-Maker Perspectives (Gregory E. Simon, MD, MPH; Susan Huang, MD, MPH; Elizabeth Turner, PhD)

Posted on by Sophia Ramirez

Speakers

Gregory E. Simon, MD, MPH
Kaiser Permanente Washington Health Research Institute

Susan Huang, MD, MPH
University of California Irvine

Elizabeth Turner, PhD
Duke University

Keywords

P-Values; Significance; Statistical Analysis; Pragmatic Trials; Decision-Makers

Key Points

  • P-values are a part of the statistical process of hypothesis and significance testing. They quantify of the degree of “surprise” in a finding. The result is dichotomous; a P-value of less than 0.05 is considered statistically significant, while a P-value greater than or equal to 0.05 is not.
  • 0.05 is a useful but somewhat arbitrary cutoff. It was probably first described in Statistical Methods for Medical Workers by R. A. Fisher: “It is convenient to take this point as a limit in judging whether a deviation is to be considered significant or not.” According to an anecdote shared by Fisher’s daughter, he identified the cutoff as “convincing enough” based on an informal experiment with a colleague.
  • Using a single threshold to determine significance can be problematic in real-world settings. Healthcare decisionmakers are seeking solutions to multi-dimensional problems, and they care about subgroups. Dr. Huang illustrated this point with an overview of ABATE Infection trial and her team’s subsequent collaboration with decision-makers.
  • ABATE Infection was a pragmatic, cluster-randomized trial assessing universal decolonization in non-ICUs. While decolonization wasn’t effective for all non-ICU patients, a post-hoc analysis found that the intervention was highly effective in patients with medical devices. This finding was practically significant and was included in national guidance around decolonization.
  • In a cost-effectiveness analysis of universal, targeted, or no decolonization for patients with medical devices, the ABATE team found that the optimal outcome was dependent on site circumstances, i.e. prevalence of device use, adherence to targeted decolonization, and financial penalties for bloodstream infection.
  • For years, experts have questioned the reliance on P-values. On the other hand, there are concerns that rejecting “H1 – H0” could prove to be a slippery slope to data dredging and “post-hoc chicanery.”
  • The dogma of the P-value may be more applicable to a clinical trial setting than to a pragmatic setting. Establishing the standard of care requires a high level of certainty. Scientific rigor demands rules and a threshold that isn’t affected by cost.
  • In hospitals, clinical decisions are rarely based on certainty; safe interventions that are low-cost and have a possible benefit are given more consideration. Decision-makers should understand the probability of benefit at a given P-value; circumstances may warrant adoption.
  • In pragmatic trials, valuable information may include the intervention effect size, the effect for various outcomes and on various subgroups, and information pertinent to implementation: fidelity, reach, cost, etc.
  • Decision-making is complex and multidimensional. What is important may depend on context, audience, or other situational factors. While P-values can be useful in decision-making, they aren’t the only piece of the puzzle.

Discussion Themes

Changing the reliance on P-values would require a multi-pronged, multi-dimensional approach; sponsors, journals, and other stakeholders each uphold the use of P-values for various reasons. Perhaps the best way to start integrating this perspective shift into the clinical trials ecosystem is to hold the line, routinely seeking and providing information about a variety of outcomes and confidence levels.

If we hold that the underlying but unknown truth is fixed, then our process for arriving at conclusions regarding a treatment’s effectiveness (or whether the treatment has a favorable benefit-risk profile) inherently has important operating characteristics, such as the Type I error rate. If we move away from P-values, we will need to define a design approach that considers these operating characteristics.

Maybe it’s more practical to think about honing into a standard of care as an iterative process, in the way that human learning is an iterative process; to state that we know something to some degree of certainty, then modify, refine, and get closer to defining these truths.

Grand Rounds September 19, 2025: Hurdles for the Delivery of Clinical Trials: Insights From the REMAP-CAP Trial in Europe (Denise van Hout, MD, PhD)

Posted on by terren.green@duke.edu

Speaker

Denise van Hout, MD, PhD
Postdoctoral Researcher
Julius Center for Health Sciences and Primary Care
University Medical Center Utrecht, the Netherlands

Keywords

Adaptive platform trial, Regulatory efficiency, REMAP-CAP, Study design, Study startup.

Key Points

  • Randomised Embedded Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) began in 2016 as a data driven analysis of ethical, administrative, and logistical and ethical (EARL) delays in clinical trials studying respiratory infections. The goal was embedded trials that are flexible, efficient, and agile to provide clinicians with high-quality evidence to make the best treatment decisions.
  • REMAP-CAP is a global multifactorial adaptive platform trial with a master protocol that can investigate multiple interventions in different treatment domains for a single disease.
  • Over 8000 patients in REMAP-CAP were randomized to 44 interventions in 16 different treatment domains between January 2019 and June 2023. Patients could be randomized to more than 1 domain resulting in 15656 randomizations. Enrollment increased during the COVID-19 pandemic.
  • Dr. van Hout believes that to improve clinical trials, we should treat the challenges as a scientific problem and solve them with the same rigor.
  • Regulatory requirements and informed consent regulations differed among sites causing confusion for the researchers about what documents should be submitted with the contract and protocol in each country. Drug labeling requirements in some countries also slowed protocol approval. EARL processes also slowed trial initiation and patient enrollment.
  • It was clear that overall enrollment in the UK outpaced the other 257 sites worldwide. The UK had a shorter period of time to a fully signed study contract and protocol approval compared with sites in other countries (5 days in the UK compared with 183 days in non-UK countries). This quicker time to signed contract was accomplished by either accepting the contract as-is or rejecting the contract – without negotiating small details. The UK was also 3 months faster than non-UK countries at enrolling the first patient after study approval (1 month vs 4 months, respectively) leading to more enrollment and more research questions answered.
  • In January of 2022 the EU centralized regulatory submission to a single portal (CTIS) to ease and speed the process of starting a new trial.

Discussion Themes

Adaptive platform trials were uncommon before the COVID-19 pandemic, but their value became clear during the pandemic. After the pandemic, REMAP-CAP focuses on different treatment domains for pneumonia. Maintaining the infrastructure for an adaptive platform trial is difficult if there is not a clear need such as there was during the COVID-19 pandemic.

Centralizing approval for trials under one government body could speed the approval process for studies. During times of high need, prioritizing one or two good trials over a lot of smaller trials can also help speed the process.

 

Learn more about REMAP-CAP at https://www.remapcap.eu/

Grand Rounds September 5, 2025: The Non-Learning Health System (Robert Califf, MD)

Posted on by Sophia Ramirez

Speaker

Robert Califf, MD
Instructor in Medicine
Duke University Medical Center
Former Commissioner of Food and Drugs

Keywords

Healthcare; Learning Health System; Evidence-Based Practices; Health Outcomes

Q&A

The following reflects key takeaways from a fireside chat with Dr. Robert Califf, in which he shared his perspective on the “non-learning” health system. For a comprehensive account of Dr. Califf’s insights, watch the recording.

What do you mean by the “non-learning” health system?

25 years ago, certain visionaries looked at the advancement of computing, electronic health records, and other digital data and noted that data could and should be used to improve healthcare delivery and, in turn, health outcomes.

But increasingly, the healthcare system in the United States is “learning” based on institutional financial outcomes as opposed to patient outcomes. That’s not to say it’s a zero-sum game—but efforts are being directed towards expensive technologies that offer marginal benefit (but deliver good economic returns) as opposed to primary care, prevention, and interventions that address basic risk factors.

How can we reshape those incentives?

If the goal is to optimize the longevity, well-being, and functionality of the American population, incentives within the healthcare system should be aligned with health outcomes.

Why has it been so difficult to integrate evidence-based practices into healthcare settings? And how can we begin to change that?

If we align health care systems’ incentives with health outcomes, they will figure out how to operationalize these practices. But if we assume the incentives will not be realigned in the near future, we will need to eke out areas of alignment with decision-makers, incremental improvements that are not so disruptive that they get squashed. And finally, we need to develop disruptive external systems to challenge health systems.

What tasks should this community focus on?

Keep working on pragmatic trials; show that interventions have practical applications. Keep developing the skills to communicate about your work to the public. And be prepared to put our system back together when it breaks.

Discussion Themes

Other discussion themes included the critical role of randomized trials and the potential role of AI in answering scientific questions; what the research community can learn from other industries; and anticipated changes to the healthcare system and research landscape.

Grand Rounds August 22, 2025: Avoiding the Fumble: Building on a Decade of Lessons from Pragmatic Clinical Trials (Emily O’Brien, PhD, FAHA)

Posted on by Sophia Ramirez

Speaker

Emily O’Brien, PhD, FAHA
Associate Professor
Duke Clinical Research Institute
Duke University School of Medicine
Department of Population Health Sciences

Keywords

Pragmatic Trials; Best Practices; PCORnet; Evidence-Based Practices

Key Points

  • Historically, the healthcare industry has been limited by an insufficient body of evidence driving everyday clinical decision-making. Roughly a decade ago, pragmatic clinical trials (PCTs) began to gain traction as a promising solution.
  • There are several advantages of PCTs. They can be embedded within healthcare systems without disrupting the clinical workflow; answer questions of major public health importance; streamline procedures and infrastructure by making use of existing data; and include diverse, representative study populations for highly generalizable results.
  • But a recent analysis of clinical research site challenges noted that protocol complexity, site workload, and patient burden have increased since 2015. Though the analysis was not specific to pragmatic trials, a fundamental shift in how researchers think about study design is required across the clinical trials space.
  • Additionally, evidence-based practices – even those that have been stress-tested in PCTs – are not always adopted by health systems. Trial success does not necessarily coincide with system priorities; different audiences, i.e. systems and funders, require different kinds of evidence; and 5- to 10-year studies are misaligned with systems’ 2- to 3-year decision horizons.
  • The NIH Pragmatic Trials Collaboratory philosophy holds that fumbles are part of the game; we can’t improve if we only share wins, and transparency and teamwork has helped this community iterate and improve. Accordingly, the PCORnet team developed “The Playbook,” inspired by the NIH Collaboratory’s Living Textbook, as a tool for sharing and refining the best approach to national-scale research.
  • The Playbook contains practical “drills” for avoiding common fumbles in recruitment, workflow, and outcome capture, and was created using a user-centered design process. They engaged PCORnet groups, partners, and members of the Playbook’s intended audience to inform and guide the content.
  • Modules 1 – 5 of the Playbook, launching this year, will provide an introduction to the network. They include sections on getting started with PCORnet, utilizing the network’s resources, dissemination and implementation expectations for PCORnet studies, and case studies.
  • In the long-term, the PCORnet team plans to actively review, maintain, and expand the Playbook. Additional modules are in process and targeted for release in 2026.

Discussion Themes

The success of the Playbook may depend on the willingness of investigators to share both their “best plays” and their mistakes. Dr. O’Brien was optimistic that research teams will buy into this philosophy and acknowledge it as an important piece of the evidence generation process.

The case studies that the team selected serve to illustrate A) that PCORnet trials are unique, innovative, and approaching challenges in a thoughtful, inspiring way and B) the many ways to engage with the network.

Grand Rounds August 15, 2025: Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients: The A2B Randomized Clinical Trial – Addressing a Complex Clinical Question With Novel Integrated Methodological Approaches (Tim Walsh, MD, FFICM; Chris Weir, PhD; Richard Parker, MsC)

Posted on by terren.green@duke.edu

Speakers

Professor Tim Walsh, MD, FFICM
Chair of Critical Care, Usher Institute, University of Edinburgh

Professor Chris Weir, PhD
Chair of medical statistics, Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh

Richard Parker MSc, Research Fellow
Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh

Keywords

Dexmedetomidine; Clonidine; Propofol; Sedation; Critical care; Mechanical ventilation.

Key Points

  • Critically ill, mechanically ventilated patients often require sedation for comfort. Avoiding deep sedation, agitation, and delirium is a priority in these patients. To accomplish this, current usual care for sedation internationally is the GABAergic agent propofol along with an opioid or other analgesia, but the alpha-2 agonists Dexmedetomidine or Clonidine are increasingly being used in the ICU.
  • Dexmedetomidine is licensed for ICU sedation and is believed to achieve a lighter level of sedation compared with propofol, but has a higher cost and, some studies have shown, a potentially higher rate of mortality in younger ICU patients. Clonidine, despite widespread use in the UK, is not licensed for ICU sedation and has a limited evidence base but is lower in cost.
  • This 3-arm, A2B pragmatic open-label effectiveness trial compared dexmedetomidine plus an opioid analgesic or clonidine plus an opioid analgesic with propofol plus an opioid analgesic in 1404 critically ill, mechanically ventilated patients (457 dexmedetomidine, 476 clonidine, 471 standard care [propofol]) in 41 ICUs across the UK from December 2018-December 2024.
  • The trial’s primary outcome was time to successful extubation post-randomization, and secondary outcomes included sedation quality, time to optimum sedation, delirium, ICU mortality, ICU length of stay, and drug related adverse events. Hypothesis for clonidine and dexmedetomidine were determined through 2 separate 3-stage pathways.
  • There were no significant differences found in either dexmedetomidine or clonidine compared with propofol (sHR 1.09, 95% CR 0.96 to 1.25, P =0.20; sHR 1.05, 95% CR 0.95 to 1.17, P=0.34; respectively) for the cumulative incidence of time to extubation. There were also no statistically significant differences in the percent of patients successfully extubated within 7 days, patient survival time to ICU mortality, outcome by age, SOFA score, or PRE-DELIRIC risk score. Unlike previous studies, no interaction was found between age and mortality in this study.
  • Rates of agitation were higher in the dexmedetomidine and clonidine groups, but rates of pain behavior, unnecessary deep sedation, and overall optimum sedation did not reach statistically significant differences compared with the propofol group. There were higher rates of severe bradycardia and cardiac arrythmia in the dexmedetomidine arm.
  • Interviews with clinical and research staff showed that multiple factors influence sedation practice within the trial context including context-specific sedation ‘culture’; clinician preference and equipoise; staff capacity, training, and capability; safety concerns; and engrained practices such as more deeply sedating patients overnight.

Discussion Themes

The latest European Society of Intensive Care Medicine guidelines, which don’t include the data from this trial, leave the decision to use dexmedetomidine or propofol up to clinician judgement. Trial data don’t support using clonidine widely, but if used, ICU staff should be confident with and have support for any adverse effects.

While delirium is associated with a range of outcomes like mortality and cost of care, no trial has shown that altering delirium translates into a benefit on those outcomes. A primary outcome of mortality would have needed a large number of participants, making the trial much more difficult to accomplish. For this reason, time to successful extubation was chosen as the primary outcome for this trial.

This A2B trial was not a blinded trial. Blinded drug trials have their place but are not really feasible pragmatic real-world trials. In addition, the cost of blinding this A2B trial would have been very high. Also, patients had strong views that they wanted the clinicians to know what drug they were delivering so they would be prepared to handle any adverse events.

Read more about the protocol and results of this A2B randomized clinical trial of sedation in clinically ill patients.

Grand Rounds August 8, 2025: Youth Nicotine Vaping Cessation: RCT of Varenicline Added to Remote Young Adult Lay Counselor Delivered Behavioral Cessation Support Vs. Texting Support (A. Eden Evins, MD, MPH)

Posted on by Sophia Ramirez

Speaker

A. Eden Evins, MD, MPH
Cox Family Professor of Psychiatry, Harvard Medical School
Founding Director, MGH Center for Addiction Medicine
Director for Faculty Development, Mass General Hospital Department of Psychiatry

Keywords

Vaping; Nicotine; Cessation; Behavioral Support; Texting

Key Points

  • Vaping, though technically a less harmful alternative to cigarette smoking, is the primary route to nicotine addiction in youth. Initially promoted to help with smoking cessation, vaping devices are increasingly marketed towards young people and have transformed teen nicotine and cannabis use.
  • Few treatments for vaping cessation have been tested. The research team hypothesized that the pharmacotherapy varenicline could help young adults abstain from nicotine vaping.
  • They conducted a randomized clinical trial with 2 aims: evaluate the efficacy of varenicline in addition to behavioral support for cessation of vaped nicotine and assess the safety and tolerability of varenicline. The target population was adolescents attempting vaping cessation.
  • According to the original design, participants would be randomized to 1 of 2 arms: varenicline + behavioral therapy and placebo + behavioral therapy. The possibility arose that the behavioral intervention would be particularly effective, they wouldn’t be able to differentiate between the arms, and the trial would fail. So they added a third arm: a referral to a widely-available messaging app supporting youth vaping cessation.
  • The research team made a few additional modifications to cut costs and enhance adherence. These included fully remote intervention and assessment; non-clinical personnel delivering the behavioral interventions; and video documentation of adherence, with compensation of $1 per video.
  • Over half of participants offered varenicline + counseling quit vaping and were abstinent for the last 4 weeks of treatment. The 4-week abstinence rate was 14% in the placebo + counseling group and 6% in the group that received texting support.
  • The study had a 97% completion rate using remote methods for intervention delivery and data collection. The research team received video evidence for 52% of varenicline doses and 42% of placebo doses. Behavioral counseling attendance was higher in the varenicline group (84%) than in the placebo group (66%).
  • Nausea, vivid dreams, and insomnia were more common in the group that received varenicline.

Discussion Themes

There’s interest in testing the effectiveness of varenicline without the addition of behavioral support. It’s an important question, Dr. Evins noted, given that behavioral support can be hard to come by.

Varenicline has been associated with exacerbation of psychiatric symptoms, including suicidal ideation. However, this has not been replicated in large clinical trials or epidemiologic trials. Explanations for the association include the effects of nicotine withdrawal symptom or the manifestation of comorbid psychiatric illnesses.