Grand Rounds Archive

Grand Rounds June 23, 2023: Improving Delivery of Care for Chronic Kidney Disease, Diabetes and Hypertension (Miguel A. Vazquez, MD and George Oliver, MD, PhD)

Posted on by Hannah Webster

Speakers

Miguel A. Vazquez, MD
Robert Toto, MD
University of Texas Southwestern Medical Center
Dallas, TX

George Oliver, MD, PhD
Parkland Center for Clinical Innovation
Dallas, TX

Keywords

ICD-Pieces, pragmatic clinical trial, chronic kidney disease, type 2 diabetes, hypertension

Key Points

  • ICD-Pieces, an NIH Collaboratory Trial, was a cluster randomized, pragmatic clinical trial testing an intervention that used an electronic health record–based algorithm and practice facilitators in 141 primary care practices.
  • The study team randomly assigned more than 11,000 adults to receive either the intervention or usual care. The study population was diverse—20% were Black and almost 20% were Hispanic or Latino—representative of the population with chronic kidney disease, type 2 diabetes, and hypertension in the United States.
  • In the intervention group, the study team used an algorithm to identify patients in the electronic health record in real time.
  • Practice facilitators worked with the participating primary care providers and patients in the intervention group to meet blood pressure targets, promote use of appropriate medications, achieve goals for blood glucose control, and engage in other guideline-directed care. The intervention period lasted 12 months. The primary outcome was hospitalization for any reason.
  • The hospitalization rate was similar between the intervention group and the usual care group. Rates of key secondary outcomes, such as emergency department visits and cardiovascular events, were also similar between the groups.
  • The study team successfully completed study in 4 different health systems with a variety of EHR systems. The intervention was delivered with a high degree of fidelity, showing the feasibility of the study approach.
  • Engaging multiple stakeholders is key. Technology is helpful but not sufficient; delivery of the intervention required sustained effort.

Discussion Themes

- A more sustained intervention, greater engagement with pharmacists, and use of more patient-facing technology would have added to the success of intervention delivery.

- The longer the trial duration, the more complicated the challenges with site-level staff turnover, unanticipated changes in institutional policies and procedures, and changes in technology and EHR systems.

Tags

#pctGR, @Collaboratory1

Grand Rounds June 9, 2023: Emulating Randomized Clinical Trials with Non-randomized Real-world Evidence Studies: Results From The RCT DUPLICATE Initiative (Shirley V. Wang, PhD)

Posted on by Lauren Stewart

Speaker

Shirley V. Wang
Associate Professor
Division of Pharmacoepidemiology and Pharmacoeconomics
Brigham and Women’s Hospital
Harvard Medical School

 

Keywords

Pragmatic Clinical Trials; Emulation; Design; Database Study; Replicate

 

Key Points

  • RCT DUPLICATE is a series of methods NIH Collaboratory Trials with the the goal of understanding when and how database studies can support regulatory decision making. The first aim of the project is to use healthcare databases to emulate the design of 30 completed trials and predict the results of 7 ongoing trials. The goal with this aim is to determine if the same conclusion can be drawn from a database study and a trial. The second aim is to test the transparent and reproducible process with the FDA to evaluate Real World Evidence (RWE) studies. The third aim is to evaluate factors that predict concordance between the trials and the databases.
  • The study team used three predefined binary agreement metrics that they applied to each trial. They also used correlation coefficients to summarize agreement across the trial emulations.
  • The results showed that when the emulated trials were more pragmatic, the ability to closely emulate the trial design and obtain similar results was higher. However, when attempting to emulate a trial that had more explanatory design features, such as a run in or strict measures in place to ensure prolonged adherence, it was more difficult to disentangle whether the diversions in results were due to design emulation differences, which are differences between randomized controlled trials (RCT) and RWE, or biases, which are differences between RWE treatment arms.
  • In any trial emulation, researchers encounter design emulation differences in addition to potential sources of bias. The emulation differences in this trial included inclusion-exclusion criteria of the trial, population distribution, quality of the comparator emulation, outcome emulation, placebo control, in-hospital start time of medication, loading dose or dose titration protocol during follow-up, delayed effect with a long follow-up window, run-in window, discontinuation of maintenance therapy at randomization, and robustness of findings.
  • The team created an exploratory indicator that split the trials into two categories: those with fewer design emulation differences and those with more substantive design emulation differences. For trials with fewer emulation challenges, there was a closer agreement in agreement metrics. For trials with more emulation challenges, the correlation was low and results diverged more. The real benefit of database studies is the opportunity to generate evidence that is complementary to trials as well as to explore relevant clinical questions in which, for a variety of reasons, a trial cannot be conducted.
  • When the team was able to emulate the design and analysis closely, database studies often drew similar conclusions as trials. It is more challenging to emulate trials that are designed with many constraints to show effects under ideal conditions. The team saw greater success when replicating results of trials with more pragmatic design features.
  • When evaluating when and how RWE studies complement RCTs, it’s important to consider the target trial design that would best match the need or questions of the end users.

Discussion Themes

–What’s next for this initiative? Ongoing work we’re tackling is understanding that the methods and validity of trial emulation using EHR data or EHR-linked claims instead of claims data alone, as we used for these 32 trial emulations. We’ve also launched a spin-off project called ENCORE which is focused on emulating oncology trials using oncology specialty EHR data.

–What are you interested in on the analytic front regarding this topic? In general, I feel that the design trumps analytics in this case. We’re getting through the study design and making sure we’re asking the right questions. A lot of these analytics are about dealing with confounding in a better way, but if you can’t get the design right, then the analytics aren’t going to be closer.

-How do we teach our students and colleagues how to use the target trial framework and use these emulation approaches to advance our comparative effectiveness studies? It’s useful to lay out the parameters, or all of the questions to define the estimate for the target trial, whether hypothetical or real. Then lay out the same parameters you’re intending to set next to the real-world data. In our case, we color-coded these parameters and made a decision on whether it was feasible to continue or not based on whether it was possible to answer that same question. It’s a great approach to directly compare the parameters to see what question you’re truly asking.

Tags

#pctGR, @Collaboratory1

Grand Rounds June 2, 2023: PROACT Xa and The Wizard of Oz: Behind the Curtain of a Pragmatic Decentralized Clinical Trial (John Alexander, MD, MHS)

Posted on by Elizabeth Mccamic

Speaker

John Alexander, MD, MHS
Professor of Medicine/Cardiology
DCRI/Duke University

 

Keywords

PROACT Xa, Aortic Valve Replacement, Warfarin, Apixaban, Pragmatic Clinical Trial

 

Key Points

  • In the PROACT Xa trial, researchers wanted to learn if patients with an On-X mech valve implanted in the aortic position can be maintained on a factor Xa inhibitor (Apixaban) with a safe level of thromboembolic events compared to standard warfarin.
  • The trial was designed to randomize 1,000 patients who had an On-X aortic valve replacement at least 3 months prior to randomization with either a standard dose of Apixaban (5mg) or continued warfarin (the standard of care). The primary endpoint was composite of valve thrombosis or valve-related thromboembolism, and the primary safety endpoint was major bleeding. The drugs were administered open label and all patients were given a low dose of aspirin. The trial took place at 64 sites, and randomized 863 patients.
  • Sites were selected based on their On-X AVR volume, and the study leveraged the surgeon/patient relationship for recruitment. The study used remote enrollment, and there was also a centralized outreach to patients with On-X AVR by mail to all U.S. patients with a link to clinicaltrials.gov to learn more about the study. Several sites could enroll patients from outside of their system, based on regional or state requirements from local IRBs.
  • The study drug was mailed directly to participants, and at the end of the trial participants were instructed to destroy the drug. The price for Apixaban was $600 per bottle/$6M, and the price for warfarin was $50K. Follow up was conducted with a standardized script to ascertain events, and medical records were collected for event adjudication.
  • On Sept. 21, 2022, the PROACT Xa  DSMB recommended stopping enrollment and transitioning patients off of the study drug due to an observed excess in thromboembolic events in the Apixaban arm compared to the warfarin arm. Enrollment was stopped and all enrolled patients were contact to transition off of the study drug and back onto standard of care warfarin.
  • Of the total 863 enrolled patients, 20 on Apixaban had a valve thrombosis or valve-related thromboembolism event, compared to 6 events in the warfarin arm. The study determined that Apixaban was not non-inferior to warfarin for the prevention of valve thrombosis or valve-related thromboembolism and resulted in more thromboembolic events than warfarin in patients with an On-X mechanical aortic valve.

Learn more

Read about the PROACT Xa study.

Discussion Themes

-What was your impression of the challenges imposed for doing this trial? Tracy Wang: It is safe to say that none of us predicted COVID, and it hit pretty soon after we started enrollment. We never had to make too many procedural operations because everything was set up as much as possible for remote recruitment. The pragmatic elements were already in place so when COVID happened the main thing that had the biggest impact on our study was the shortage of study coordinators that effected every trial, and a few of our study sites went under due to difficulty of staffing and sustaining a research enterprise. We never had an amendment to the protocol.

-How are you taking it forward now that you are at PCORI? Tracy Wang: What lessons learned are your taking forward at PCORI? There are several things that are going to be in the PCORI rubric. We have a strong focus on comparative effectiveness and looking at critical health decisions. We are trying to do more of that and ask the more impactful questions to help patients and stakeholders make critical decisions in their care. From a funder’s perspective, trials of this size and impact can be done for prices that are not in the $200-300 million range. A lot of this has to do with the infrastructure, PROACT tapped into a unique device infrastructure.

-Since you demonstrated that a couple sites were able to care for subjects in any location, would you say more about the value that the additional separate clinical sites provided? John Alexander: One of the things we did in PROACT X-a is we allowed flexibility. There were sites that did no remote consent or enrollment. We said that was fine. Then others did remote. At times they changed their mind, based on other people doing it. There were some sites that allowed remote within a specific region. There were 2 sites that would take patients from anywhere in the U.S. It was very individualized.  Tracy Wang: Until there is more widespread experience in supporting decentralized trials, I do think there’s still value to the “local” clinical sites and certainly more patient familiarity and comfort.

Tags

#pctGR, @Collaboratory1

Grand Rounds May 19, 2023: Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis After a Fracture (Robert O’Toole, MD)

Posted on by Elizabeth Mccamic

Speaker

Robert O’Toole, MD
Chief of Orthopaedics, R Adams Cowley Shock Trauma Center
Head, Division of Orthopaedic Trauma
Department of Orthopaedics
Director, Clinical Research, Department of Orthopaedics
University of Maryland School of Medicine

 

Keywords

Pragmatic trials, orthopedic surgery, orthopedic trauma, Venous thromboembolism

 

Key Points

  • Venous thromboembolism (VTE) is a potentially fatal complication after orthopedic trauma. Prophylaxis (chemical or mechanical) reduces risk deep vein thrombosis (DVT) by around 50%. The North American guideline is to give Low Molecular Weight Heparin (LMWH) in cases of orthopedic trauma for VTE prophylaxis.
  • Aspirin is now the most commonly used VTE prophylaxis for Arthroplasty patients, in which Aspirin and LMWH are both safe and effective prophylaxis options.
  • Aspirin as an oral pill is a less expensive and easier option for the orthopedic trauma population, which has a high proportion of uninsured patients. Researchers aimed to test the safety and effectiveness of Aspirin use as prophylaxis in orthopedic trauma cases.
  • A pilot study, called the ADAPT trial, demonstrated feasibility, similar in-patient compliance and similar post-discharge adherence for the 2 options.
  • Through the Patient-Centered Outcomes Research Institute (PCORI), the team conducted a Discrete Choice Experiment (DCE), which highlighted patient concern for risk of death compared to risk of complication. This inspired the research team to shift the primary outcome to death.
  • Aspirin vs. Low Molecular Weight Heparin for Thromboprophylaxis: A Randomized Clinical Trial of Over 12,000 Orthopedic Trauma Patients (PREVENT CLOT) was conducted through METRC at 21 centers across the country.
  • The primary hypothesis was that all-cause mortality is non-inferior with Aspirin compared to LMWH among orthopedic trauma patients. The study required an FDA exemption because Aspirin is not approved for this indication. The pragmatic randomized control trial was designed from a hospital policy perspective.
  • Adult patients who fit the inclusion criteria were randomized at the patient level and stratified by treatment site. Patients and clinicians were non-blinded.
  • The primary outcome was all-cause mortality. Secondary outcomes were pulmonary embolism-related death, non-fatal pulmonary embolism, and DVT. Secondary safety outcomes were bleeding events, wound complications, and surgical site infections.
  • The study found that Aspirin is non-inferior to LMWH in preventing all-cause mortality after orthopedic trauma. There were similar results in the secondary outcomes, except LMWH showed lower risk of distal DVT. Therefore, it can be considered an acceptable option when clinicians, patients and hospital consider these data.
  • Using the Win Ratio, which strategically considers the primary outcome as well as secondary outcomes like patient satisfaction, the researchers found that Aspirin was still acceptable even among higher-risk patients.

 

Discussion Themes

-Researchers decided to use a two-arm study with only Aspirin because of its low cost and its use in orthopedic arthroplasty.

-While people may be interested in specific subpopulations or outcomes, the confidence interval is not adjusted for multiple comparisons, so slicing the data could risk spurious findings.

-Clinician buy-in and understanding the social component of clinical work was essential to the pragmatic trial.

-The research team did not run into institutional barriers in the trial, likely because of the opportunity of Aspirin to be a much lower cost option if proven safe and effective.

Tags

#pctGR, @Collaboratory1

Grand Rounds May 12, 2023: Design and Pragmatic Trial of COACH: A Patient Portal/EHR Information System for Home Blood Pressure Monitoring in Hypertension (Richelle J. Koopman, MD, MS)

Posted on by Elizabeth Mccamic

Speaker

Richelle J. Koopman, MD, MS
Jack M. and Winifred S. Colwill Professor and Vice Chair
Department of Family and Community Medicine
University of Missouri

 

Keywords

Electronic Health Record, Pragmatic Clinical Trial

 

Key Points

  • Patients bring patient-generated home blood pressure data into the clinical workflow. It is difficult to enter and create visualizations of this data in the electronic health record (EHR), so the research team developed an EHR data visualization of home blood pressure from data entered via the patient portal.
  • Starting in 2015, researchers held 10 focus groups with patients, family medicine and general internal medicine physicians and 1 CMIO. Researchers assessed the effect of the data visualization on patient risk perception and the interaction of health literacy, numeracy, and graph literacy with the data visualization.
  • The team’s goals were to design for the primary care setting because 85% of hypertension care is in this setting. The team wanted the visualization designed for shared decision making, with an emphasis on patient information needs and comprehension and physician information needs and workflow. The visualization needed to have an intuitive design, and the team was cognizant of how data visualization can affect decision making.
  • The data visualization started with a basic list of information needed, including systolic and diastolic data; clinic and home data; raw data numbers, effect of medications on blood pressure; goal ranges; out of range values; customizable goal ranges; patient burden of entry; data variability relative to control, and contextual life event data. From there, the team iterated based on patient-physician needs, resulting in the COACH (Collaborative Oriented Approach to Controlling High Blood Pressure) app.
  • Later this year, the study team will launch the COACH trial, a pragmatic clinical trial with 550 adult primary care patients with uncontrolled hypertension who are portal users. The trial will take place across 3 sites, University of Missouri, OHSU, and Vanderbilt and across 2 EHR platforms, EPIC and Oracle. The primary outcome is blood pressure at 6 months. The trial is doing a consolidated framework for implementation research to understand the preferred workflows and concerns for patients and physicians.

 

Discussion Themes

-Who provided the text support for the app and how were they resourced and trained? We specified adverse events that were largely hypotension, ER visits and hospitalizations. We are evaluating the usability of the app. At MU we have a collaboratory called the Tiger Institution that does programming. They estimated 5,000 hours to put it in the EHR, and they did it for free. We are paying now. It works in the Oregon EPIC EHR, and we are working on translating it to Vanderbilt.

–Can you speak to sustainability and what you are doing with billing codes? It was data that was sitting there without alerts in our system. We need to have some way to create a better actionable alert. There is billing potential here. There are mechanisms to bill for home blood pressure monitoring for Medicare. The sustainability comes from being able to bill for these services and keeping it lean in messaging.

–What about the patients who are not in the portal? That is definitely a problem. At MU and OHSU we are at about 80-90%. You can access the portal from desktop and phones. Lots of people have smartphones but they do not have the portal. Vanderbilt has a plan for bridging this gap through care managers.

Tags

#pctGR, @Collaboratory1

Grand Rounds May 5, 2023: All of Us Research Program: Improving Health Through Diverse Technology, Huge Cohorts, and Precision Medicine (Joshua C. Denny, MD, MS)

Posted on by Elizabeth Mccamic

Speaker

Joshua C. Denny, MD, MS
CEO, All of Us Research Program

 

Keywords

Precision Medicine, All of Us Research Program

 

Key Points

  • The mission of the All of Us Research Program is to accelerate health research and medical breakthroughs, enabling individualized prevention, treatment, and care for all of us.  The program will nurture partnerships for decades with at least a million participants who reflect the diversity of the U.S.; deliver one of the largest, richest biomedical datasets that is broadly available and secure; and catalyze an ecosystem of communities, researchers, and funders who make All of Us an indispensable part of research.
  • Participation in All of Us is open to all and reflects the rich diversity of the U.S. Participants are partners, and trust will be earned through transparency. Participants have access to their information, data will be access broadly for research purposes, and security and privacy will be of highest importance. The program will be a catalyst for positive change in research.
  • All of Us started in 2016 by asking communities what is important to them. The program held 77 listening studios in 17 cities with 654 community members. More than 631,000 participants have enrolled in All of Us with continued growth. More than 80% of All of Us participants are underrepresented in biomedical research.
  • Returning value is a key part of the program. Participants shared that genetic information is a type of information they want to get back. All of Us also provides back survey data, EHR and claims data, ongoing study updates, aggregate results, scientific findings, and opportunities to be contacted for other research opportunities.
  • All of Us has a philosophy to get data to researchers quickly. The Research Workbench data browser is available with no log in and you get aggregate results. The Researcher Workbench is a cloud-based central resource with a passport access model. It is currently open to U.S. nonprofits and nonprofit/for-profit academic and healthcare organizations.
  • By the end of 2026, the goal is to reach 1 million participants who reflect the diversity of the U.S., cover the lifespan, and have shared all baseline elements. Of these participants, 500,000 participate in ongoing data donation opportunities. All of Us will expand the data available for participants, launch ancillary studies as a core and scalable capability, establish a diverse global community of 10,000 researchers, and incorporate participant return of value into data collections and assess its impact.
  • All of Us is currently working on developing a pediatric population and will soon be launching 2 modules looking at mental health and well-being.

 

Discussion Themes

-From a researcher perspective, how do researchers leverage All of Us and how should the costs be included in grants and funding opportunities? New researchers get $300 of free credits which will handle a lot of EHR access. At the NIH we are recognizing that we want this to be part of people’s grants. We are a platform, so we do not have awards open that support science. Those funds would come from NIH.

–How can one use this for prospective studies? We are thinking about this as the future of these studies. We are not at the capability yet where we can open this up. We want to make sure that we are not an off ramp for clinical trials. We want trials to adhere to our core values and have the data come back to our ecosystem. We are looking forward to supporting more.

Tags

#pctGR, @Collaboratory1

Grand Rounds April 28, 2023: Oxygen-Saturation Targets for Critically Ill Adults Receiving Mechanical Ventilation: An Embedded Cluster-crossover Trial (Matthew W. Semler, MD, MSc)

Posted on by Elizabeth Mccamic

Speaker

Matthew W. Semler, M.D., M.Sc.
Assistant Professor of Medicine and Biomedical Informatics
Medical Director, VICTR Center for Learning Healthcare
Vanderbilt University Medical Center

 

Keywords

Pragmatic Clinical Trials, Cluster-crossover Trial

 

Key Points

  • More than 3 million adults receive invasive mechanical ventilation each year in the U.S. and providing mechanical ventilation to critically ill adults involved titrating the fraction of inspired oxygen (FiO2) to maintain arterial oxygenation. Yet, even though millions of patients have received oxygen during mechanical ventilation in clinical care for decades, the oxygen target that optimizes outcomes has been unknown.
  • There are 3 basic approaches to oxygenation targets in clinical care. There is an approach that targets values in the low end of the range commonly seen in critical care (about 88-92% range of SpO2 values), an approach that targets a middle range (92-96% SpO2), or an approach that targets values at the higher end of the range (96-100% SpO2).
  • Each approach has theoretical pros and cons, with oxygen levels on the higher end providing a larger buffer against hypoxia but might increase exposure to hyperoxymia while oxygen levels in the lower range might minimize those risks but might not provide as big a buffer against hypoxia, and oxygen levels in the middle of the range might avoid the risk of hyperoxia and hypoxia or might intermittently expose patients to both sets. Because of the lack of data about these 3 approaches, the recommended targets vary among 3 international guidelines.
  • In 2017 the study team developed a pilot trial with the aim of determining the effect of lower intermediate and higher SpO2 targets on clinical outcomes for mechanically validated critically ill adults.
  • The pilot trial was a pragmatic, unblinded, cluster-randomized, cluster-crossover trial that began in April 2018, paused from April 1-May 31, 2020 due to the COVID-19 pandemic, and concluded on Aug. 31, 2021. Study sites were in the emergency department and medical intensive care unit at Vanderbilt University. All adults in the medical ICU or in the ED with planned medical ICU admission were eligible and enrolled at the time of the first receipt of invasive mechanical ventilation.
  • All patients in the ED and ICU were assigned together to an SpO2 target. Every 2 months, the ED and ICU switched together between SpO2 targets in a sequence generated by computerized randomization using permuted blocks of 3 to minimize impact on seasonal variation of changes over time. There was a washout period the last 7 days of each two-month period. The trial was conducted under waiver of informed consent.
  • For the intervention, respiratory therapists titrated FiO2 to achieve SpO2 beginning within 15 minutes of initiation of mechanical ventilation and ending at discontinuation from mechanical ventilation or transfer. If a clinician, patient, or family member determined that an oxygenation target other than the assigned target would be best for the patient, that target was used and the reason was recorded.
  • The primary outcome was ventilator-free days, the number of days alive and free of mechanical ventilation through study day 28. The secondary outcome was in-hospital mortality. The sample size was 2,250 patients over 36 months.
  • The pilot trial found that for mechanically ventilated critically ill adults, clinical outcomes do not differ between lower, intermediate, and higher SpO2 targets. This was also true for all prespecified subgroups, and the 3 target groups did not differ for the secondary, exploratory, and safety outcomes.

 

Discussion Themes

-What was the experience doing these repeated crossovers? I think this is philosophically something that our ICU is used to when we don’t know what the right treatment is for a patient. That culture is very deep in our ICU and we benefited from it. The amount of education and interaction with clinical personnel at the start of the trial and at the first crossover is huge to help understand why we are doing this. By the second half of the trial, our team is available but everyone knows what and why we are doing it. For this type of trial all of the work happens in the first 3 months and then it is more streamlined?

–How many times were patients not included because the clinician had a good idea of the target for the patient. About 5% of patients developed a condition where the clinician knew what the target should be. For many patients, this did not happen. It was important to us that clinicians exercise their autonomy when they had the evidence needed to provide treatment

Tags

#pctGR, @Collaboratory1

Grand Rounds April 21, 2023: Personalised Cooler Dialysate for Patients Receiving Maintenance Haemodialysis (MyTEMP): A Pragmatic, Cluster-randomised Trial (Amit Garg, MD, MA, FRCPC, FACP, PhD; Stephanie N. Dixon, PhD MSc)

Posted on by Elizabeth Mccamic

Speakers

Amit Garg, MD, MA (Education) FRCPC, FACP, PhD
Associate Dean, Clinical Research, Schulich School of Medicine and Dentistry
Lead, Institute for Clinical Evaluative Sciences Kidney, Dialysis and Transplantation Provincial Program
Director, Institute for Clinical Evaluative Sciences (ICES) Western Facility
Nephrologist, London Health Sciences Centre
Professor, Medicine, Epidemiology & Biostatistics, Western University

Stephanie N. Dixon, PhD MSc
Staff Scientist, Institute for Clinical Evaluative Sciences Kidney, Dialysis and Transplantation Research Program
Biostatistician, London Health Sciences Centre

 

Keywords

MyTEMP, Pragmatic Clinical Trials, Ethics, Biostatistics

 

Key Points

  • For each hemodialysis treatment clinicians typically set the temperature of dialysate on the machine to 36.5 or 37.0 degrees Celsius. The reasoning for this temperature is unclear, though it likely represents what was considered the average body temperature of most patients.
  • In a recent international survey of more than 270 centers, nearly half now use a cooler temperature dialysate in patient care of less than or equal to 36.0 degrees C. This change in practice is based on data that suggests the at cooler (vs. standard) temperature dialysate is beneficial. However, in two recent systematic reviews the overall quality of evidence for dialysate cooling was deemed low with a high risk of bias.
  • The MyTEMP trial is a pragmatic, cluster randomized controlled trial in Ontario, Canada, to determine if adopting a default center-wide policy of personalized cooler dialysate is superior to a standard temperature dialysate of 36.5 degrees C.
  • MyTEMP was innovative and pragmatic, implemented as part of a learning healthcare system, with covariate constrained randomization, registry-based, and embedded in routine care delivered by more than 2,000 nurses at 84 centers.
  • During the 4-year study period, about 8,000 patients were randomized for the personalized cooler dialysate and about 7,400 were randomized for the standard temperature dialysate. The mean temperature for the standard group was 36.4 degrees C, and the mean temperature for cooler group was 35.8 degrees C.
  • The primary composite outcome was cardiovascular mortality or hospital admission with MI, stroke, or heart failure. There is a high risk of these events in the hemodialysis population with a cumulative instance at 30% at 4 years. There was no appreciable difference in the estimate for the cooler temperature group. Additionally, the cooler temperature group reported a higher likelihood of discomfort.
  • The lack of cardiovascular benefit and higher likelihood of patient discomfort provides no justification to adopt cooler dialysate as a center-wide policy vs. use of 36.5 degrees. After MyTEMP, centers in Ontario stopped adopting colder temperature dialysate as a center-wide policy, and patients felt less discomfort during hemodialysis care.
  • Cluster randomized trials of hemodialysis center-wide policies raise complex ethical issues. Many patients who receive hemodialysis are vulnerable. A patient or their nephrologist could decide to opt-out of the randomly allocated center-wide default policy but could not opt out of the symptom data but not de-identified health records. The REB approved the MyTEMP request to use an altered patient consent process because the research was deemed of minimal risk to patients.
  • MyTEMP worked with patients and caregivers to develop the trial, and Kidney Patient and Family Advisory Councils guided the choice of additional outcomes. Participants were debriefed on the trial results.

Learn more

Read about the MyTEMP trial in The Lancet.

Read about the MyTEMP statistical analysis plan.

Discussion Themes

–We run into situations where we are talking to stakeholders and thinking about criteria for waiver of consent and it’s just not right. Where the risks and benefits are equal, but I wouldn’t want to be randomly assigned. There is a natural assertion of autonomy. Did some of these questions of autonomy vs. risk come up? I think it is very complex, and it is not black and white. You need to identify the principles before the process. In terms of the dialysis component, in routine care we get consent when we start treatment but there are many things in the background. As a clinician when I am providing care, I’m not discussing these concerns; we are talking about other things. Am I delivering great medicine when I’m not sure what to do here when there is practice variability?

Tags

#pctGR, @Collaboratory1

Grand Rounds April 14, 2023: RECOVER in Action – Status of Clinical Trial Protocols (Kanecia Zimmerman, PhD, MD, MPH)

Posted on by Elizabeth Mccamic

Speaker

Kanecia Zimmerman, MD, PhD, MPH
Associate Professor of Pediatrics
Duke Clinical Research Institute
Duke University School of Medicine

 

Keywords

COVID-19, RECOVER, Clinical Trials

 

Key Points

  • Long COVID is a set of multiple conditions with diverse clinical manifestations that can affect every major organ/tissue system, reflecting varied potential underlying and co-existing causes.
  • There are many hypothesized causes that may co-exist in the same patient, such as persistent virus or antigens, reactivation of other viruses, uncontrolled immune responses, damage to a wide range of organs and tissues, and injury to blood vessels and abnormal blood clotting. This broad set of clinical conditions and varied underlying causes underscore the need for testing a broad portfolio of therapeutic agents.
  • RECOVER is a patient-centered, integrated, adaptive research network. The goals of RECOVER is to understand how people are recovering from COVID and changes in our bodies over time; define risk factors, number of people getting Long COVID, and if there are specific different Long COVID types; study how Long COVID progresses over time and how that may relate to other illnesses; and identify possible treatments to help with Long COVID symptoms.
  • RECOVER has used cohort data to identify major symptom clusters and develop 5 platform protocols that will investigator priority symptom clusters and their causes; test known and novel interventions across domains; and evaluate treatments to improve Long COVID symptoms.
  • The 5 platform protocols are integrated rather than siloed, disparate studies to achieve efficiencies, allow researchers to rapidly assess targeted therapeutics and pivot as needed to new treatment arms, maximize knowledge gained from patient participation, and to enable cross-trial analysis and accelerated knowledge acquisition.
  • The 5 trials, RECOVER-VITAL, RECOVER-AUTONOMIC, RECOVER-SLEEP, RECOVER-NEURO, and RECOVER-ENERGIZE, will enroll about 2,600 total participants, and each trial will include between 25-100 sites. The first trial will begin enrolling in July 2023.

Learn more

Visit https://recovercovid.org

Discussion Themes

– What experts are being convened for the different trials? It’s all over the place. We have people with experience with post-viral symptoms, treating ME/CFS, general COVID knowledge, biomarker experience, clinical trials, patient-reported outcomes, and more.

– As people think about the health measures and outcomes, can you describe the process for how to understand and select those types of measures? It was such an iterative process to get to where we are. People with experience to prior disease that might be similar is where we started. Can we use measures that have been used previously for those populations and if we can how do we tweak them to make sure they are valid within this population? Prior information, data and experience and then adapt it for patients with PASC.

-While the pandemic is transitioning from pandemic to endemic state, do you see any signs that PASC will go away? No, there are no signs PASC is going away. It seems the most severely affected people came from the early waves of COVID. Over time the epidemiology has changed some for those people with PASC, but there are still people who are still symptomatic and want answers.

Tags

#pctGR, @Collaboratory1

Grand Rounds April 7, 2023: A Nudge Towards Cardiovascular Health: Incorporating Insights From Behavioral Science to Improve Cardiovascular Care Delivery (Srinath Adusumalli, MD, MSHP, MBMI, FACC)

Posted on by Hannah Webster

Speaker

Srinath Adusumalli, MD, MSHP, MBMI, FACC
Adjunct Assistant Professor of Medicine, Perelman School of Medicine
Adjunct Professor of Healthcare Management, The Wharton School
Affiliated Faculty, Center for Health Incentives and Behavioral Economics
Staff Cardiologist, Hospital of the University of Pennsylvania and Philadelphia VAMC University of Pennsylvania
Senior Medical Director, Enterprise

Keywords

Pragmatic trials, cardiovascular medicine, cardiovascular care delivery, behavioral science, electronic health records, implementation science

Key Points

  • A nudge is a subtle change in design that is intended to impact human behavior. They are intended to remind, guide, or motivate a decision, and they should be transparent. Dr. Srinath Adusumalli described a nudge as something that helps make the right choice an easier choice.
  • Nudges and other behavioral interventions are prevalent in industries like business and entertainment, but there is an opportunity for nudges in medicine and health care delivery.
  • Launched in 2016, the Penn Medicine Nudge Unit is the world’s first behavioral design team embedded within a health system. It works to improve health care value and outcomes, advance the science of designing interventions to change behavior and evaluate and disseminate the impact of interventions. The team then worked to incorporate an implementation science lens for designing interventions for scale to the health system.
  • The health behavior is supported by a technology backbone, including the Penn Medicine EHR and other systems that bring insight and nudge within workflows. The context and stakeholder input have been key in developing and implementing nudges.
  • Useful nudge principles are limitations of information provisions, inertia or status quo bias, choice overload, loss aversion or framing, social ranking and the limits of willpower.
  • Implementing the nudge tool within the Penn Medicine revealed several positive impacts, including referral rates increasing significantly via the implementation of a default pathway.
  • The PRESCRIBE trial revealed the value of active choice as well as peer decision-making to prompt decision-making.
  • The randomized controlled trial Effect of Nudges to Clinicians, Patients or Both to Increase Statin Prescribing published in JAMA found that the clinician nudge and the combined nudge interventions significantly increased the proportion patients prescribed a statin compared with usual care but the patient nudge had no impact.
  • Key considerations for developing and implementing a nudge include the right information and guidelines, the right individual to receive the nudge, the right intervention format, the best channel for the nudge and the best time in a provider’s workflow to receive the nudge.
  • Key learnings from the studies highlighted included the need for more transparency as to the reason for a nudge, limiting the number of choices in CDS intervention, passive CDS is often ineffective and it is critical to provide the path for the individual to immediately act.
  • New frontiers in nudging include integrating nudges and behavioral science with applied machine learning, phenotyping patient and clinician behavior to more precisely target single or combination nudges, the simplification and automation of downstream actions, and the alignment of incentive and behaviors across health care actors, including systems and payers.

Discussion Themes

– In the last few years, there has been great reception to the value of behavioral science and implementation science in the field of cardiology. There is opportunity for more evidence to be developed and to implement lessons that have been learned.

– Behavioral science tools, such as these EHR-integrated nudges, must be modified to fit within different settings and EHR systems, but they often provide a strong foundation for other contexts. Customizing existing tools to different systems can save significant time and resources in developing behavioral health tools.

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#pctGR, @Collaboratory1