Grand Rounds Archive

Grand Rounds July 26, 2024: Interventions for Optimization of Guideline-Directed Medical Therapy for Heart Failure (Gregg C. Fonarow, MD, FACC, FAHA, FHFSA)

Posted on by Sophia Ramirez

Speaker

Gregg C. Fonarow, MD, FACC, FAHA, FHFSA
Eliot Corday Professor of Cardiovascular Medicine and Science
Director, Ahmanson-UCLA Cardiomyopathy Center
Codirector, UCLA Preventative Cardiology Program
UCLA Division of Cardiology

Keywords

Heart failure; HFrEF; guideline-directed medical therapy; implementation; systematic review

Key Points

  • Despite the availability of effective therapies for heart failure (HF), a large number of eligible patients are not receiving one or more evidence-based, guideline-recommended therapies. This implementation gap has stymied improvements in morbidity and mortality.
  • The benefits of evidence-based heart failure medications are cumulative. If all therapies are used, there is a relative risk reduction of 74.0% and an absolute risk reduction of 25.9%. Simultaneous or rapid initiation of therapies reduces HF hospitalizations, rehospitalizations, and mortality.
  • Reasons for underutilization of Guideline-Directed Medical Therapy (GDMT) for heart failure include a lack of systems to reliably implement therapies; gaps in knowledge and awareness of guidelines; therapeutic inertia; and insufficient urgency.
  • Dr. Fonarow’s team conducted a systematic review of interventions for the optimization of GDMT, including 28 randomized clinical trials with an aggregate sample of over 19,000 patients. They found that the initiatives that used interdisciplinary teams, largely comprised of nurses and pharmacists, most consistently led to improvements in GDMT. Clinician education, electronic health record initiatives, and patient interventions, on the other hand, resulted in no or modest improvements in GDMT.
  • Implementation of GDMT needs to improve in all clinical settings. Programs that successfully implement GDMT often have access to current and accurate data on treatment outcomes; administrative and clinician support; use care maps and pathways; and use data to provide feedback. There is also a need for further implementation science innovation and testing.

 

Discussion Themes

– Do you still see lack of education as a major problem that needs to be approached differently, or should we really be focusing on something else? I do think it need to be further studied. I think our educational efforts around the clinician need to center on the really practical aspects, on what the common pitfalls are in trying to apply and uptitrate these medications. Interdisciplinary teams and cross-discipline education are critically important. [The study results] don’t mean that education shouldn’t be part of further interventions, but I think we need to look at what’s truly going to see a meaningful increase in medication titration and persistence of GDMT.

– The polypill could address some of the clinical inertia issues and patient resistance. Patients hate it when you keep adding on four different medications and you’re increasing the doses. Is it being studied in this context? There is work going on, editorials have been written about it, the concept has been laid out. There are small pilot studies that have been done. There are challenges; is titration necessary? You’ll need a series of polypills to uptitrate, or you’ll get the therapy started and then you’ll bring them together as a polypill. One thing I do want to highlight, though, is that starting medications simultaneously defeats that patient question of, “Why are you adding this extra medication? Are the prior medications not working?” It’s a different mindset upfront: “Here are these four medications you’re going to be on.”

 

 

Tags

#pctGR, @Collaboratory1

Grand Rounds July 12, 2024: Causal Estimands: Should We Ask Different Causal Questions in Randomized Trials and in the Observational Studies That Emulate Them? (Miguel Hernán, MD)

Posted on by Sophia Ramirez

Speaker

Miguel Hernán, MD
Professor of Biostatistics and Epidemiology
CAUSALab
Harvard T.H. Chan School of Public Health

Keywords

Statistical Analysis; Causal Estimands; Research Questions; Randomized Clinical Trials; Observational Studies; Intention-to-Treat Effect; Per-protocol Effect

Key Points

  • Researchers often look at the intention-to-treat (ITT) effect – i.e., the effect of being assigned to an intervention – for randomized trials, and at the per-protocol effect – i.e., the effect of receiving an intervention – for observational studies.
  • Why are we giving estimates for 2 different effects? If a causal question is important enough to be asked in an observational study, Dr. Hernán posed, then we should also ask it in a randomized trial, and vice versa.
  • He walked through some of the field’s justifications for asking different causal questions. If adherence patterns vary, the ITT effect may differ across trials that study the same treatment. Arguments in favor of using the ITT effect often include that it preserves the null; it’s conservative; and it measures effectiveness in the real world.
  • But null preservation is not guaranteed; most pragmatic trials are not blinded, for instance, so assignment may make patients and doctors alter their behavior. Through hypotheticals and case examples, Dr. Hernán made the case that ITT effects are not necessarily a measure of effectiveness, nor are they of primary interest for doctors and patients.
  • The per-protocol effect represents another causal question that randomized trials could answer. The issue with per-protocol analysis is that valid estimate of the effect requires adjustment for confounding. Historically, trialists have been suspicious of these analyses as potentially biased.
  • In the past few decades, however, statistical methods have been developed that allow researchers to adjust for confounders at baseline and after baseline. Provided a few criteria are met, there is hope for the estimation of per-protocol effects as a way to contrast generic treatment strategies.
  • For a long time, regulators were reluctant to consider causal effects other than the ITT effect. Under increasing pressure from industry, a group of methodologists from pharma and regulatory agencies worked together to generate the “estimand framework.” This manifested as an addendum to the ICH E9 guidelines.
  • The addendum was a great step forward for more rigorous causal influence, Dr. Hernán noted. But it has room for improvement, specifically in terms of choice (of standard terminology and of estimands) and a lack of emphasis on both treatment strategies and trial design.
  • Researchers do not compare treatments but treatment strategies. Therefore, the causal contrast needs to specify the treatment strategies of interest; typically, these will be the treatment strategies specified in the protocol. Observational studies for causal inference already try to estimate well-defined per-protocol effects when emulating target trials. It’s time to turn to randomized trials.

Discussion Themes

The intention-to-treat effect is not always the primary interest. When there is a safety outcome or in a non-inferiority trial, the per-protocol effect is necessarily the estimand of interest.

When we say the ITT effect is biased towards the null, we mean it’s biased for the per-protocol effect. I.e., “I’m interested in the per-protocol effect because it’s going to be harder to find differences between treatments using ITT analysis.”

One issue with the estimand framework is that it doesn’t give the per-protocol effect much consideration; it is not named and is part of a set of estimands, all of which are given equal importance. Dr. Hernán argued that the per-protocol effect should be made more explicit, as it’s the main question that we can ask of a trial outside of the ITT effect.

The person who designs the trial is responsible for pre-specifying the procedure when a participant switches treatments.

Grand Rounds June 28, 2024: Using ChatGPT to Facilitate Truly Informed Medical Consent (Fatima N. Mirza, MD, MPH)

Posted on by Sophia Ramirez

Speaker

Fatima N. Mirza, MD, MPH
Chief Resident
Department of Dermatology
Warren Alpert Medical School of Brown University

Keywords

Artificial Intelligence; ChatGPT; Informed Consent

Key Points

  • Artificial Intelligence (AI), when implemented thoughtfully in clinical settings, can lead to meaningful results for patients.
  • Medicine has long fallen short of the ideal of informed consent, in part due to the limited readability of informed consent forms; as of 2020, 54% of Americans were estimated to read below the sixth-grade reading level. This has implications for patient understanding and quality of care.
  • Using ChatGPT-4, the research team took LifeSpan Healthcare System’s (LHS) surgical consent form from a 12.6 Flesch-Kincaid reading level to a 6.7. After hospital leadership reviewed the revised form and the research team had addressed concerns around biases, approvals, and future needs, the revised form was deployed across LHS.
  • This real-world implementation demonstrated the potential for AI to make meaningful improvements to patient care and communication. As a proof-of-concept, it sparked the interest of other health systems.
  • To investigate the clinical implications of consent form readability, the research team analyzed 798 federally funded clinical trials providing accessible informed consent forms. A 16% increase in the dropout rate was associated with each additional Flesch-Kincaid grade-level increase in the language.
  • The observed association between consent form complexity and participant dropout rate could be attributed to misaligned expectations; erosion of trust; participant surprise and dissatisfaction; and reduced engagement. This highlights the importance of clear, accessible communication throughout the entire trial process, not just enrollment.
  • Improved readability of consent forms is crucial for the design and implementation of clinical trials, potentially leading to more inclusive, efficient, and impactful clinical research.

Discussion Themes

Medical malpractice attorneys were part of the cohort that reviewed the simplified consent forms. They shared that when these cases go to court, a jury will often review the informed consent document. In these cases, it can more protective to have documentation that people can understand.

There is the potential for tailored chatbots that could personalize the consent process for patients, but expert oversight would be crucial. AI models can “hallucinate,” saying something incorrect with absolute certainty. Dr. Mirza indicated that the field isn’t ready for those bespoke consents; centralized documents, as least for the time being, are the way to go.

AI is going to be integrated into our healthcare system. It’s important for clinicians, researchers, and people who really care about patients, as well as the patients themselves, to have a seat at the table discussing these early models.

Grand Rounds June 21, 2024: Efficacy and Safety of Electronic Cigarettes for Smoking Cessation: Keeping a Trial on a Polarizing Topic Running Under Regulatory and Epidemic Changes (Reto Auer, MD, MAS)

Posted on by Sophia Ramirez

Speaker

Reto Auer, MD, MAS
Associate Professor in Primary Health Care, Head Substance Use Unit, Institute of Primary Health Care (BIHAM), University of Bern
Adjunct Physician, University Center for Primary Care and Public Health (Unisanté), Switzerland

Keywords

Smoking; cessation; e-cigarettes; nicotine

Key Points

  • For cigarette smokers who are struggling to quit, e-cigarettes may be a viable and less risky alternative. When it comes to smoking cessation, there is substantial evidence that nicotine e-cigarette usage increases quit rates compared to nicotine replacement therapies (NRTs). Because the nicotine is inhaled, rather than delivered more slowly by way of a patch or gum, e-cigarettes provide quick relief from cravings much in the way a traditional cigarette would.
  • E-cigarette use is a polarizing topic in the medical field. The somatic health risks posed by e-cigarettes are lower than that of conventional cigarettes. However, their addictive potential is similar. So, while the availability of e-cigarettes could substantially reduce the health risks of nicotine dependence for existing smokers, it poses a substantial risk of nicotine addiction to a new generation.
  • A study team led by Dr. Reto Auer ran a randomized clinical trial to assess the efficacy and safety of free e-cigarettes in addition to standard care vs standard care alone. Their secondary aim was to assess the effect of the intervention on respiratory symptoms.
  • 1,246 participants at five study sites in Switzerland were randomized at a 1:1 ratio to the control group (standard-of-care smoking cessation counseling, AKA SOC) and the intervention group (SOC + free e-cigarettes, along with advice on use of products). The intervention included a choice between 6 different aromas and 4 different nicotine concentrations. Researchers followed up with participants at 6-months (later extended to 12-, 24-, and 60 months).
  • At the end of the six months, the proportion of participants who reported zero tobacco use was 21% higher in the intervention group than in the control group; however, the percentage of participants in the intervention group who abstained from nicotine entirely altogether was almost 14% lower. In other words, the intervention group ended up smoking less tobacco, but consuming more nicotine. The intervention resulted in more adverse events but not more serious adverse events.
  • In conclusion, their study found that e-cigarette use plus standard counseling may be a viable option for tobacco smokers who want to abstain from smoking without necessarily abstaining from nicotine but may be less appropriate for those who want to abstain from both tobacco and nicotine.
  • Dr. Auer also discussed ethical considerations for the trial, namely the potential consequences if health care professionals were to state that e-cigarettes are less harmful that tobacco cigarettes. On the one hand, some smokers may quit smoking tobacco thanks to e-cigarettes; on the other hand, non-smokers may be more likely to use e-cigarettes and become addicted to nicotine as a result.

 

Discussion Themes

– There isn’t always heterogeneity in the products presently on the market. So, I have a little consternation about the devices that people are picking up in vape shops. Do you have any thoughts or comments on that? Of course, you need regulation. You cannot have a drug like this without oversight. I think in the U.S., you might be in a better place with FDA review. And there are now e-cigarettes [in the U.S.] that have been have gone through all the regulatory oversight… I’m completely with you, there’s a lot of research to be done before everyone can embrace recommending these.

– From your perspective, how has the conversation about this trade off, this ethical balance that you described, evolved over time? Are you seeing movement, or do people tend to be entrenched in their positions? That question was at the core of our work. If you speak with some people in England, they say “Why do this trial? This is evident, you don’t need to.” But others will say “We will never allow e-cigarettes.” Our job was to be in the middle of it; to be the boring researchers who produced the evidence, who are not involved in the politics, and who try to understand the difference and see how the conversation moves.

– The trial focused on switching away from combustible cigarettes as opposed to nicotine cessation. As a physician, I would not want indefinite e-cigarette use for my patients. Do you think that was the optimal goal, or was it about what was feasible to achieve with a trial? Smoking is a chronic condition. As a clinician, how I translate this, is that the discussion is about shared decision making and your preference as a patient. If someone says, “I want to quit both [cigarettes and nicotine],” I’ll say, “Well, e-cigarettes might not be the best way.” But if someone says, “I don’t care about nicotine, I’ll be using nicotine for the rest of my life,” … At least they don’t smoke. The approach is different, and with e-cigarettes we can address a population we could never address before.

 

 

Tags

#pctGR, @Collaboratory1

Grand Rounds June 14, 2024: DAPA-MI – A Pragmatic Registry-Based Double-Blind RCT Trial Designed For Regulatory Evaluation (Stefan James; Jonas Oldgren)

Posted on by Sophia Ramirez

Speakers

Stefan James
Professor of Cardiology
Dept. of Medical Sciences and Uppsala Clinical Research Center
Uppsala University
Uppsala, Sweden

Jonas Oldgren
Professor of Cardiology
Dept. of Medical Sciences and Uppsala Clinical Research Center
Uppsala University
Uppsala, Sweden

Keywords

DAPA-MI, R-RCT, myocardial infarction, regulatory evaluation, SGLT-2 inhibitors, pharmacological, pragmatic

Key Points

  • Previously observed improvements in post-Myocardial Infarction (MI) prognosis have reached a plateau in recent years. Given that SGLT-2 inhibitors have positive effects on almost all cardiometabolic parameters, investigators at the Uppsala Clinical Research Center (UCR) hypothesized that dapagliflozin could reduce the risk of heart failure following MI. SGLT-2 inhibition could become the first new beneficial pharmacological treatment concept for patients with MI in over a decade. Dapagliflozin is already known to be beneficial to patients with diabetes or chronic heart failure, and has a known safety profile.
  • The DAPA-MI team conducted a pragmatic, registry-based, double-blind randomized clinical trial using national registry data, also known as an R-RCT, from 103 sites in the U.K. and Sweden. Their objective was to evaluate the effect of dapagliflozin on cardiometabolic outcomes in patients with acute myocardial infarction without diabetes or chronic heart failure. Data was collected as part of routine clinical care and transferred to the UCR web application, which helped the PIs to identify and enroll patients. That data was then transferred to the DAPA-MI database.
  • An R-RCT is a prospective randomized controlled trial that uses a clinical quality registry for one or several major functions for trial conduct and outcomes reporting. The DAPA-MI study team saw this approach as combining the best of two worlds: real-world registry data with the features of a randomized trial.
  • The registry would allow them to enroll as many patients as possible, in a pragmatic setting, at a lower cost, while the RCT would allow them to draw causal inference and understand the efficacy of the agent. The team’s other objective in conducting this trial was to evaluate the possibility to conduct a registrational clinical trial in a very new way for a marketed product with a known safety profile.
  • Their initial primary endpoint was a composite of hospitalization for heart failure and cardiovascular death, the traditional standard outcome for heart failure trials. During the course of the trial, however, it became evident that the number of collected primary composite outcomes in the DAPA-MI trial was substantially lower than anticipated. In February 2023, the trial was modified from an event-driven time-to-event approach to a hierarchical composite outcome approach including clinically relevant cardiometabolic outcomes.
  • They found that DAPA-MI met the primary endpoint and dapagliflozin treatment demonstrated significant clinical benefit compared to the placebo. With a Win ratio of 1.34, the likelihood for a better cardiometabolic outcome with dapagliflozin is 34% higher compared to placebo.
  • The feasibility of the R-RCT design was confirmed with the recruitment of 4017 patients with acute MI without diabetes and chronic HF in only two countries and 103 sites. Collaboration between UCR and NICOR enabled the success of the trial; excellent data quality confirmed the regulatory-grade of R-RCT design; and the registry-based approach was appreciated and attracted Investigators all over Sweden and the UK representing both large and small hospitals.

 

Discussion Themes

-Why did you reduce the power of the study when you shifted to the hierarchical endpoint? What would’ve been the power of the hierarchical endpoint if you’d stayed at 6,000 patients? The trial enrolled well, but we realized we wouldn’t be able to double the number of patients from 6,000 to 12,000, which might have been required to get power on the first primary endpoint. I think many of us would like to have continued to enroll patients above 6,000 or 6,500, but there with multiple issues with that. If we had a sufficient power to stop at 4,000 patients, it was difficult to convince the sponsor, perhaps the trial organization to continue enrolling if it wasn’t absolutely necessary.

–What were your interactions with the regulators like? It was interesting to have these regulatory discussions with the different agencies, with very different comments and requests on our trial for the proposal. I would frankly say that the FDA was the easiest regulatory agency to discuss with, very supportive of a new way of doing trials, very supportive of not adjudicating events, finding pragmatic solutions. The U.K, they requested that we do specific, cumbersome safety testing with blood tests, renal function tests. They were afraid that dapagliflozin would hurt the kidneys. The journals were even more difficult. They wanted us to not do a pragmatic trial at all; they wanted us to understand the mechanisms of the drug with repeated echo measurements. So very different ideas.

–Did you have any feedback that was different across the different agencies around safety reporting? Yes, safety reporting was also viewed differently. The FDA were also supportive of not doing specific safety reporting more than we do in regular care. The EMA and the other European agencies were more concerned about safety reporting, but we were able to get support on doing minimal safety reporting since the agent and the safety profile were so well known. We also set up a study in which we are now retrospectively comparing safety reporting with what we can get from registries. So that’s an ongoing process to compare and see if the safety reporting that we can achieve from registries allows us to understand the safety profile as good as or better than the safety reporting.

 

 

Tags

#pctGR, @Collaboratory1

Grand Rounds June 7, 2024: The NIH COvid-19 and Diabetes Assessment (CODA) Study: Leveraging PCORnet For A Novel Cohort Study (Russell Rothman, MD, MPP; Jason Block, MD)

Posted on by Elizabeth Mccamic

Speakers

Russell Rothman, MD, MPP
Professor, Internal Medicine, Pediatrics, & Health Policy
Senior Vice President, Population and Public Health
Director, Institute for Medicine and Public Health

Jason Block, MD
Assistant Professor, Harvard Medical School
Faculty Member, Harvard Center for Population and Development Studies
Physician, Brigham and Women’s Hospital

Keywords

CODA, PCORnet, diabetes, COVID-19, pragmatic research

Key Points

  • PCORnet has been around for 10 years and was designed to bring together health systems, clinicians and researchers as well as harnessing medical electronic data and other partners to focus on patient-centered research. The network can support real-world evidence studies, population health research, comparative effectiveness research, pragmatic research, health systems research, and more.
  • PCORnet includes 8 clinical research networks at more than 75 large health systems health systems, including academic health centers and community clinics, which gives a diverse population to recruit into clinical trials with reach across the U.S. The PCORnet sites have a common data model so it is standardized across systems.
  • The COVID-19 Diabetes Assessment (CODA) Study worked with PCORnet Front Door to rapidly identify diverse sites for the study. PCORnet Front Door is the access point for PCORnet resources and services and can support study design, connections to network collaborators, and PCORnet study designation.
  • CODA will recruit and follow a cohort of 1,600 adult and pediatric participants with recent diagnosis of Type 1 (T1D) and Type 2 (T2D) diabetes to examine the relationship between SARS-CoV-2 exposure and glycemic control, metabolic function, inflammation, cardiovascular risk, and patient-reported outcomes.
  • CODA will explore the role of genomic/social/environmental factors on glycemic control, inflammation, and metabolic function, and it will also leverage EHR data from 38 PCORnet health systems participating in the NIH RECOVER program to explore the role of COVID-19 infection on diabetes development and progression.
  • There is epidemiologic evidence that suggests increases in the incidence of T1 and T2 diabetes in both adults and children plus possible worsening of preexisting disease after COVID-19 infection. Mechanisms may include direct effects on pancreatic beta cells that produce insulin, increase in inflammation, immune dysregulation, and other metabolic changes caused by infection with SARS-CoV-2. Other factors may contribute to increased rates of diabetes and worsening of disease including social factors, environmental stressors, health disparities, and other issues.
  • The study will take place at 15 PCORnet sites across the U.S. Five sites are from PEDSnet with large children’s hospitals to help recruit pediatric participants. Participants with a new diagnosis of T1D and T2D, English and Spanish speakers, age 11 and older are eligible for the study, with an enrollment goal of 1,000 adults and 600 children at 3 levels (surveys, mixed meal tolerance test (MMTT), and SphygmoCor to assess arterial stiffness) over 24 months.
  • CODA also will integrate and leverage supplement EHR data to explore the role of COVID on diabetes development and potential remission in T2D.

 

Discussion Themes

-What are your expectations about the folks who will participate and if there are differences between the pops who will participate at the different levels. We do provide additional compensation to engage participants at different levels. Particularly with participants with T1D who are younger, families are very interested in understanding more about the diabetes. Our plans are to recruit 400 total patients (25% of total) for MMTTs and 200 total patients (12.5%) for the vascular stiffness study.

–How did you develop your patient recruitment materials? The infographic that we developed to explain the different levels of participation was created by someone on our team with experience in health literacy. We tried designing materials at a sixth grade reading level, with white space on the page to help with the recruitment and consent process and increase participant understanding.

 

Tags

#pctGR, @Collaboratory1

Grand Rounds May 31, 2024: INSPIRE Abdominal & Skin/Soft Tissue Infection Trials: INtelligent Stewardship Prompts to Improve Real-time Empiric Antibiotic Selection for Patients (Shruti K. Gohil, MD, MPH)

Posted on by Sophia Ramirez

Speaker

Shruti K. Gohil, MD, MPH
Assistant Professor, Infectious Diseases
Associate Medical Director, Epidemiology & Infection Prevention
University of California, Irvine School of Medicine

Keywords

Antibiotics; Antibiotic Resistance; Infection; Prompts; Clinical Decision-Making

Key Points

  • Multidrug-resistant organisms are a major public health threat, with more than 2.8 million antibiotic-resistant infections occurring annually in the U.S. This leads to increased readmissions, healthcare costs, and thousands of attributable deaths. Overprescribing is a major contributor to antibiotic resistance.
  • The culture of empiric antibiotic selection currently reflects a “start broad, narrow later” approach: an effort to avoid missing resistant infections at the cost of unnecessary broad spectrum antibiotics. The INSPIRE trials aim to encourage a new practice: “start narrow, broaden if needed,” in which physicians use data on resistance risk to spare broad spectrum antibiotic use. This delay in broadening is not high-risk for the vast majority of patients.
  • The 4 most commonly treated infections in U.S. hospitals (pneumonia, urinary tract infections (UTI), abdominal infections, and skin/soft tissue infections) do not reflect the multi-drug resistant organisms that physicians most worry about, but comprise the bulk of what physicians prescribe extended spectrum antibiotics for.
  • Risk factor research typically reports relative risk, AKA odds. This can exaggerate physician perception of risk. The INSPIRE trials sought to reframe risk perceptions by using absolute risk, based on a series of models for every extended-spectrum antibiotic and multidrug-resistant organism pair.
  • The research team developed a computerized provider order entry (CPOE) smart prompt, activated when a physician in a non-ICU location selected extended-spectrum antibiotics to treat abdominal or skin/soft tissue infections. These real-time prompts provided the absolute risk of infection due to multidrug-resistant organisms, in a manner that was patient-specific, infection syndrome-specific, and pathogen-specific.
  • The INSPIRE Abdominal and Skin/Soft Tissue Trials consisted of 2 cluster-randomized, 92-hospital trials. Arm 1 received routine care, and Arm 2 received the INSPIRE CPOE bundle intervention, in which physicians received the CPOE smart prompts recommending appropriate antibiotic choice.
  • The INSPIRE trials demonstrated the effectiveness of real-time, individualized smart prompts. In both the abdominal infection trial and the skin and soft tissue infection trial, the group that received the CPOE prompts saw a 35% and 28% reduction in extended-spectrum days of therapy, respectively. There was no difference in safety outcomes for either trial.
  • The intervention was rolled out as a bundle; this makes it difficult to know the impact of the individual components. One limitation of this intervention is that activating it requires CPOE capability and a live link to the EHR.
  • The research team took some proactive steps, including actively extracting and cleaning data starting in the CPOE prompt development stage. That allowed them to identify issues early in the process, adjust accordingly, and ultimately speed the analysis.
  • Precision medicine trials for antibiotic stewardship can work; physicians are willing to make different choices when they’re given the right kind of information. If you thoughtfully construct a prompt-based intervention and populate it with useful and applicable information, these interventions could help lead to new best practices for empiric treatment in the U.S.

Discussion Themes

The trial defined the threshold for acceptable risk – i.e., differentiated between high and low risk – at 10%. This was based on precedence set by the Infectious Diseases Society of America (IDSA) guidelines and vetted by the INSPIRE steering committee and national experts. Each patient had their own risk profile – comprised of a series of risk factors, pulled from the EHR – that the algorithm drew upon to place the patient on either side of the risk threshold.

Patient rates of ICU transfer and length of stay were equal between the intervention and control groups. This addresses a significant concern amongst physicians when it comes to reducing broad-spectrum antibiotic prescription, as many worry about incurring any unnecessary risk for their patients.

The prompts were intensely vetted. One important consideration making sure they appeared only for low-risk patients. This was an important step in getting local physicians on board with the prompts as a clinical decision support tool. Stewardship teams played an important role in this provider education.

Nurse practitioners, physician assistants, and residents were another key audience, as they often play a significant role in ordering antibiotics.

Grand Rounds May 17, 2024: CardioHealth Alliance: A Platform to Improve Care (Ken Mahaffey, MD; Neha Pagidipati, MD, MPH; Nishant Shah, MD)

Posted on by Elizabeth Mccamic

Speakers

Ken Mahaffey, MD
Professor of Cardiovascular Medicine
Associate Dean for Clinical Research, School of Medicine
Vice Chair for Clinical Research, Department of Medicine
Director, Stanford Center for Clinical Research (SCCR)
Stanford University

Nishant Shah, MD
Assistant Professor of Medicine
Duke University School of Medicine
The REVEAL Project: Identifying Real World Gaps and Areas for Improvement

Neha Pagidipati, MD, MPH 
Associate Professor of Medicine
Duke University School of Medicine
Test to Treat – Improving lipid management on a health system level

Keywords

CardioHealth Alliance, Research, ASCVD, LDL-C, REVEAL, Test 2 Treat

Key Points

  • The CardioHealth Alliance is focused on establishing a health system alliance with engaged clinicians, data scientists, and healthcare leaders to develop new care-pathways and real-world data to improve cardiovascular, renal disease, and metabolic disease outcomes for patients.
  • The CardioHealth Alliance wanted to do this work to establish a reusable real-world data platform to rapidly answer clinical questions, shorten implementation of evidence into practice, generate real-world evidence to inform stakeholders, and establish an alliance to address the value of care through policy.
  • Since its inception in November 2020, 9 health systems and 6 industry partners have joined the Alliance. The Alliance has 4 pillars that include partnering with clinical scientists to use real-world data to inform real world care; scaling and optimizing best practices; developing and testing new pathways and practices; continuously addressing the value of care through effective policy.
  • The CardioHealth Alliance REVEAL study looked at the current landscape for atherosclerotic cardiovascular disease (ASCVD) management because even though the guidelines are clear, implementation of LDL-C management across the world has not been optimal.
  • REVEAL looked at two cohorts. One cohort looked at LDL-C testing and management patterns. The study wanted to understand, within a chronic ASCVD population, how many ASCVD patients had LDL-C guideline-recommended goals, what factors were associated with achieving LDL-C goals in patients with ASCVD, and what patterns of liped lowering therapy (LLTs) prescriptions before and after LDL-C test by LDL-C level.
  • REVEAL also wanted to assess Lipoprotein (a) (Lp(a)), a biomarker that can lead to early onset and aggressive ASCVD. REVEAL wanted to find out what the proportion of patients with ASCVD had a LP (a) test, what factors associated with undergoing Lp(a) testing in patients with ASCVD, and whether or not Lp(a) testing influenced lipid management.
  • REVEAL identified a patient population across the Alliance that had an LDL-C value during the study period, had at least 2 outpatient encounters, and an ASCVD event within the last 5 years. The study identified 216,074 patients with ASCVD across 5 health systems. REVEAL found that only 86,188 (40%) had guideline-recommended LDL-C goals.
  • Patients who were at their goal tended to be male, white, had established coronary disease, heart failure, diabetes, and atrial fibrillation. Several factors were independently associated with not achieving the target: female sex, Black race, and Hispanic ethnicity.
  • For the Lp(a) cohort, REVEAL identified about 595,000 patients who were active within the health systems and either had or did not have an Lp(a) test. The study found that only 2,588 (0.4%) were tested for Lp(a) and those who were older, Black, or Hispanic were less likely to have Lp(a) testing. Those with a family history of hypercholesterolemia, ischemic stroke/TIA, PAD, prior LLT, or LDL-C greater than 130mg/dL were more likely to be tested for Lp(a). Having elevated Lp(a) was associated with higher initiation of non-statin lipid-lowering therapy (LLT); however, overall initiation of any LLT after an elevated Lp(a) test was low.
  • The CardioHealth Alliance study Test 2 Treat is an implementation science project aimed at improving LDL-C management after an ASCVD event by improving coordination of care between inpatient and outpatient teams, with the goal of preventing downstream morbidity and mortality in this high-risk population.
  • There is a window of opportunity when a patient is admitted for a coronary event to review medications and understand where there are gaps and risk factors, but this is not happening. Less than half of patients get their LDL-C checked within 6 months of the MI. The goal of Test 2 Treat is to bridge the transition from inpatient to outpatient care.
  • Test 2 Treat has two programs one focused on the inpatient, hospital-level intervention, the other focused on patients as they transition to the outpatient setting.
  • For the inpatient program, a hospital level intervention to address barriers and measure the proportion of patients who get their LDL-C measured and their LLTs adjusted in the hospital.
  • For the outpatient program, Test 2 Treat is looking at whether or not a nurse champion can navigate the transition verses usual care. The nurse champion or medical assistant will remotely go along with the patient to navigate inpatient-to-outpatient transition, including addressing questions about LDL-C medications, goals, and access to medications, ensuring follow-up, and facilitating communication with the outpatient team.
  • Test 2 Treat will develop intervention components that will be publicly available after the study if it is effective. Test 2 Treat has identified patient stakeholders to make sure the study is making sense from a patient perspective.

Learn more

Visit the CardioHealth Alliance website

Discussion Themes

-What do you see as the major challenges that the Alliance can solve? I think what we have learned through the initial work in the Alliance and other programs is that we have an incredible amount of data. We have learned we can access an incredible amount of data and touch an incredible amount of patients. But the data are messy. We need to continue our efforts in data mapping to curate the data more rigorously to allow us to answer more questions.

–What kind of topics or questions will the Alliance take on in the future? We are starting with cardio/kidney/metabolic and the principles of implementation should be applicable more broadly. I anticipate moving beyond CKMI and anticipate moving outwards beyond the traditional patients that we always reach and moving toward patients that are not traditionally included in routine care or clinical research. We want to move toward equitable care. We also want to leverage the idea of the platforms to address patients in a comprehensive manner, across interventions and diseases, to get at all of the issues but in a way that does not cost too much or is not feasible for health systems.

 

Tags

#pctGR, @Collaboratory1

Grand Rounds May 3, 2024: Comparative Effectiveness of Kidney Stone Surgery in Pediatric Patients: The PKIDS Trial (Gregory Tasian, MD, MSc, MSCE)

Posted on by Elizabeth Mccamic

Speaker

Gregory Tasian, MD, MSc, MSCE
Associate Professor of Surgery and Epidemiology
Children’s Hospital of Philadelphia

Keywords

PKIDS, PCORnet, Comparative Effectiveness Research, Kidney, Kidney Stone, Pediatrics

Key Points

  • The demographic of people who get kidney stones has changed over the past 30 years, which has left gaps in evidence base to support care. Increasingly, kidney stones affect children and adolescents, particularly adolescent girls. The Pediatric KIDney Stone Care Improvement Network (PKIDS) was founded to address this evidence gap.
  • PKIDS study was a prospective observational cohort study across 30 sites nationwide answering the participant-identified research question, what is the best surgery for my child who has a kidney or ureteral stone? Surgery for kidney stones usually includes minimally invasive surgical procedures including ureteroscopy (URS), shockwave lithotripsy (SWL), and percutaneous nephrolithotomy (PCNL).
  • The participant population included males and females, 8-21 years of age, undergoing URS, SWL, or PCNL for the removal of at least one kidney and/or ureteral stone.
  • The primary outcome was a clinical outcome of stone clearance defined by the absence of any stone under 4mm measured by ultrasound 4-8 weeks after surgery, consistent with standard of care. The secondary outcomes were the physical, social, and emotional health measured by patient-reported outcomes, as well as urinary symptoms, missed school/work, and ED visits, repeat surgery, admissions.
  • The trial took place between April 2020-October 2023. There were a total of 1,228 participants enrolled, with 1,070 receiving URS, 197 receiving SWL, and 98 receiving PCNL. There was a 50% completion of ultrasounds within the specified window due to the COVID-19 pandemic; the trial extended the window to 16 weeks with a 75% completion of postoperative ultrasound.
  • The PKIDS trial supports revisions of the American Urological Association guidelines including: A new size threshold of 15mm for kidney stones; recommend SWL over URS for stones less than 10mm; consider possible greater stone clearance and worse patient experiences with URS for kidney stones 10-15mm; remove SWL from guidelines for stones greater than 15mm; recommend PCNL over URS for stone greater than 15mm.

Grand Rounds April 26, 2024: Waiver or Alteration of Informed Consent for Minimal Risk Clinical Investigations – FDA Regulation Development and Research Landscape (Lauren Milner, PhD; Jonathan Casey, MD, MSCI; Matthew Semler, MD, MSCI)

Posted on by Elizabeth Mccamic

Speakers

Lauren Milner, PhD
Office of Clinical Policy
U.S. Food and Drug Administration (FDA)

Jonathan Casey, M.D., MSCI
Assistant Professor, Division of Pulmonary and Critical Care Medicine
Vanderbilt University Medical Center
Director, Coordinating Center Pragmatic Critical Care Research Group

Matthew Semler, M.D., MSCI
Associate Professor, Division of Pulmonary and Critical Care Medicine
Vanderbilt University Medical Center
Director, Steering Committee Pragmatic Critical Care
Research Group
Co-Director, Vanderbilt Center for Learning Healthcare

Keywords

Food and Drug Administration, FDA, Waiver of Consent, Alteration of Informed Consent, IRB, Ethics, Regulatory

Key Points

  • Section 3024 of the FDA 21st Century Cures Act (2016) amends the Food, Drug and Cosmetics Act and provides the U.S. Food and Drug Administration (FDA) with the authority to permit an exception from informed consent requirements when the proposed clinical testing poses no more than minimal risk to the human subject and includes appropriate safeguards to protect the rights, safety, and welfare of participants.
  • In 2018, FDA issued the Proposed Rule that would allow an IRB to waive or alter certain informed consent elements, or to waive the requirement to obtain informed consent, under limited conditions, for certain minimal risk clinical investigators.
  • The Final Rule (2023) finalizes 4 criteria for waiver or alteration of consent with minor edits and adopts a 5th criterion for waiver or alteration of consent for identifiable information and biospecimens.
  • The Final Rule is not new for IRBs and investigators familiar with the minimal risk waiver/alteration provision in the Common Rule. It has the same criteria, same process. It is relatively new to FDA’s regulated community. Previously, FDA regulations allowed waiver only for certain types of emergency research.
  • The goal of the Final Rule is to advance medical product development without compromising the rights, safety and welfare of people participating in clinical research. FDA will develop a draft guidance to accompany the final rule and communicate with researchers, IRBs, patient communities and other interested parties about the rule.
  • To understand how the regulations are being applied currently, a team at Vanderbilt systematically reviewed all studies meeting the NIH definition of clinical trial, published in the last year (May 2023 to April 2024) in JAMA and the New England Journal of Medicine (NEJM). Each trial was reviewed to determine whether informed consent prior to enrollment was required.
  • During that time period, 33 trials were published in JAMA or NEJM that did not require informed consent. The reasons they did not require informed consent fell into 3 buckets: 1. Emergency and critical care studies (19 RCTs enrolling more than 15,000 patients where informed consent before enrollment was considered impracticable because of the urgency of the intervention and the condition of the patient); 2. Cluster-level: Infection Prevention (11 RCTs enrolling almost 3 million patients where consent was considered impracticable because the intervention was delivered to a group of patients different than the patients who would experience the outcomes (i.e. infection control) and due to the scale); 3. Interventions to promote communication and facilitate care (3 RCTs).
  • In all, the systematic review found that 13% of trials did not require informed consent before enrollment, and 89% of patients (more than 3 million) in trials that did not require informed consent before enrollment.
  • Upcoming FDA guidance on waiver and alteration of consent could provide the first regulatory guidance for minimal risk interventional research. While U.S. federal regulators do not currently provide guidance on minimal risk for interventional trial, trials are occurring with waiver and alteration.
  • Upcoming FDA regulations present an important opportunity for the NIH Collaboratory’s goal of facilitating Learning Healthcare Systems capable of using embedded pragmatic trials to improve patient outcomes

 

Discussion Themes

-What is next from FDA in terms of the release of any further guidance? The timeline is challenging. It is under development and the FDA is working through the process.

–How does one judge the minimal risk criteria? For example, there are a lot of people who treat patients with diabetes with various medications. They may vary in terms of side effects, some of which might be rare. How do you identify if it is minimal risk? You have to meet 2 criteria to be considered for waiver of informed consent, both minimal risk and impracticability. Regardless of how you assess risk for a modestly sized study of a non-urgent intervention, then it would be conceivable to do it under consent and you would not need a waiver. If you are talking about health care system level studies, and for example, a study where these medications are already being used commonly and they are considered to be equivalent, that might be a case where people could consider choices like that. The framework of thinking is always “compared to what” and who is making the decisions. In clinical care is this something where the data is already good enough that physicians feel confident most of the time about one choice or would the patient have a strong preference about or a situation where the patient and clinician are not making the decision and there’s a spectrum in between. The question what does it look like now in clinical care can give a qualitative sense about the risk.

 

Tags

#pctGR, @Collaboratory1