Discoveries & Impact (April 2022)

Discoveries & Impact highlights select scientific discoveries per section across the Department of Internal Medicine...

The PRECISE Trial: a Patient-centric Approach for Chest Pain

A multicenter randomized study could improve clinical decision-making for patients with chest pain. Previous studies have found that clinicians tend to order noninvasive tests such as treadmill stress testing, even in patients with a very low risk for coronary artery disease (CAD). Despite the recent American College of Cardiology and American Heart Association guidelines for the evaluation and diagnosis of chest pain, there is no one standard approach. The lack of a standardized process has been shown to impact patient care and increase healthcare spending.

The PRECISE trial (Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularization), led by principal investigator Pamela Douglas, MD, from Duke Clinical Research Institute, included over 2,000 participants with chest pain and suspected CAD across 68 outpatient international sites.

PRECISE is the first randomized trial to compare usual care testing with a risk-based precision evaluation strategy, which assigns the lowest risk, stable chest pain patients to deferred testing and higher risk patients to coronary computed tomographic angiography (CTA) with selective hemodynamic evaluation or fractional flow reserve (FFR_CT). The aim of PRECISE is to determine whether this investigational precision approach improves clinical outcomes, efficiency, and cost over usual care diagnostic testing for this exceedingly common clinical scenario.

The rationale and design for PRECISE, as well as baseline characteristics for patients enrolled, was published March 19 in the American Heart Journal. Lead author Michael Nanna, MD, MHS, an assistant professor at Yale School of Medicine, hopes that PRECISE will shed light on the optimal diagnostic strategy for patients presenting with stable chest pain while also providing the first randomized trial evidence for a deferred testing strategy in the lowest risk patients.

Nanna MG, Vemulapalli S, Fordyce CB, Mark DB, Patel MR, Al-Khalidi HR, Kelsey M, Martinez B, Yow E, Mullen S, Stone GW, Ben-Yehuda O, Udelson JE, Rogers C, Douglas PS. The prospective randomized trial of the optimal evaluation of cardiac symptoms and revascularization: Rationale and design of the PRECISE trial. American Heart Journal 2022, 245: 136-148. doi: 10.1016/j.ahj.2021.12.004. PMID: 34953768.

GI Hospitalists Provide Timely Care But Challenges Exist

The role of hospitalists has expanded since the concept was originally introduced. Yale started introducing specialty hospitalists over a year ago, and in “Adapting to the Challenge of Hospital-Based Care: The Evolving Role of Gastroenterology Hospitalists,” the authors outline the advantages and challenges of utilizing a hospitalist model in gastroenterology (GI).

Having a designated GI hospitalist permits more timely care for acute issues that may arise in the inpatient setting. Adding this role also eliminates the disruptions to outpatient and/or endoscopy clinics. To learn about the challenges of and steps to implement this model, read the publication in The American Journal of Gastroenterology.

Hughes ML, Li DK, Hung KW, Laine L. Adapting to the Challenge of Hospital-Based Care: The Evolving Role of Gastroenterology Hospitalists. The American Journal Of Gastroenterology 2022, 117(3): 361-363. doi: 10.14309/ajg.0000000000001585. PMID: 34904965.

Lower Doses of Pioglitazone Prevents Heart Attack, Stroke

Insulin resistance affects many people with type 2 diabetes, but it is also a common metabolic condition even in those without diabetes. Therapies for insulin resistance include weight loss, dietary changes, exercise, and certain medications. As reported in the NEJM in 2016 by Yale investigators, the Insulin Resistance Intervention in Stroke (IRIS) trial was the first to show that the insulin sensitizing drug of the thiazolidinedione class, pioglitazone, reduced the risk of heart attack or stroke in patients without diabetes who had insulin resistance and a recent stroke or transient ischemic attack.

The new research in Diabetes, Obesity and Metabolism builds upon those landmark findings. Despite the impressive effects of pioglitazone in IRIS, there were concerns about its dose related side effect profile, particularly weight gain and edema. In their recent publication, the researchers found that 15 and 30 mg seemed to be as effective as the protocol-specified higher dose of 45 mg higher dose for the prevention of heart attack or stroke. Moreover, side effects were, for the most part, indistinguishable from placebo. The investigators suggested that lower doses of pioglitazone may capitalize on the potent metabolic actions and anti-atherosclerotic effects of the drug, while minimizing adverse effects. Learn more in “Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance

Spence JD, Viscoli C, Kernan WN, Young LH, Furie K, DeFronzo R, Abdul-Ghani M, Dandona P, Inzucchi SE. Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance. Diabetes, Obesity & Metabolism 2022 doi: 10.1111/dom.14687. PMID: 35253334.

VACHS Quality Improvement Initiative Increased Vax Rates

COVID-19 vaccines have been proven to lessen serious illness and death, yet vaccine hesitancy remains a challenge across the United States. Clinicians at the VA Connecticut Healthcare System (VACHS) set out to see if they could improve COVID-19 vaccine acceptance. Across eight primary care sites, healthcare providers care for 47,000 veterans.

In late December 2020, outreach consisting of phone calls, emails, mailings, and social media posts began. As vaccine supply increased, walk-in clinics and mass-vaccination events were launched. For those veterans still unvaccinated by March 2021, VACHS created additional steps to reach this population. They named a primary care physician champion, added educational sessions, and created tools in the electronic medical record targeting vaccine hesitancy. After six months of implementing this quality improvement initiative, the rate of veterans vaccinated across VACHS was higher as compared to the rest of the New England region. Learn more in “Addressing COVID-19 Vaccine Acceptance Within a Large Healthcare System: a Population Health Model.”

Spelman JF, Kravetz JD, Bastian L, Ruser C. Addressing COVID-19 Vaccine Acceptance Within a Large Healthcare System: a Population Health Model. Journal Of General Internal Medicine 2022, 37(4): 954-957. doi: 10.1007/s11606-021-07353-9. PMID: 35025069. PMCID: PMC8757394.

Advance Care Planning Awareness Needed

Advance care planning (ACP), a process by which individuals can help define their future treatment goals and preferences, is important, especially for older adults. The use of ACP has been shown to have many benefits for the patient as well as their family. But the adoption of ACP is not consistent. In this new Yale Geriatrics study, researchers sought to examine whether perceived susceptibility to dementia affected ACP behaviors.

The team looked at data from 711 survey respondents from the Health and Retirement Survey who were asked about their perceived risk of dementia. More than 1 in 10 adults believed they had no chance of developing dementia. They were less likely to have engaged in ACP compared to those who perceived themselves to be at risk of developing dementia. However, a higher level of perceived risk didn’t lead to ACP completion in many older adults. Healthcare providers should address the importance of ACP to increase adoption rates, especially in those people at risk for dementia. Read more in the Journal of the American Geriatrics Society.

Lee YK, Fried TR, Costello DM, Hajduk AM, O'Leary JR, Cohen AB. Perceived dementia risk and advance care planning among older adults. Journal Of The American Geriatrics Society 2022 doi: 10.1111/jgs.17721. PMID: 35274737.

Are the Current Treatment Guidelines for ITP Cost-Effective?

Immune thrombocytopenia is an autoimmune disorder which leads to a shortage of platelets, which helps blood clot. When a patient has immune thrombocytopenia for 12 months or more, the condition is considered chronic, or chronic immune thrombocytopenia (ITP). While the American Society of Hematology recommends guidelines for ITP care, data on the cost-effectiveness of available treatment strategies did not exist.

In this new research published in the American Journal of Hematology, the researchers created a Markov model to evaluate six possible sequences of the three major second-line treatments. They used 51 years as the starting age for care, and used conservative assumptions that a priori favored the status quo of current clinical utilization. From their analysis, they determined the cost-effective treatment strategy. To learn more about their methodology and results, read “Cost-effectiveness of second-line therapies in adults with chronic immune thrombocytopenia.”

Goshua, G, Sinha, P, Kunst, N, Pischel, L, Lee, AI, Cuker, A. Cost-effectiveness of second-line therapies in adults with chronic immune thrombocytopenia. Am J Hematol. 2022; 1- 9. doi:10.1002/ajh.26497

Highlighting the Global Need for COVID-19 Vaccine Boosters

The emergence of the SARS-CoV-2 Omicron variant raised concerns because of its increased transmissibility and potential to evade neutralizing antibodies elicited by COVID-19 vaccines especially among the large number of the world’s population who have received less effective inactivated vaccines. Yale scientists evaluated the effects of a BNT162b2 mRNA vaccine booster on the humoral immunity of participants who had received a two-dose regimen of the inactivated vaccine, CoronaVac. Read more in Nature Medicine.

Pérez-Then E, Lucas C, Monteiro VS, Miric M, Brache V, Cochon L, Vogels CBF, Malik AA, De la Cruz E, Jorge A, De Los Santos M, Leon P, Breban MI, Billig K, Yildirim I, Pearson C, Downing R, Gagnon E, Muyombwe A, Razeq J, Campbell M, Ko AI, Omer SB, Grubaugh ND, Vermund SH, Iwasaki A. Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination. Nature Medicine 2022, 28(3): 481-485. doi: 10.1038/s41591-022-01705-6. PMID: 35051990.

Yale Precision Tumor Board Case Histories

Two case histories from the Yale Precision Tumor Board -- a 56-year-old man who was diagnosed with a borderline resectable pancreatic adenocarcinoma, and a 50-year-old man who was diagnosed with a stage III ampullary adenocarcinoma -- are detailed in The Lancet Oncology. These cases illustrate distinct genetic mechanisms that lead to loss of canonical p53 tumor suppressor activity in cancer. They also highlight the usefulness of broad next-generation sequencing (NGS) testing to detect these alterations and allow for rational clinical trial enrollment using targeted approaches to restore activity of a protein long thought to be undruggable. Full case histories and the board’s recommendations can be found in The Lancet Oncology.

Grant MJ, Finberg KE, Walther Z, Stein SM, Lacy J, Eder JP, Goldberg SB. Yale Precision Medicine Tumor Board: reawakening the guardian of the genome. The Lancet. Oncology 2022, 23(3): 337-338. doi: 10.1016/S1470-2045(22)00037-7. PMID: 35240081.

Predicting Acute Kidney Injury After Cardiac Surgery

Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 40% of patients, impairs heart, lung, brain, and gut function, and is associated with an increased risk of death during hospitalization. AKI -- renal failure that develops rapidly in people who are critically ill and hospitalized --has other negative effects. Patients with AKI who survive are more likely to develop chronic kidney disease and dialysis-dependent kidney failure in the following years than those without postoperative AKI. In an editorial in JAMA Network, F. Perry Wilson, MD, and colleagues comment on a paper that reports on new models for predicting the risk of AKI in adult patients undergoing coronary artery bypass graft, valve, or aorta surgery. Read the editorial here.

Ostermann M, Lumlertgul N, Wilson FP. Predictive Models for Acute Kidney Injury Following Cardiac Surgery: The Importance of Accurate and Actionable Prediction. JAMA 2022, 327(10): 927-929. doi: 10.1001/jama.2022.1823. PMID: 35258544.

Can Telehealth Promote Physical Activity in People with COPD?

Physical activity is a reflection of how much a person moves throughout the course of their day. People with COPD typically have low levels of physical activity, which is associated with poor health outcomes, including increased symptoms, a more rapid decline in lung function, increased health care use, and increased mortality risk. Pulmonary rehabilitation improves exercise capacity and as such can, but does not always, increase the physical activity of these patients. Also, accessibility to pulmonary rehabilitation programs is problematic in some areas. Using telehealth interventions to provide pulmonary rehabilitation conveniently over a distance would have the benefit of reaching a larger proportion of individuals with COPD. Carolyn L. Rochester, MD, reviews the findings of clinical trials testing telehealth to promote physical activity. Read the review in Life journal.

Rochester CL. Does Telemedicine Promote Physical Activity? Life (Basel, Switzerland) 2022, 12(3) doi: 10.3390/life12030425. PMID: 35330176. PMCID: PMC8948765.

Understanding the Stress Responses of Cells

In the “Voices” article of Cell Systems, Yale Immunobiology graduate student Kavita Israni-Winger and Andrew Wang, MD, PhD present a short essay based on the question, “What differentiates a stress response from responsiveness in general?” Israni-Winger and Wang describe how cells have evolved to changes in the environment, such as temperature and oxygen tension, in order to maintain their function. They do this by responding to environmental fluctuations and returning to an ideal set-point. However, some environmental variables, such as pathogens, predators, or poisons, can turn on a stress state that can enable the cell to survive but often at the cost of normal function. When environmental conditions persist outside of ideal set-points, a cell’s response can become maladaptive and lead to disease. Read more in Cell Systems.

Vogel C, Balázsi G, Löwer A, Jiang C, Schmid AK, Sommer M, Yang L, Münch C, Wang A, Israni-Winger K, Mühlhaus T, Des Marais DL, Oster H, Socolovsky M. What differentiates a stress response from responsiveness in general? Cell Systems 2022, 13(3): 195-200. doi: 10.1016/j.cels.2022.02.002. PMID: 35298910.