Survey Reveals the Hidden Costs of Care Cascades

Almost all physician reported seeing incidental findings set off a cascade of care for a patient, many of which did not lead to clinically meaningful outcomes yet caused harm to patients and their physicians

Just about any medical test can turn up an incidental finding that leads to a cascade of follow-up tests. For instance, a patient comes in for a routine test to measure their heart activity before cataract surgery and the test picks up what could be an irregularity, which leads to a stress test, which leads to a cardiac catherization, which may reveal that the patient’s heart function is just fine and all of the tests, costs and anxiety were for nothing. Anecdotes about these so-called care cascades abound. Through a national survey of physicians, investigators from the Brigham have found that 99 percent of physicians have experienced these cascades of care firsthand and report that such cascades have caused their patients psychological harm, physical harm and financial burden and have caused frustration and anxiety for physicians. The team’s findings are published in JAMA Network Open.

“Our findings are both shocking and not surprising at all. Every clinician I have ever spoken to has experienced an incidental finding that led to downstream care that didn’t help a patient in the long run,” said corresponding author Ishani Ganguli, MD, MPH, a physician researcher in the Division of General Internal Medicine and Primary Care at the Brigham and an assistant professor of Medicine at Harvard Medical School. While in some cases, incidental findings may reveal a clinically important and intervenable discovery, such as an early-stage cancer, more often, subsequent evaluations may find nothing significant.


To determine the national scope of incidental findings and the cascades that can follow, Ganguli and her colleagues conducted a web-based national survey of U.S. internists who are members of the American College of Physicians. The team received 376 completed surveys and found that more than 99 percent of respondents reported experiencing cascades of care. About 90 percent had experienced cascades with clinically important and intervenable outcomes and about 94 percent had experienced cascades with no such outcome. Physicians reported that cascades caused their patients psychological harm, physical harm, and financial burden and personally caused the physicians wasted time and effort, frustration, and anxiety.

The survey also asked physicians about their ideas for possible solutions to the problem of cascades of care. Most physicians believed that having access to guidelines about incidental findings that they could reference while seeing a patient would help limit negative consequences. Many also thought that further educating both physicians and patients about the potential harms of unnecessary medical testing would help both groups.

The authors note that, as with any survey, their study relies on the memory of respondents, which may be influenced by more dramatic outcomes. The study doesn’t capture out-of-pocket costs for patients, which is something the researchers are interested in investigating in the future.

“Patients need to know that unexpected findings on medical tests can lead to cascades that can cause patients harm, including out of pocket costs, invasive tests and anxiety,” said Ganguli. “We’re interested both in quantifying how pervasive a problem cascades of care are as well as solutions to prevent the cascade of unnecessary medical care and harm that may be set off by an incidental finding.”

This study was funded by grant 1R01HS023812 from the Agency for Healthcare Research and Quality (AHRQ). Ganguli reported receiving grants from AHRQ and International Business Machines (IBM) Corporation and receiving personal consultancy fees from Haven.

Paper cited: Ganguli, I et al. “Cascades of Care After Incidental Findings in a US National Survey of Physicians” JAMA Network Open DOI: 10.1001/jamanetworkopen.2019.13325

More Patients with Cardiovascular Disease Now Die at Home Than in the Hospital

Analysis finds 31 percent of deaths now occurring at home, suggesting opportunity for productive focus on end-of-life care

Despite their wishes, many patients die in hospitals or other facilities. Cardiovascular disease (CVD) is the leading cause of death both globally and in the U.S., yet little is known about where patients with CVD die. In a new study, Haider Warraich, MD, of Brigham and Women’s Hospital, and colleagues assessed place of death for CVD patients from 2003 to 2017, finding that home has surpassed the hospital as the most common place of death for these patients. The results of their analysis are published in the Journal of the American College of Cardiology.

“When I talk to my patients about what’s most important to them as they begin to reach the end of life, so many of them tell me they want to spend their last moments surrounded by the familiarity of home,” said Warraich, who joined the Division of Cardiovascular Medicine at the Brigham in September as an associate physician. “Understanding where patients die can help us determine how we can deliver care to them and what services they’ll require in those settings.”

To conduct their study, investigators examined more than 12 million deaths in the Mortality Multiple Cause-of-Death Public Use Record from the National Center for Health Statistics. They looked at whether deaths occurred in a hospital, home, nursing or long-term care facility, inpatient hospice facility, or other (including outpatient medical facility, emergency department, and dead-on-arrival at the hospital). They also analyzed demographic characteristics, including race, ethnicity, sex, marital status, education level and rural-urban status.

The team found that 330,905 CVD deaths occurred in the hospital in 2003, decreasing to 234,703 in 2017. Deaths at home increased from 192,986 in 2003 to 265,133 in 2017, accounting for about 31 percent of the CVD deaths that year. The team also found that underserved racial and ethnic groups were more likely to die in the hospital and less likely to die at home.

Warraich notes that while the data provide insights, they do not reveal what the last days or weeks of patients’ life were like and whether they received hospice care at home, nor do the data capture patients’ wishes and whether their place of death reflected those wishes.

“Cardiology has lagged behind other specialties in focusing on end-of-life care, but we’re now seeing more interest in this important area,” said Warraich. “We’re seeing that more people are dying at home than at any other location, but we need to better understand what that experience is like so that we can focus our energy on the needs of our patients.”

Paper cited: Cross, SH et al. “Trends in Place of Death for Individuals With Cardiovascular Disease in the United States” Journal of the American College of Cardiology DOI: 10.1016/j.jacc.2019.08.1015

Out-of-Pocket Prices for Prescription Drugs Vary Widely Throughout the U.S.

Study finds prices for 16 commonly used prescription drugs varied substantially across the country and by type of retail pharmacy

How much you pay for a prescription drug at a pharmacy may vary greatly depending on what part of the country you live in and where you buy your prescriptions, according to a new study led by investigators at Brigham and Women’s Hospital. The team reports that cash prices — the amount that a consumer pays out of pocket — at independent pharmacies for a group of generic drugs ranged from eight times less expensive to eight times more expensive than the price for the exact same group of drugs at a large retail chain drug store. The team also analyzed results by zip code, finding more moderate differences in cash prices for prescriptions depending upon the type of pharmacy making the sale. Results of the study are published in Annals of Internal Medicine.

“Increasingly, consumers are paying out of pocket for prescription drugs. We set out to understand variation in the prices patients are paying for the drugs they are prescribed,” said corresponding author Jing Luo, MD, MPH, who conducted this research while serving as a faculty member at the Brigham and Harvard Medical School. Luo is now an assistant professor of Medicine at the University of Pittsburgh. “This was a very large study looking at drug prices at pharmacies across the country. We demonstrated wide variation in cash prices for the set of drugs we looked at. In general, when we stratified by zip code, prices were less expensive at big box pharmacies, but this difference was swamped by the variation we saw across the country.”

To conduct their study, Luo and colleagues in the Division of Pharmacoepidemiology and Pharmacoeconomics at the Brigham analyzed data provided by GoodRx, an online tool for comparing drug prices. The dataset included information from more than 60,000 pharmacies from the fall of 2015. The team analyzed cash prices for a one-month supply of 16 prescription drugs, including the top 10 generic prescription drugs by volume (albuterol, amlodipine, atorvastatin, hydrocodone–acetaminophen, L-thyroxine, lisinopril, metformin, metoprolol, omeprazole, and simvastatin) and the top six brand-name prescription drugs by sales (aripiprazole, fluticasone–salmeterol, rosuvastatin, duloxetine, glargine, and esomeprazole).

The team categorized pharmacies into large chains with at least 100 stores nationwide (such as Walgreens, CVS, and Rite Aid), small chains with four to 100 stores nationwide (such as Discount Drug Mart and Thrifty White), pharmacies based in a grocery store or supermarket (such as Kroger and Publix), big box pharmacies (such as Costco, Sam’s, Walmart, and BJ’s), and independent pharmacies. Specialty, infusion, compounding, long-term care pharmacies (such as those at hospitals) and mail-order services were not included in the analysis.

The mean cash prices for individual generic drugs varied widely. The team found the largest degree of variation among independent and small chain pharmacies; although cash prices at most independent pharmacies were higher than those at the largest chain pharmacy, some independent pharmacies had lower prices. In rare cases, the cash price for a group of generic drugs at one specific independent pharmacy could be several times less than that at the largest chain pharmacy. Most grocery-based and big box pharmacies had cash prices that were below those at the largest chain pharmacy, although some had prices that were higher. Large chain pharmacies had the least variation in cash prices. The team found a similar pattern for brand-name drugs, although with less degree of variation.

When the team stratified by zip code, they found that the cash price for the generic drugs at big box and grocery-based pharmacies was generally less than at large chain pharmacies. Cash prices at small chain and independent pharmacies were greater than at large chain pharmacies. Again, the team found that brand-name drugs followed a similar pattern, but to less of a degree of magnitude.

The authors note that their study could not take into account discount codes and price matching that independent and smaller pharmacies may be able to offer. Their study is also blind to zip codes where there may not be a large chain pharmacy to which prices could be compared.

Luo emphasizes that the study’s findings should not be interpreted to mean that consumers should simply go to big box pharmacies; instead, given the wide variation in drug pricing, consumers looking for the lowest price may find it helpful to comparison shop online.

“Online access to transparent, reliable drug prices may help consumers navigate variations in drug pricing and may mean lower out-of-pocket payments and greater prescription adherence,” said Luo.

Funding for this work was provided by Arnold Ventures. Luo reports salary support from Alosa Health and Arnold Ventures outside the submitted work.

Paper cited: Luo, J et al. “Variation in Prescription Drug Prices by Retail Pharmacy Type” Annals of Internal Medicine DOI: 10.7326/M18-1138

Study Supports Taking Blood Cultures Before Beginning Treatment for Sepsis

Blood cultures drawn after antimicrobial administration resulted in a loss of almost 50 percent of available clinical information

Severe bacterial infections are a leading cause of death globally. Delays in effective treatment can increase the chance that a patient dies but treating a patient before blood cultures are drawn may make it impossible to identify the bacteria causing the infection and make it challenging to identify the best choice of treatment. Current clinical guidelines recommend that blood cultures be drawn before treatment begins, but no previous studies have definitively compared drawing a blood culture shortly after a patient begins antimicrobial treatment with drawing blood cultures prior to treatment. In a new study led by investigators from Brigham and Women’s Hospital, a team performed a prospective study in seven centers across North America and found that blood cultures drawn after antimicrobial administration resulted in a loss of almost 50 percent of available clinical information. The team reports these findings, which provide a basis for clinical guidelines for the care of patients with sepsis, in Annals of Internal Medicine.

“These findings are important in considering the optimal balance between prompt antimicrobial administration and the need for accurate microbiological data in the care of patients with sepsis,” said corresponding author Matthew Cheng, MD, a clinical instructor in the Brigham’s Division of Infectious Diseases.  “Given the global burden of sepsis, deepening our understanding of how best to treat this condition is critically important.”

Cheng and colleagues conducted a study known as FABLED (eFfect of Antimicrobial administration on BLood culture positivity in patients with severe manifestations of sepsis in the Emergency Department), a patient-level, single-group, diagnostic study. Between November 2013 and September 2018, the team enrolled adult patients who presented to the emergency department with severe manifestations of sepsis. Each patient had two blood cultures drawn before treatment initiation and repeat blood cultures drawn within two hours after starting treatment.

Pre-treatment blood cultures were positive for one or more microbial pathogens in 102-of-325 (31.4 percent) patients. After-treatment blood cultures were positive for one or more microbial pathogens in 63-of-325 (19.4 percent) patients. The sensitivity of post-treatment cultures, or percentage of samples accurately identified as having the same pathogens pre-treatment, was 52.9 percent.

Patients with sepsis are generally treated initially with a broad-spectrum antibiotic, but Cheng and colleagues note the importance of identifying the right narrow-spectrum antibiotic based on a patient’s blood culture. Without an accurate picture of the microbial landscape prior to initiating treatment, it may be extremely challenging for physicians to select the right antibiotic.

“When it comes to treating sepsis safely and effectively, microbiological diagnosis is key,” said Cheng. “Despite the importance of starting treatment early for sepsis patients, our results support the Surviving Sepsis Campaign guidelines and suggest that blood cultures should not be routinely deferred.”

Funding for this work was provided by Vancouver Coastal Health, St. Paul’s Hospital Foundation Emergency Department Support Fund, the Fonds de Recherche Santé –Québec, and the Maricopa Medical Foundation.

Paper cited: Cheng M et al. “Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis” Annals of Internal Medicine DOI doi/10.7326/M19-1696.

New Biomarker for Dementia Improves Risk Prediction

In a study of cognitively healthy adults, elevated plasma levels of IGFBP-2 were associated with an increased risk of all-cause dementia, including Alzheimer’s disease dementia

Identifying individuals who are at risk for developing dementia, including Alzheimer’s disease, is critical for the development of new therapies and interventions to slow or reverse cognitive symptoms. But current strategies are limited, both in terms of accuracy and the ability to incorporate them into routine practice. Unlike cerebrospinal fluid biomarkers that require a spinal tap, plasma biomarkers can be extracted from the blood, making their collection much less invasive and much more appealing. In a new study led by investigators from Brigham and Women’s Hospital, researchers have measured circulating levels of insulin-like growth factor binding protein 2 (IGFBP-2), a potential biomarker for dementia. In a paper published in Annals of Clinical and Translational Neurology, the team reports that IGFBP-2 levels were associated with an increased risk of both all-cause dementia and Alzheimer’s disease dementia. When added to a model of traditional risk factors for dementia, IGFBP-2 significantly improved dementia risk classification, suggesting that it may be a useful biomarker for predicting dementia risk.

“Identifying biomarkers for dementia could improve our ability to predict a person’s risk of dementia and his or her future outcomes,” said corresponding author Emer McGrath, MD, PhD, an associate neurologist in the Brigham’s Neurology Department and an investigator with the Framingham Heart Study. “Novel biomarkers could also inform our understanding of complex biological pathways underlying the development of dementia, help to more accurately define disease subgroups and inform future clinical trials.”

Recently, researchers have begun to focus on the role of metabolic dysfunction and insulin resistance in the brain in the development of dementia. The insulin-like growth factor (IGF) signaling system is known to play a role in neuroregeneration, neuronal survival and proliferation. IGFBP-2 is thought to impair IGF signaling, thereby inhibiting the neuroprotection and proliferation.

In the current study, investigators measured levels of IGFBP-2 in plasma samples from almost 1,600 participants from the Framingham Offspring cohort. The team analyzed risk of dementia, cognitive performance and structural MRI brain measures predictive of dementia.

They found that elevated circulating IGFBP-2 levels were associated with an increased risk of both all-cause dementia and Alzheimer’s disease dementia, as well as poorer performance on tests of abstract reasoning. Addition of IGFBP2 plasma levels to a model of traditional risk factors significantly improved dementia risk classification: based on the net reclassification improvement (NRI) index, 32 percent of individuals with dementia were correctly assigned a higher predicted risk, while 8 percent of individuals without dementia were correctly assigned a lower predicted risk.

The authors note that the Framingham Offspring cohort is predominantly Caucasian, potentially limiting the generalizability of the findings to more diverse populations. They were also unable to explore the association between cerebrospinal fluid levels of IGFBP-2 or Tau levels with IGFBP-2 plasma levels and cognitive outcomes.

“There is increasing interest in manipulating insulin sensitivity and IGF signaling in the brain to help target cognitive decline and dementia,” said McGrath. “Our work suggests that manipulating IGF-signaling pathways via IGFBP-2 may be a promising therapeutic target for dementia prevention.”

Funding for this work was provided by an Alzheimer’s Association Clinician Scientist Fellowship (AACSF-18- 566570), the National Heart, Lung, and Blood Institute (R01 HL60040 and R01 HL70100), the National Institute on Aging (R01 AG054076, R01AG049607, R01 AG033193, U01 AG049505,U01 AG052409), and National Institute of Neurological Disorders and Stroke (NS017950 and UH2 NS100605).

Paper cited: McGrath, E et al. “Circulating IGFBP-2: a novel biomarker for incident dementia” Annals of Clinical and Translational Neurology DOI: 10.1002/acn3.50854

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