Artificial intelligence (A.I.) is likely to change almost everything in medical practice, according to a new book called “Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again,” by Eric Topol, MD.

archy13/Getty Images

Dr. Topol told The Hospitalist that his book’s subtitle “is the paradox: the unexpected, far-reaching goal of A.I. that can, if used properly, restore the most important part of medicine – a deep patient-doctor relationship.”

That’s because A.I. can do more than enhance diagnoses; it can also help with tasks such as note-taking and reading scans, making it possible for hospitalists to spend more time connecting with their patients. “Hospitalists could have a much better handle on a patient’s dataset via algorithmic processing, providing alerts and augmented performance of hospitalists (when validated),” Dr. Topol said. “They can also expect far less keyboard use with the help of speech recognition, natural language processing, and deep learning.”In an interview with the New York Times, Dr. Topol said that by augmenting human performance, A.I. has the potential to markedly improve productivity, efficiency, work flow, accuracy and speed, both for doctors and for patients, giving more charge and control to consumers through algorithmic support of their data.

“We can’t, and will never, rely on only algorithms for interpretation of life and death matters,” he said. “That requires human expert contextualization, something machines can’t do.”Of course, there could be pitfalls. “The liabilities include breaches of privacy and security, hacking, the lack of explainability of most A.I. algorithms, the potential to worsen inequities, the embedded bias, and ethical quandaries,” he said.
 

Reference

1. O’Connor A. How Artificial Intelligence Could Transform Medicine. New York Times. March 11, 2019. https://www.nytimes.com/2019/03/11/well/live/how-artificial-intelligence-could-transform-medicine.html.

Artificial intelligence (A.I.) is likely to change almost everything in medical practice, according to a new book called “Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again,” by Eric Topol, MD.

archy13/Getty Images

Dr. Topol told The Hospitalist that his book’s subtitle “is the paradox: the unexpected, far-reaching goal of A.I. that can, if used properly, restore the most important part of medicine – a deep patient-doctor relationship.”

That’s because A.I. can do more than enhance diagnoses; it can also help with tasks such as note-taking and reading scans, making it possible for hospitalists to spend more time connecting with their patients. “Hospitalists could have a much better handle on a patient’s dataset via algorithmic processing, providing alerts and augmented performance of hospitalists (when validated),” Dr. Topol said. “They can also expect far less keyboard use with the help of speech recognition, natural language processing, and deep learning.”In an interview with the New York Times, Dr. Topol said that by augmenting human performance, A.I. has the potential to markedly improve productivity, efficiency, work flow, accuracy and speed, both for doctors and for patients, giving more charge and control to consumers through algorithmic support of their data.

“We can’t, and will never, rely on only algorithms for interpretation of life and death matters,” he said. “That requires human expert contextualization, something machines can’t do.”Of course, there could be pitfalls. “The liabilities include breaches of privacy and security, hacking, the lack of explainability of most A.I. algorithms, the potential to worsen inequities, the embedded bias, and ethical quandaries,” he said.
 

Reference

1. O’Connor A. How Artificial Intelligence Could Transform Medicine. New York Times. March 11, 2019. https://www.nytimes.com/2019/03/11/well/live/how-artificial-intelligence-could-transform-medicine.html.

Artificial intelligence (A.I.) is likely to change almost everything in medical practice, according to a new book called “Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again,” by Eric Topol, MD.

archy13/Getty Images

Dr. Topol told The Hospitalist that his book’s subtitle “is the paradox: the unexpected, far-reaching goal of A.I. that can, if used properly, restore the most important part of medicine – a deep patient-doctor relationship.”

That’s because A.I. can do more than enhance diagnoses; it can also help with tasks such as note-taking and reading scans, making it possible for hospitalists to spend more time connecting with their patients. “Hospitalists could have a much better handle on a patient’s dataset via algorithmic processing, providing alerts and augmented performance of hospitalists (when validated),” Dr. Topol said. “They can also expect far less keyboard use with the help of speech recognition, natural language processing, and deep learning.”In an interview with the New York Times, Dr. Topol said that by augmenting human performance, A.I. has the potential to markedly improve productivity, efficiency, work flow, accuracy and speed, both for doctors and for patients, giving more charge and control to consumers through algorithmic support of their data.

“We can’t, and will never, rely on only algorithms for interpretation of life and death matters,” he said. “That requires human expert contextualization, something machines can’t do.”Of course, there could be pitfalls. “The liabilities include breaches of privacy and security, hacking, the lack of explainability of most A.I. algorithms, the potential to worsen inequities, the embedded bias, and ethical quandaries,” he said.
 

Reference

1. O’Connor A. How Artificial Intelligence Could Transform Medicine. New York Times. March 11, 2019. https://www.nytimes.com/2019/03/11/well/live/how-artificial-intelligence-could-transform-medicine.html.

Several practice-changing developments in the treatment of ovarian cancer were seen in 2019, including the results of the pivotal trial Gynecologic Oncology Group (GOG)-213, which were published in November in the New England Journal of Medicine.¹ This trial randomly assigned women with ovarian cancer who had achieved a remission of more than 6 months after primary therapy (“platinum sensitive”) to either a repeat surgical cytoreduction followed by chemotherapy versus chemotherapy alone. It found that the addition of surgery provided no benefit in overall survival, challenging the notion that repeat surgical “debulking” should be routinely considered for the treatment of women with platinum-sensitive ovarian cancer.

Alexander Raths/Fotolia

The primary treatment of ovarian cancer includes a combination of surgery and chemotherapy, after which the vast majority of patients will experience a complete clinical response, a so-called “remission.” At that time patients enter surveillance care, in which their providers evaluate them, typically every 3 months in the first 2-3 years. These visits are designed to address ongoing toxicities of therapy in addition to evaluation for recurrence. At these visits, it is common for providers to assess tumor markers, such as CA 125 (cancer antigen 125), if they had been elevated at original diagnosis. As a gynecologic oncologist, I can vouch for the fact that patients “sweat” on this lab result the most. No matter how reassuring my physical exams or their symptom profiles are, there is nothing more comforting as a normal, stable CA 125 value in black and white. However, the results of GOG-213 should make us question whether drawing CA 125 in the surveillance period is of any value to patients beyond objective reassurance, and may, in fact, be harmful.

Providers have drawn tumor markers at surveillance exams under the working premise that abnormal or rising values signal the onset of asymptomatic recurrence, and that earlier treatment will be associated with better responses to salvage therapy. However, this has not been shown to be the case in randomized, controlled trials. In a large European cooperative-group trial, more than 500 patients with a history of completely treated ovarian cancer were randomized to either reinitiation of chemotherapy (salvage therapy) when CA 125 values first doubled or to reinitiation of therapy when they became symptomatic without knowledge of their CA 125 values.² In this trial the mean survival of both groups was the same (26 months for the early initiation of chemotherapy vs. 27 for late initiation). However, what did differ were the quality of life scores, which were lower for the group who initiated chemotherapy earlier, likely because they received toxic therapies for longer periods of time.

The results of this trial were challenged by those who felt that this study did not evaluate the role that surgery might play. Their argument was that surgery in the recurrent setting would improve the outcomes from chemotherapy for certain patients with long platinum-free intervals (duration of remission since last receiving a platinum-containing drug), oligometastatic disease, and good performance status, just as it had in the primary setting. Retrospective series seemed to confirm this phenomenon, particularly if surgeons were able to achieve a complete resection (no residual measurable disease).^3,4 By detecting asymptomatic patients with early elevations in CA 125, they proposed they might identify patients with lower disease burden in whom complete debulking would be more feasible. Whereas, in waiting for symptoms alone, they might “miss the boat,” and discover recurrence when it was too advanced to be completely resected.

The results of the GOG-213 study significantly challenge this line of thought, although with some caveats. Because this new trial showed no survival benefit for women with secondary debulking prior to chemotherapy, one could question whether there is any benefit in screening for asymptomatic, early recurrence. The authors of the study looked in subgroup analyses to attempt to identify groups who might benefit over others, such as women who had complete surgical cytoreduction (no residual disease) but still did not find a benefit to surgery. The trial population as a whole included women who had very favorable prognostic factors, including very long disease-free intervals (median, 20.4 months), and most women had only one or two sites of measurable recurrence. Yet it is remarkable that, in this group of patients who were predisposed to optimal outcomes, no benefit from surgery was observed.

However, it is important to recognize that the equivalent results of single-modality chemotherapy were achieved with the majority of women receiving bevacizumab with their chemotherapy regimen. An additional consideration is that the chemotherapy for platinum-sensitive, recurrent ovarian cancer has changed in recent years as we have learned the benefit of poly (ADP-ribose) polymerase (PARP) inhibitor drugs as maintenance therapy following complete or partial response to chemotherapy.⁵ It is unclear how the addition of PARP inhibitor maintenance therapy might have influenced the results of GOG-213. Further advancements in targeted therapies and consideration of hyperthermic intraperitoneal chemotherapy at the time of surgery also are being developed, and so, the answer of optimal therapy for platinum-sensitive ovarian cancer is a fluid one and might include a role for surgery for some of these patients.

However, in the meantime, before routinely ordering that tumor marker assessment in the surveillance period, it is important to remember that, if secondary cytoreduction is not beneficial and early initiation of chemotherapy is not helpful either, then these tumor marker results might provide more hindrance than help. Why search for recurrence at an earlier time point with CA 125 elevations if there isn’t a benefit to the patient in doing so? There certainly appears to be worse quality of life in doing so, and most likely also additional cost. Perhaps we should wait for clinical symptoms to confirm recurrence?

In the meantime, we will continue to have discussions with patients after primary therapy regarding how to best monitor them in the surveillance period. We will educate them about the limitations of early initiation of chemotherapy and the potentially limited role for surgery. Hopefully with individualized care and shared decision making, patients can guide us as to how they best be evaluated. While receiving a normal CA 125 result is powerfully reassuring, it is just as powerfully confusing and difficult for a patient to receive an abnormal one followed by a period of “doing nothing,” otherwise known as expectant management, if immediate treatment is not beneficial.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant financial disclosures. Email her at [email protected].

References

1. N Engl J Med. 2019 Nov 14;381(20):1929-39.

2. Lancet. 2010 Oct 2;376(9747):1155-63.

3. Gynecol Oncol. 2009 Jan;112(1):265-74.

4. Br J Cancer. 2011 Sep 27;105(7):890-6.

5. N Engl J Med. 2016 Dec 1;375(22):2154-64.

Several practice-changing developments in the treatment of ovarian cancer were seen in 2019, including the results of the pivotal trial Gynecologic Oncology Group (GOG)-213, which were published in November in the New England Journal of Medicine.¹ This trial randomly assigned women with ovarian cancer who had achieved a remission of more than 6 months after primary therapy (“platinum sensitive”) to either a repeat surgical cytoreduction followed by chemotherapy versus chemotherapy alone. It found that the addition of surgery provided no benefit in overall survival, challenging the notion that repeat surgical “debulking” should be routinely considered for the treatment of women with platinum-sensitive ovarian cancer.

Alexander Raths/Fotolia

The primary treatment of ovarian cancer includes a combination of surgery and chemotherapy, after which the vast majority of patients will experience a complete clinical response, a so-called “remission.” At that time patients enter surveillance care, in which their providers evaluate them, typically every 3 months in the first 2-3 years. These visits are designed to address ongoing toxicities of therapy in addition to evaluation for recurrence. At these visits, it is common for providers to assess tumor markers, such as CA 125 (cancer antigen 125), if they had been elevated at original diagnosis. As a gynecologic oncologist, I can vouch for the fact that patients “sweat” on this lab result the most. No matter how reassuring my physical exams or their symptom profiles are, there is nothing more comforting as a normal, stable CA 125 value in black and white. However, the results of GOG-213 should make us question whether drawing CA 125 in the surveillance period is of any value to patients beyond objective reassurance, and may, in fact, be harmful.

Providers have drawn tumor markers at surveillance exams under the working premise that abnormal or rising values signal the onset of asymptomatic recurrence, and that earlier treatment will be associated with better responses to salvage therapy. However, this has not been shown to be the case in randomized, controlled trials. In a large European cooperative-group trial, more than 500 patients with a history of completely treated ovarian cancer were randomized to either reinitiation of chemotherapy (salvage therapy) when CA 125 values first doubled or to reinitiation of therapy when they became symptomatic without knowledge of their CA 125 values.² In this trial the mean survival of both groups was the same (26 months for the early initiation of chemotherapy vs. 27 for late initiation). However, what did differ were the quality of life scores, which were lower for the group who initiated chemotherapy earlier, likely because they received toxic therapies for longer periods of time.

The results of this trial were challenged by those who felt that this study did not evaluate the role that surgery might play. Their argument was that surgery in the recurrent setting would improve the outcomes from chemotherapy for certain patients with long platinum-free intervals (duration of remission since last receiving a platinum-containing drug), oligometastatic disease, and good performance status, just as it had in the primary setting. Retrospective series seemed to confirm this phenomenon, particularly if surgeons were able to achieve a complete resection (no residual measurable disease).^3,4 By detecting asymptomatic patients with early elevations in CA 125, they proposed they might identify patients with lower disease burden in whom complete debulking would be more feasible. Whereas, in waiting for symptoms alone, they might “miss the boat,” and discover recurrence when it was too advanced to be completely resected.

The results of the GOG-213 study significantly challenge this line of thought, although with some caveats. Because this new trial showed no survival benefit for women with secondary debulking prior to chemotherapy, one could question whether there is any benefit in screening for asymptomatic, early recurrence. The authors of the study looked in subgroup analyses to attempt to identify groups who might benefit over others, such as women who had complete surgical cytoreduction (no residual disease) but still did not find a benefit to surgery. The trial population as a whole included women who had very favorable prognostic factors, including very long disease-free intervals (median, 20.4 months), and most women had only one or two sites of measurable recurrence. Yet it is remarkable that, in this group of patients who were predisposed to optimal outcomes, no benefit from surgery was observed.

However, it is important to recognize that the equivalent results of single-modality chemotherapy were achieved with the majority of women receiving bevacizumab with their chemotherapy regimen. An additional consideration is that the chemotherapy for platinum-sensitive, recurrent ovarian cancer has changed in recent years as we have learned the benefit of poly (ADP-ribose) polymerase (PARP) inhibitor drugs as maintenance therapy following complete or partial response to chemotherapy.⁵ It is unclear how the addition of PARP inhibitor maintenance therapy might have influenced the results of GOG-213. Further advancements in targeted therapies and consideration of hyperthermic intraperitoneal chemotherapy at the time of surgery also are being developed, and so, the answer of optimal therapy for platinum-sensitive ovarian cancer is a fluid one and might include a role for surgery for some of these patients.

However, in the meantime, before routinely ordering that tumor marker assessment in the surveillance period, it is important to remember that, if secondary cytoreduction is not beneficial and early initiation of chemotherapy is not helpful either, then these tumor marker results might provide more hindrance than help. Why search for recurrence at an earlier time point with CA 125 elevations if there isn’t a benefit to the patient in doing so? There certainly appears to be worse quality of life in doing so, and most likely also additional cost. Perhaps we should wait for clinical symptoms to confirm recurrence?

In the meantime, we will continue to have discussions with patients after primary therapy regarding how to best monitor them in the surveillance period. We will educate them about the limitations of early initiation of chemotherapy and the potentially limited role for surgery. Hopefully with individualized care and shared decision making, patients can guide us as to how they best be evaluated. While receiving a normal CA 125 result is powerfully reassuring, it is just as powerfully confusing and difficult for a patient to receive an abnormal one followed by a period of “doing nothing,” otherwise known as expectant management, if immediate treatment is not beneficial.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant financial disclosures. Email her at [email protected].

References

1. N Engl J Med. 2019 Nov 14;381(20):1929-39.

2. Lancet. 2010 Oct 2;376(9747):1155-63.

3. Gynecol Oncol. 2009 Jan;112(1):265-74.

4. Br J Cancer. 2011 Sep 27;105(7):890-6.

5. N Engl J Med. 2016 Dec 1;375(22):2154-64.

Several practice-changing developments in the treatment of ovarian cancer were seen in 2019, including the results of the pivotal trial Gynecologic Oncology Group (GOG)-213, which were published in November in the New England Journal of Medicine.¹ This trial randomly assigned women with ovarian cancer who had achieved a remission of more than 6 months after primary therapy (“platinum sensitive”) to either a repeat surgical cytoreduction followed by chemotherapy versus chemotherapy alone. It found that the addition of surgery provided no benefit in overall survival, challenging the notion that repeat surgical “debulking” should be routinely considered for the treatment of women with platinum-sensitive ovarian cancer.

Alexander Raths/Fotolia

The primary treatment of ovarian cancer includes a combination of surgery and chemotherapy, after which the vast majority of patients will experience a complete clinical response, a so-called “remission.” At that time patients enter surveillance care, in which their providers evaluate them, typically every 3 months in the first 2-3 years. These visits are designed to address ongoing toxicities of therapy in addition to evaluation for recurrence. At these visits, it is common for providers to assess tumor markers, such as CA 125 (cancer antigen 125), if they had been elevated at original diagnosis. As a gynecologic oncologist, I can vouch for the fact that patients “sweat” on this lab result the most. No matter how reassuring my physical exams or their symptom profiles are, there is nothing more comforting as a normal, stable CA 125 value in black and white. However, the results of GOG-213 should make us question whether drawing CA 125 in the surveillance period is of any value to patients beyond objective reassurance, and may, in fact, be harmful.

Providers have drawn tumor markers at surveillance exams under the working premise that abnormal or rising values signal the onset of asymptomatic recurrence, and that earlier treatment will be associated with better responses to salvage therapy. However, this has not been shown to be the case in randomized, controlled trials. In a large European cooperative-group trial, more than 500 patients with a history of completely treated ovarian cancer were randomized to either reinitiation of chemotherapy (salvage therapy) when CA 125 values first doubled or to reinitiation of therapy when they became symptomatic without knowledge of their CA 125 values.² In this trial the mean survival of both groups was the same (26 months for the early initiation of chemotherapy vs. 27 for late initiation). However, what did differ were the quality of life scores, which were lower for the group who initiated chemotherapy earlier, likely because they received toxic therapies for longer periods of time.

The results of this trial were challenged by those who felt that this study did not evaluate the role that surgery might play. Their argument was that surgery in the recurrent setting would improve the outcomes from chemotherapy for certain patients with long platinum-free intervals (duration of remission since last receiving a platinum-containing drug), oligometastatic disease, and good performance status, just as it had in the primary setting. Retrospective series seemed to confirm this phenomenon, particularly if surgeons were able to achieve a complete resection (no residual measurable disease).^3,4 By detecting asymptomatic patients with early elevations in CA 125, they proposed they might identify patients with lower disease burden in whom complete debulking would be more feasible. Whereas, in waiting for symptoms alone, they might “miss the boat,” and discover recurrence when it was too advanced to be completely resected.

The results of the GOG-213 study significantly challenge this line of thought, although with some caveats. Because this new trial showed no survival benefit for women with secondary debulking prior to chemotherapy, one could question whether there is any benefit in screening for asymptomatic, early recurrence. The authors of the study looked in subgroup analyses to attempt to identify groups who might benefit over others, such as women who had complete surgical cytoreduction (no residual disease) but still did not find a benefit to surgery. The trial population as a whole included women who had very favorable prognostic factors, including very long disease-free intervals (median, 20.4 months), and most women had only one or two sites of measurable recurrence. Yet it is remarkable that, in this group of patients who were predisposed to optimal outcomes, no benefit from surgery was observed.

However, it is important to recognize that the equivalent results of single-modality chemotherapy were achieved with the majority of women receiving bevacizumab with their chemotherapy regimen. An additional consideration is that the chemotherapy for platinum-sensitive, recurrent ovarian cancer has changed in recent years as we have learned the benefit of poly (ADP-ribose) polymerase (PARP) inhibitor drugs as maintenance therapy following complete or partial response to chemotherapy.⁵ It is unclear how the addition of PARP inhibitor maintenance therapy might have influenced the results of GOG-213. Further advancements in targeted therapies and consideration of hyperthermic intraperitoneal chemotherapy at the time of surgery also are being developed, and so, the answer of optimal therapy for platinum-sensitive ovarian cancer is a fluid one and might include a role for surgery for some of these patients.

However, in the meantime, before routinely ordering that tumor marker assessment in the surveillance period, it is important to remember that, if secondary cytoreduction is not beneficial and early initiation of chemotherapy is not helpful either, then these tumor marker results might provide more hindrance than help. Why search for recurrence at an earlier time point with CA 125 elevations if there isn’t a benefit to the patient in doing so? There certainly appears to be worse quality of life in doing so, and most likely also additional cost. Perhaps we should wait for clinical symptoms to confirm recurrence?

In the meantime, we will continue to have discussions with patients after primary therapy regarding how to best monitor them in the surveillance period. We will educate them about the limitations of early initiation of chemotherapy and the potentially limited role for surgery. Hopefully with individualized care and shared decision making, patients can guide us as to how they best be evaluated. While receiving a normal CA 125 result is powerfully reassuring, it is just as powerfully confusing and difficult for a patient to receive an abnormal one followed by a period of “doing nothing,” otherwise known as expectant management, if immediate treatment is not beneficial.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She had no relevant financial disclosures. Email her at [email protected].

References

1. N Engl J Med. 2019 Nov 14;381(20):1929-39.

2. Lancet. 2010 Oct 2;376(9747):1155-63.

3. Gynecol Oncol. 2009 Jan;112(1):265-74.

4. Br J Cancer. 2011 Sep 27;105(7):890-6.

5. N Engl J Med. 2016 Dec 1;375(22):2154-64.

NEW ORLEANS – Teens need to drive for a wide range of reasons, from going to and from school or work to overall mobility, but driving still is the most dangerous thing teenagers do, according to Brian Johnston, MD, MPH, professor of pediatrics at the University of Washington in Seattle.

Kali9/E+/Getty Images

Motor vehicle traffic accidents continue to be the leading cause of death of adolescents aged 15-19 years, according to 2017 data from the National Center for Health Statistics at the Centers for the Disease Control and Prevention.

“Inexperience drives the statistics we see,” Dr. Johnston said at the annual meeting of the American Academy of Pediatrics. “There is a steep learning curve among drivers of all ages, and crash rates are highest during the first few months after teens begin driving without supervision.”

Although the risk of accidents is higher than average for any new driver, it’s disproportionately higher for younger teens, compared with other ages: 16-year-old novice drivers have a higher accident risk than that of 17-year-olds, whose risk is similar to that of 18- and 19-year-old novices.

How long drivers have been licensed has a far bigger impact on crash risk, Dr. Johnston said (Traffic Inj. Prev. 2009 Jun;10[3]:209-19).

But the risk of an accident also increases with each additional passenger a teen driver has, particularly for younger and male drivers (Traffic Inj Prev. 2013;14[3]:283-92). More passengers likely means more distraction, and distraction, driving too fast for road conditions, and not scanning the roadway are the three most common errors – together accounting for about half of all teen drivers’ crashes.

Risk factors for accidents

Speed is a contributing factor in just over a third (36%) of teens’ fatal crashes. Adolescents drive faster and keep shorter following distances than adults do. But as with adults, wearing seat belts substantially reduces the risk of death in accidents.

Lap-shoulder seat belts reduce the risk of death in a crash by 45%, but teens use their seat belts far less often than do older drivers. Nationally, 90% of drivers use seat belts, with higher rates in states with primary enforcement (92%) than those in states with secondary enforcement (83%).

But barely more than half (54%) of U.S. high school students say they “always” wear a seat belt, and just under half of teens (47%) who died in crashes in 2017 weren’t wearing one. As seen in adults, teens are more likely to buckle up, by 12%, in states with primary seat belt laws.

Distraction during driving can be visual, manual, or cognitive – and handheld electronic devices such as smartphones cause all three distraction types. Cell phones nearly double the proportion of teen drivers who die in crashes, from 7% to 13%.

But if teens can keep their eyes on the roadway at all times, even the risks posed by cellphones drop considerably.

“The best evidence shows that secondary tasks only degrade driving performance when they require drivers to look away from the road,” Dr. Johnston said. Looking away for 2 seconds or longer increases crash risk more than fivefold.

Two other risk factors for teen car accidents are drowsiness and nighttime driving. Sleepiness can play a role in crashes at any time of day, and Dr. Johnston noted that some research has associated later high school start times with reduced crash risk.

Teens aged 16-19 years are about four times more likely to have a car accident at night than during the day per each mile driven, the pediatrician noted. Many licensing laws restrict teen driving starting at 11 p.m. or later, but about 50%-60% of their crashes occur between 9 and 11 p.m.

One reason for the increased risk is less experience driving in more difficult conditions, but teens also are more likely to have teen passengers, to be driving excessively fast, or to be under the influence of alcohol at night.

Adolescents’ crash risk is higher than that of adults for any level of blood alcohol content. Self-reported driving after drinking dropped by almost half – from 10% to 5.5% – from 2013 to 2017, but alcohol still is implicated in a substantial number of fatal teen crashes.

As drunk driving has declined, however, driving while under the influence of marijuana has been increasing. According to the National Highway Traffic Safety Administration, case control studies show drivers with tetrahydrocannabinol (THC) in their blood have a 25% increased risk of accidents – but the excess risk associated with THC vanishes when researchers control for age, sex, and concurrent use of alcohol. Not enough research exists to determine what the crash risk would be for adolescent drivers using THC alone.

A less-recognized risk factor for car accidents in teen drivers is ADHD, which increases a teen’s risk of crashing by 36%, particularly in the first month after getting a license, Dr. Johnston said.

ADHD medication appears to mitigate the danger, according to data: Crash risk was 40% lower in adult drivers with ADHD during months they filled their stimulant prescriptions. But one study found only 12% of teens with ADHD filled their prescriptions the month they got their license, and adolescents may not take their medications or still have them in their system on weekends or at night.

Teens recovering from concussion also may have an increased risk. Some evidence suggests driving impairment continues even when other symptoms have resolved, but not enough data exist to determine appropriate criteria for clearing teens to begin driving again.

Interventions to improve teens’ driving safety

Most teens take a basic driver education course before getting their licenses, but no evidence shows that it reduces risk of citations, crashes, or injury. In fact, “skid control training and other kinds of advanced skill training seem to increase crash risk, particularly among young males,” Dr. Johnston said.

What helps teens most is, ironically, more driving.

“If I say inexperience is the single most important risk factor for dying in a crash as a teen, driving experience is the intervention,” he said. More time spent driving – “with supervision in particular, and under diverse conditions,” Dr. Johnston said – increases the repertoire of skills and abilities.

Parents should be encouraged to ride along as their teens drive under diverse road conditions: different roads, different times of the day, and different weather conditions, for example. Parents can narrate their own driving, pointing out hazards and times when they slow down for increased caution, Dr. Johnston said. It might feel “awkward and unnatural,” but “some of the things you as a driver notice all the time are novel to teen drivers.”

Parents can influence road safety for teens in terms of their own behavior and in selecting a safer vehicle. A strong correlation exists between parental texting while driving when children are younger and what they do as teen drivers, for example.

Safer vehicles are bigger, heavier cars with electronic stability control, which reduces risk of death about as much as wearing seat belts. Parents should avoid vehicles with high horsepower and look for cars with the best safety ratings they can afford, Dr. Johnston said.

Several special features in newer cars can help reduce crash risk, such as blind spot detection, automatic breaking, collision avoidance systems, lane departure warning systems, and driver drowsiness detection. Parents may worry that relying on this technology could reduce teens’ learning, but it actually can compensate for skill deficits as they are becoming more skilled drivers.

Parents can look into feedback programs such as smartphone apps or other in-car units that allow parents to see data on teens’ speed, unsafe driving, “near-misses,” and similar driving behaviors. Research has shown that unsafe driving in newly licensed teens dropped by 66% over 4 months of using one of these feedback programs, compared with teens who didn’t use it.

Dr. Johnston also discussed the idea of prelicensure medical exams, similar to physicals that are required before playing sports. These already exist for commercial licenses in most states, but no data exist on whether it’s effective for teens. The goal would be to promote a discussion between parents and their teens about driving: reviewing medications the teen is taking and whether they affect driving; discussing safety of different vehicles; and assessing the teens’ risks, including any cognitive or other medical conditions that could affect driving safety. Even if such a “driving physical” is not currently required, pediatricians can do their own version of one with families.

Dr. Johnston had no disclosures.

NEW ORLEANS – Teens need to drive for a wide range of reasons, from going to and from school or work to overall mobility, but driving still is the most dangerous thing teenagers do, according to Brian Johnston, MD, MPH, professor of pediatrics at the University of Washington in Seattle.

Kali9/E+/Getty Images

Motor vehicle traffic accidents continue to be the leading cause of death of adolescents aged 15-19 years, according to 2017 data from the National Center for Health Statistics at the Centers for the Disease Control and Prevention.

“Inexperience drives the statistics we see,” Dr. Johnston said at the annual meeting of the American Academy of Pediatrics. “There is a steep learning curve among drivers of all ages, and crash rates are highest during the first few months after teens begin driving without supervision.”

Although the risk of accidents is higher than average for any new driver, it’s disproportionately higher for younger teens, compared with other ages: 16-year-old novice drivers have a higher accident risk than that of 17-year-olds, whose risk is similar to that of 18- and 19-year-old novices.

How long drivers have been licensed has a far bigger impact on crash risk, Dr. Johnston said (Traffic Inj. Prev. 2009 Jun;10[3]:209-19).

But the risk of an accident also increases with each additional passenger a teen driver has, particularly for younger and male drivers (Traffic Inj Prev. 2013;14[3]:283-92). More passengers likely means more distraction, and distraction, driving too fast for road conditions, and not scanning the roadway are the three most common errors – together accounting for about half of all teen drivers’ crashes.

Risk factors for accidents

Speed is a contributing factor in just over a third (36%) of teens’ fatal crashes. Adolescents drive faster and keep shorter following distances than adults do. But as with adults, wearing seat belts substantially reduces the risk of death in accidents.

Lap-shoulder seat belts reduce the risk of death in a crash by 45%, but teens use their seat belts far less often than do older drivers. Nationally, 90% of drivers use seat belts, with higher rates in states with primary enforcement (92%) than those in states with secondary enforcement (83%).

But barely more than half (54%) of U.S. high school students say they “always” wear a seat belt, and just under half of teens (47%) who died in crashes in 2017 weren’t wearing one. As seen in adults, teens are more likely to buckle up, by 12%, in states with primary seat belt laws.

Distraction during driving can be visual, manual, or cognitive – and handheld electronic devices such as smartphones cause all three distraction types. Cell phones nearly double the proportion of teen drivers who die in crashes, from 7% to 13%.

But if teens can keep their eyes on the roadway at all times, even the risks posed by cellphones drop considerably.

“The best evidence shows that secondary tasks only degrade driving performance when they require drivers to look away from the road,” Dr. Johnston said. Looking away for 2 seconds or longer increases crash risk more than fivefold.

Two other risk factors for teen car accidents are drowsiness and nighttime driving. Sleepiness can play a role in crashes at any time of day, and Dr. Johnston noted that some research has associated later high school start times with reduced crash risk.

Teens aged 16-19 years are about four times more likely to have a car accident at night than during the day per each mile driven, the pediatrician noted. Many licensing laws restrict teen driving starting at 11 p.m. or later, but about 50%-60% of their crashes occur between 9 and 11 p.m.

One reason for the increased risk is less experience driving in more difficult conditions, but teens also are more likely to have teen passengers, to be driving excessively fast, or to be under the influence of alcohol at night.

Adolescents’ crash risk is higher than that of adults for any level of blood alcohol content. Self-reported driving after drinking dropped by almost half – from 10% to 5.5% – from 2013 to 2017, but alcohol still is implicated in a substantial number of fatal teen crashes.

As drunk driving has declined, however, driving while under the influence of marijuana has been increasing. According to the National Highway Traffic Safety Administration, case control studies show drivers with tetrahydrocannabinol (THC) in their blood have a 25% increased risk of accidents – but the excess risk associated with THC vanishes when researchers control for age, sex, and concurrent use of alcohol. Not enough research exists to determine what the crash risk would be for adolescent drivers using THC alone.

A less-recognized risk factor for car accidents in teen drivers is ADHD, which increases a teen’s risk of crashing by 36%, particularly in the first month after getting a license, Dr. Johnston said.

ADHD medication appears to mitigate the danger, according to data: Crash risk was 40% lower in adult drivers with ADHD during months they filled their stimulant prescriptions. But one study found only 12% of teens with ADHD filled their prescriptions the month they got their license, and adolescents may not take their medications or still have them in their system on weekends or at night.

Teens recovering from concussion also may have an increased risk. Some evidence suggests driving impairment continues even when other symptoms have resolved, but not enough data exist to determine appropriate criteria for clearing teens to begin driving again.

Interventions to improve teens’ driving safety

Most teens take a basic driver education course before getting their licenses, but no evidence shows that it reduces risk of citations, crashes, or injury. In fact, “skid control training and other kinds of advanced skill training seem to increase crash risk, particularly among young males,” Dr. Johnston said.

What helps teens most is, ironically, more driving.

“If I say inexperience is the single most important risk factor for dying in a crash as a teen, driving experience is the intervention,” he said. More time spent driving – “with supervision in particular, and under diverse conditions,” Dr. Johnston said – increases the repertoire of skills and abilities.

Parents should be encouraged to ride along as their teens drive under diverse road conditions: different roads, different times of the day, and different weather conditions, for example. Parents can narrate their own driving, pointing out hazards and times when they slow down for increased caution, Dr. Johnston said. It might feel “awkward and unnatural,” but “some of the things you as a driver notice all the time are novel to teen drivers.”

Parents can influence road safety for teens in terms of their own behavior and in selecting a safer vehicle. A strong correlation exists between parental texting while driving when children are younger and what they do as teen drivers, for example.

Safer vehicles are bigger, heavier cars with electronic stability control, which reduces risk of death about as much as wearing seat belts. Parents should avoid vehicles with high horsepower and look for cars with the best safety ratings they can afford, Dr. Johnston said.

Several special features in newer cars can help reduce crash risk, such as blind spot detection, automatic breaking, collision avoidance systems, lane departure warning systems, and driver drowsiness detection. Parents may worry that relying on this technology could reduce teens’ learning, but it actually can compensate for skill deficits as they are becoming more skilled drivers.

Parents can look into feedback programs such as smartphone apps or other in-car units that allow parents to see data on teens’ speed, unsafe driving, “near-misses,” and similar driving behaviors. Research has shown that unsafe driving in newly licensed teens dropped by 66% over 4 months of using one of these feedback programs, compared with teens who didn’t use it.

Dr. Johnston also discussed the idea of prelicensure medical exams, similar to physicals that are required before playing sports. These already exist for commercial licenses in most states, but no data exist on whether it’s effective for teens. The goal would be to promote a discussion between parents and their teens about driving: reviewing medications the teen is taking and whether they affect driving; discussing safety of different vehicles; and assessing the teens’ risks, including any cognitive or other medical conditions that could affect driving safety. Even if such a “driving physical” is not currently required, pediatricians can do their own version of one with families.

Dr. Johnston had no disclosures.

NEW ORLEANS – Teens need to drive for a wide range of reasons, from going to and from school or work to overall mobility, but driving still is the most dangerous thing teenagers do, according to Brian Johnston, MD, MPH, professor of pediatrics at the University of Washington in Seattle.

Kali9/E+/Getty Images

Motor vehicle traffic accidents continue to be the leading cause of death of adolescents aged 15-19 years, according to 2017 data from the National Center for Health Statistics at the Centers for the Disease Control and Prevention.

“Inexperience drives the statistics we see,” Dr. Johnston said at the annual meeting of the American Academy of Pediatrics. “There is a steep learning curve among drivers of all ages, and crash rates are highest during the first few months after teens begin driving without supervision.”

Although the risk of accidents is higher than average for any new driver, it’s disproportionately higher for younger teens, compared with other ages: 16-year-old novice drivers have a higher accident risk than that of 17-year-olds, whose risk is similar to that of 18- and 19-year-old novices.

How long drivers have been licensed has a far bigger impact on crash risk, Dr. Johnston said (Traffic Inj. Prev. 2009 Jun;10[3]:209-19).

But the risk of an accident also increases with each additional passenger a teen driver has, particularly for younger and male drivers (Traffic Inj Prev. 2013;14[3]:283-92). More passengers likely means more distraction, and distraction, driving too fast for road conditions, and not scanning the roadway are the three most common errors – together accounting for about half of all teen drivers’ crashes.

Risk factors for accidents

Speed is a contributing factor in just over a third (36%) of teens’ fatal crashes. Adolescents drive faster and keep shorter following distances than adults do. But as with adults, wearing seat belts substantially reduces the risk of death in accidents.

Lap-shoulder seat belts reduce the risk of death in a crash by 45%, but teens use their seat belts far less often than do older drivers. Nationally, 90% of drivers use seat belts, with higher rates in states with primary enforcement (92%) than those in states with secondary enforcement (83%).

But barely more than half (54%) of U.S. high school students say they “always” wear a seat belt, and just under half of teens (47%) who died in crashes in 2017 weren’t wearing one. As seen in adults, teens are more likely to buckle up, by 12%, in states with primary seat belt laws.

Distraction during driving can be visual, manual, or cognitive – and handheld electronic devices such as smartphones cause all three distraction types. Cell phones nearly double the proportion of teen drivers who die in crashes, from 7% to 13%.

But if teens can keep their eyes on the roadway at all times, even the risks posed by cellphones drop considerably.

“The best evidence shows that secondary tasks only degrade driving performance when they require drivers to look away from the road,” Dr. Johnston said. Looking away for 2 seconds or longer increases crash risk more than fivefold.

Two other risk factors for teen car accidents are drowsiness and nighttime driving. Sleepiness can play a role in crashes at any time of day, and Dr. Johnston noted that some research has associated later high school start times with reduced crash risk.

Teens aged 16-19 years are about four times more likely to have a car accident at night than during the day per each mile driven, the pediatrician noted. Many licensing laws restrict teen driving starting at 11 p.m. or later, but about 50%-60% of their crashes occur between 9 and 11 p.m.

One reason for the increased risk is less experience driving in more difficult conditions, but teens also are more likely to have teen passengers, to be driving excessively fast, or to be under the influence of alcohol at night.

Adolescents’ crash risk is higher than that of adults for any level of blood alcohol content. Self-reported driving after drinking dropped by almost half – from 10% to 5.5% – from 2013 to 2017, but alcohol still is implicated in a substantial number of fatal teen crashes.

As drunk driving has declined, however, driving while under the influence of marijuana has been increasing. According to the National Highway Traffic Safety Administration, case control studies show drivers with tetrahydrocannabinol (THC) in their blood have a 25% increased risk of accidents – but the excess risk associated with THC vanishes when researchers control for age, sex, and concurrent use of alcohol. Not enough research exists to determine what the crash risk would be for adolescent drivers using THC alone.

A less-recognized risk factor for car accidents in teen drivers is ADHD, which increases a teen’s risk of crashing by 36%, particularly in the first month after getting a license, Dr. Johnston said.

ADHD medication appears to mitigate the danger, according to data: Crash risk was 40% lower in adult drivers with ADHD during months they filled their stimulant prescriptions. But one study found only 12% of teens with ADHD filled their prescriptions the month they got their license, and adolescents may not take their medications or still have them in their system on weekends or at night.

Teens recovering from concussion also may have an increased risk. Some evidence suggests driving impairment continues even when other symptoms have resolved, but not enough data exist to determine appropriate criteria for clearing teens to begin driving again.

Interventions to improve teens’ driving safety

Most teens take a basic driver education course before getting their licenses, but no evidence shows that it reduces risk of citations, crashes, or injury. In fact, “skid control training and other kinds of advanced skill training seem to increase crash risk, particularly among young males,” Dr. Johnston said.

What helps teens most is, ironically, more driving.

“If I say inexperience is the single most important risk factor for dying in a crash as a teen, driving experience is the intervention,” he said. More time spent driving – “with supervision in particular, and under diverse conditions,” Dr. Johnston said – increases the repertoire of skills and abilities.

Parents should be encouraged to ride along as their teens drive under diverse road conditions: different roads, different times of the day, and different weather conditions, for example. Parents can narrate their own driving, pointing out hazards and times when they slow down for increased caution, Dr. Johnston said. It might feel “awkward and unnatural,” but “some of the things you as a driver notice all the time are novel to teen drivers.”

Parents can influence road safety for teens in terms of their own behavior and in selecting a safer vehicle. A strong correlation exists between parental texting while driving when children are younger and what they do as teen drivers, for example.

Safer vehicles are bigger, heavier cars with electronic stability control, which reduces risk of death about as much as wearing seat belts. Parents should avoid vehicles with high horsepower and look for cars with the best safety ratings they can afford, Dr. Johnston said.

Several special features in newer cars can help reduce crash risk, such as blind spot detection, automatic breaking, collision avoidance systems, lane departure warning systems, and driver drowsiness detection. Parents may worry that relying on this technology could reduce teens’ learning, but it actually can compensate for skill deficits as they are becoming more skilled drivers.

Parents can look into feedback programs such as smartphone apps or other in-car units that allow parents to see data on teens’ speed, unsafe driving, “near-misses,” and similar driving behaviors. Research has shown that unsafe driving in newly licensed teens dropped by 66% over 4 months of using one of these feedback programs, compared with teens who didn’t use it.

Dr. Johnston also discussed the idea of prelicensure medical exams, similar to physicals that are required before playing sports. These already exist for commercial licenses in most states, but no data exist on whether it’s effective for teens. The goal would be to promote a discussion between parents and their teens about driving: reviewing medications the teen is taking and whether they affect driving; discussing safety of different vehicles; and assessing the teens’ risks, including any cognitive or other medical conditions that could affect driving safety. Even if such a “driving physical” is not currently required, pediatricians can do their own version of one with families.

Dr. Johnston had no disclosures.

Adverse childhood experiences (ACEs), such as violence, abuse, and substance abuse in the household, have dramatic and lasting effects on adult health, according to a first-ever CDC analysis of data from 25 states. Toxic stress from ACEs can “derail optimal health and development by altering gene expression, brain connectivity and function, immune system function, and organ function,” as well as compromising health coping strategies, the researchers note.

In their study, ACEs were linked to at least 5 of the 10 leading causes of death. But they also found that preventing ACEs can have equally dramatic effects: for example, potentially reducing the number of cases of coronary artery disease (CAD) by 12.6%.

The researchers analyzed data from > 144,000 adults who responded to questions in the Behavior Risk Factor Surveillance System from 2015 through 2017. ACEs are common, the researchers say: 61% of adults had at least 1, and 1 in 6 adults experienced ≥ 4types of ACE. Women and several racial/ethnic minority groups had a greater risk. People who experienced ≥ 4types of ACE accounted for a “disproportionate share of the preventable fraction” of each of the 14 negative health and socioeconomic outcomes measured, including cancer, respiratory disease, diabetes, and suicide.

Extrapolating from the 25 states to national numbers, the researchers say preventing ACEs could result in 1.9 million fewer CADs, 2.5 million fewer overweight or obese adults, and 21 million fewer adults with depression.

The CDC has recommendations for rescuing potentially millions of adults from the lingering effects of childhood trauma: early intervention. The researchers cite, for instance, studies that have found preschool enrichment and early childhood home visitation programs reduce the rates of child abuse and neglect by 48% to 52%.  

Moreover, health care providers can “anticipate and recognize” current risk for ACEs in children and history of ACEs in adults. They can refer patients to effective services and support, and link adults to family-centered treatment that includes substance abuse treatment and parenting interventions. The CDC also recommends that employers can adopt and support family-friendly policies, such as paid family leave and flexible work schedules. And states and communities can, among other initiatives, improve access to high-quality child care by expanding eligibility, activities offered, and family involvement.

Adverse childhood experiences (ACEs), such as violence, abuse, and substance abuse in the household, have dramatic and lasting effects on adult health, according to a first-ever CDC analysis of data from 25 states. Toxic stress from ACEs can “derail optimal health and development by altering gene expression, brain connectivity and function, immune system function, and organ function,” as well as compromising health coping strategies, the researchers note.

In their study, ACEs were linked to at least 5 of the 10 leading causes of death. But they also found that preventing ACEs can have equally dramatic effects: for example, potentially reducing the number of cases of coronary artery disease (CAD) by 12.6%.

The researchers analyzed data from > 144,000 adults who responded to questions in the Behavior Risk Factor Surveillance System from 2015 through 2017. ACEs are common, the researchers say: 61% of adults had at least 1, and 1 in 6 adults experienced ≥ 4types of ACE. Women and several racial/ethnic minority groups had a greater risk. People who experienced ≥ 4types of ACE accounted for a “disproportionate share of the preventable fraction” of each of the 14 negative health and socioeconomic outcomes measured, including cancer, respiratory disease, diabetes, and suicide.

Extrapolating from the 25 states to national numbers, the researchers say preventing ACEs could result in 1.9 million fewer CADs, 2.5 million fewer overweight or obese adults, and 21 million fewer adults with depression.

The CDC has recommendations for rescuing potentially millions of adults from the lingering effects of childhood trauma: early intervention. The researchers cite, for instance, studies that have found preschool enrichment and early childhood home visitation programs reduce the rates of child abuse and neglect by 48% to 52%.  

Moreover, health care providers can “anticipate and recognize” current risk for ACEs in children and history of ACEs in adults. They can refer patients to effective services and support, and link adults to family-centered treatment that includes substance abuse treatment and parenting interventions. The CDC also recommends that employers can adopt and support family-friendly policies, such as paid family leave and flexible work schedules. And states and communities can, among other initiatives, improve access to high-quality child care by expanding eligibility, activities offered, and family involvement.

Adverse childhood experiences (ACEs), such as violence, abuse, and substance abuse in the household, have dramatic and lasting effects on adult health, according to a first-ever CDC analysis of data from 25 states. Toxic stress from ACEs can “derail optimal health and development by altering gene expression, brain connectivity and function, immune system function, and organ function,” as well as compromising health coping strategies, the researchers note.

In their study, ACEs were linked to at least 5 of the 10 leading causes of death. But they also found that preventing ACEs can have equally dramatic effects: for example, potentially reducing the number of cases of coronary artery disease (CAD) by 12.6%.

The researchers analyzed data from > 144,000 adults who responded to questions in the Behavior Risk Factor Surveillance System from 2015 through 2017. ACEs are common, the researchers say: 61% of adults had at least 1, and 1 in 6 adults experienced ≥ 4types of ACE. Women and several racial/ethnic minority groups had a greater risk. People who experienced ≥ 4types of ACE accounted for a “disproportionate share of the preventable fraction” of each of the 14 negative health and socioeconomic outcomes measured, including cancer, respiratory disease, diabetes, and suicide.

Extrapolating from the 25 states to national numbers, the researchers say preventing ACEs could result in 1.9 million fewer CADs, 2.5 million fewer overweight or obese adults, and 21 million fewer adults with depression.

The CDC has recommendations for rescuing potentially millions of adults from the lingering effects of childhood trauma: early intervention. The researchers cite, for instance, studies that have found preschool enrichment and early childhood home visitation programs reduce the rates of child abuse and neglect by 48% to 52%.  

Moreover, health care providers can “anticipate and recognize” current risk for ACEs in children and history of ACEs in adults. They can refer patients to effective services and support, and link adults to family-centered treatment that includes substance abuse treatment and parenting interventions. The CDC also recommends that employers can adopt and support family-friendly policies, such as paid family leave and flexible work schedules. And states and communities can, among other initiatives, improve access to high-quality child care by expanding eligibility, activities offered, and family involvement.

The Food and Drug Administration has approved voxelotor (Oxbryta) for adults and pediatric patients aged 12 years and older with sickle cell disease.

Olivier Le Moal/Getty Images

Approval was based on results from HOPE, a randomized, double-blind, placebo-controlled, multicenter trial of 274 patients with sickle cell disease (median age, 24 years) with a baseline hemoglobin level between 5.5 and 10.5 g/dL. Just over half of patients (51.1%) who received voxelotor at 1,500 mg had a hemoglobin increase of at least 1 g/dL over the 24-week study period, compared with 6.5% of patients who received placebo.

Patients in the 1,500-mg group also had reduced indirect bilirubin and percent reticulocyte count at –29.1% and –19.9%, respectively, compared with placebo, where the change was –3.2% and 4.5%, respectively.

The most common adverse events associated with voxelotor are headache, diarrhea, abdominal pain, nausea, rash, fatigue and pyrexia. The recommended voxelotor dose is 1,500 mg orally once daily with or without food, according to the FDA.

[email protected]

The Food and Drug Administration has approved voxelotor (Oxbryta) for adults and pediatric patients aged 12 years and older with sickle cell disease.

Olivier Le Moal/Getty Images

Approval was based on results from HOPE, a randomized, double-blind, placebo-controlled, multicenter trial of 274 patients with sickle cell disease (median age, 24 years) with a baseline hemoglobin level between 5.5 and 10.5 g/dL. Just over half of patients (51.1%) who received voxelotor at 1,500 mg had a hemoglobin increase of at least 1 g/dL over the 24-week study period, compared with 6.5% of patients who received placebo.

Patients in the 1,500-mg group also had reduced indirect bilirubin and percent reticulocyte count at –29.1% and –19.9%, respectively, compared with placebo, where the change was –3.2% and 4.5%, respectively.

The most common adverse events associated with voxelotor are headache, diarrhea, abdominal pain, nausea, rash, fatigue and pyrexia. The recommended voxelotor dose is 1,500 mg orally once daily with or without food, according to the FDA.

[email protected]

The Food and Drug Administration has approved voxelotor (Oxbryta) for adults and pediatric patients aged 12 years and older with sickle cell disease.

Olivier Le Moal/Getty Images

Approval was based on results from HOPE, a randomized, double-blind, placebo-controlled, multicenter trial of 274 patients with sickle cell disease (median age, 24 years) with a baseline hemoglobin level between 5.5 and 10.5 g/dL. Just over half of patients (51.1%) who received voxelotor at 1,500 mg had a hemoglobin increase of at least 1 g/dL over the 24-week study period, compared with 6.5% of patients who received placebo.

Patients in the 1,500-mg group also had reduced indirect bilirubin and percent reticulocyte count at –29.1% and –19.9%, respectively, compared with placebo, where the change was –3.2% and 4.5%, respectively.

The most common adverse events associated with voxelotor are headache, diarrhea, abdominal pain, nausea, rash, fatigue and pyrexia. The recommended voxelotor dose is 1,500 mg orally once daily with or without food, according to the FDA.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapies have garnered a great deal of attention given their “incredible efficacy” in treating B-cell malignancies, and new findings are taking aim at the drawbacks of therapy, such as the time, expense, and toxicity involved, according to Robert A. Brodsky, MD.

One example, from a study slated for presentation during a plenary session at the upcoming annual meeting of the American Society of Hematology involves the investigational T-cell bispecific antibody mosunetuzumab, which targets both CD20 on the surface of malignant B cells, and CD3 on cytotoxic T cells, engaging the T cells and directing their cytotoxicity against B cells.

In a study (Abstract 6) of 218 non-Hodgkin lymphoma patients, including 23 who had already received CAR T-cell therapy and had relapsed or were refractory to the treatment, 64% responded, 42% had a complete response, and the median duration of response is now out to 9 months, Dr. Brodsky, ASH secretary and director of the division of hematology at Johns Hopkins University, Baltimore, said during a premeeting press conference.

“It’s basically an antibody using the patient’s own T cell to do what a CAR-T cell would do – [a] very exciting study and large study,” he said. “It is an off-the-shelf product, it completely gets around the problem of the time to generate the CAR T-cell product, and because it’s going to be much simpler and faster to produce, it’s likely going to be much cheaper than CAR T cells.”

The preliminary results also suggest it is less toxic than CAR T-cell therapy, he added.

Two other CAR T-cell therapy–related studies highlighted during the press conference address its use for multiple myeloma. One, the phase 1b/2 CARTITUDE study (Abstract 577) uses CAR T cells against the B-cell maturation antigen (BCMA) in the relapsed/refractory setting.

Of 25 patients treated with chemotherapy followed by CAR T-cell infusion and followed for a median of 3 months, 91% responded, two achieved a complete remission, and “many other responses were very deep responses,” Dr. Brodsky said, noting that the second featured multiple myeloma trial (Abstract 930) looked at bispecific CAR T-cell therapy targeting BCMA and CD38 in an effort to reduce resistance to the therapy.

“Again, very interesting preliminary results,” he said, noting that of 16 patients followed for a median of 36 weeks, 87.5% responded, the treatment was well tolerated, and progression-free survival at 9 months was 75%.

In addition to the “key theme” of overcoming CAR T-cell therapy obstacles, three other themes have emerged from among the thousands of abstracts submitted for presentation at ASH. These, as presented during the press conference, include new venous thromboembolism (VTE) therapies and approaches to research; inclusive medicine, with abstracts focused on age- and race-related issues in clinical trials; and new advances in the treatment of sickle cell disease. All of these have potentially practice-changing implications, as do the six late-breaking abstracts selected from 93 abstracts submitted for consideration for oral presentation at ASH, Dr. Brodsky said.

One of the “truly practice-changing” late-breakers is a randomized phase 3 trial (Abstract LBA-1) comparing the bispecific antibody blinatumomab to chemotherapy for post-re-induction therapy in high- and intermediate-risk acute lymphoblastic leukemia (ALL) at first relapse in children, adolescents and young adults.

The study demonstrated the superiority of blinatumomab for efficacy and tolerability, which is particularly encouraging given the challenges in getting relapsed ALL patients back into remission so they can undergo bone marrow transplant, Dr. Brodsky said.

Of 208 patients randomized, 73% vs. 45% in the blinatumomab vs. chemotherapy arms were able to get to transplant – and therefore to potential cure, he said.

“Of note, the blinatumomab arm was less toxic and there was marked improvement in disease-free and overall survival, so this is clearly going to become a new standard of care for relapsed and refractory ALL,” he added.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapies have garnered a great deal of attention given their “incredible efficacy” in treating B-cell malignancies, and new findings are taking aim at the drawbacks of therapy, such as the time, expense, and toxicity involved, according to Robert A. Brodsky, MD.

One example, from a study slated for presentation during a plenary session at the upcoming annual meeting of the American Society of Hematology involves the investigational T-cell bispecific antibody mosunetuzumab, which targets both CD20 on the surface of malignant B cells, and CD3 on cytotoxic T cells, engaging the T cells and directing their cytotoxicity against B cells.

In a study (Abstract 6) of 218 non-Hodgkin lymphoma patients, including 23 who had already received CAR T-cell therapy and had relapsed or were refractory to the treatment, 64% responded, 42% had a complete response, and the median duration of response is now out to 9 months, Dr. Brodsky, ASH secretary and director of the division of hematology at Johns Hopkins University, Baltimore, said during a premeeting press conference.

“It’s basically an antibody using the patient’s own T cell to do what a CAR-T cell would do – [a] very exciting study and large study,” he said. “It is an off-the-shelf product, it completely gets around the problem of the time to generate the CAR T-cell product, and because it’s going to be much simpler and faster to produce, it’s likely going to be much cheaper than CAR T cells.”

The preliminary results also suggest it is less toxic than CAR T-cell therapy, he added.

Two other CAR T-cell therapy–related studies highlighted during the press conference address its use for multiple myeloma. One, the phase 1b/2 CARTITUDE study (Abstract 577) uses CAR T cells against the B-cell maturation antigen (BCMA) in the relapsed/refractory setting.

Of 25 patients treated with chemotherapy followed by CAR T-cell infusion and followed for a median of 3 months, 91% responded, two achieved a complete remission, and “many other responses were very deep responses,” Dr. Brodsky said, noting that the second featured multiple myeloma trial (Abstract 930) looked at bispecific CAR T-cell therapy targeting BCMA and CD38 in an effort to reduce resistance to the therapy.

“Again, very interesting preliminary results,” he said, noting that of 16 patients followed for a median of 36 weeks, 87.5% responded, the treatment was well tolerated, and progression-free survival at 9 months was 75%.

In addition to the “key theme” of overcoming CAR T-cell therapy obstacles, three other themes have emerged from among the thousands of abstracts submitted for presentation at ASH. These, as presented during the press conference, include new venous thromboembolism (VTE) therapies and approaches to research; inclusive medicine, with abstracts focused on age- and race-related issues in clinical trials; and new advances in the treatment of sickle cell disease. All of these have potentially practice-changing implications, as do the six late-breaking abstracts selected from 93 abstracts submitted for consideration for oral presentation at ASH, Dr. Brodsky said.

One of the “truly practice-changing” late-breakers is a randomized phase 3 trial (Abstract LBA-1) comparing the bispecific antibody blinatumomab to chemotherapy for post-re-induction therapy in high- and intermediate-risk acute lymphoblastic leukemia (ALL) at first relapse in children, adolescents and young adults.

The study demonstrated the superiority of blinatumomab for efficacy and tolerability, which is particularly encouraging given the challenges in getting relapsed ALL patients back into remission so they can undergo bone marrow transplant, Dr. Brodsky said.

Of 208 patients randomized, 73% vs. 45% in the blinatumomab vs. chemotherapy arms were able to get to transplant – and therefore to potential cure, he said.

“Of note, the blinatumomab arm was less toxic and there was marked improvement in disease-free and overall survival, so this is clearly going to become a new standard of care for relapsed and refractory ALL,” he added.

[email protected]

Chimeric antigen receptor (CAR) T-cell therapies have garnered a great deal of attention given their “incredible efficacy” in treating B-cell malignancies, and new findings are taking aim at the drawbacks of therapy, such as the time, expense, and toxicity involved, according to Robert A. Brodsky, MD.

One example, from a study slated for presentation during a plenary session at the upcoming annual meeting of the American Society of Hematology involves the investigational T-cell bispecific antibody mosunetuzumab, which targets both CD20 on the surface of malignant B cells, and CD3 on cytotoxic T cells, engaging the T cells and directing their cytotoxicity against B cells.

In a study (Abstract 6) of 218 non-Hodgkin lymphoma patients, including 23 who had already received CAR T-cell therapy and had relapsed or were refractory to the treatment, 64% responded, 42% had a complete response, and the median duration of response is now out to 9 months, Dr. Brodsky, ASH secretary and director of the division of hematology at Johns Hopkins University, Baltimore, said during a premeeting press conference.

“It’s basically an antibody using the patient’s own T cell to do what a CAR-T cell would do – [a] very exciting study and large study,” he said. “It is an off-the-shelf product, it completely gets around the problem of the time to generate the CAR T-cell product, and because it’s going to be much simpler and faster to produce, it’s likely going to be much cheaper than CAR T cells.”

The preliminary results also suggest it is less toxic than CAR T-cell therapy, he added.

Two other CAR T-cell therapy–related studies highlighted during the press conference address its use for multiple myeloma. One, the phase 1b/2 CARTITUDE study (Abstract 577) uses CAR T cells against the B-cell maturation antigen (BCMA) in the relapsed/refractory setting.

Of 25 patients treated with chemotherapy followed by CAR T-cell infusion and followed for a median of 3 months, 91% responded, two achieved a complete remission, and “many other responses were very deep responses,” Dr. Brodsky said, noting that the second featured multiple myeloma trial (Abstract 930) looked at bispecific CAR T-cell therapy targeting BCMA and CD38 in an effort to reduce resistance to the therapy.

“Again, very interesting preliminary results,” he said, noting that of 16 patients followed for a median of 36 weeks, 87.5% responded, the treatment was well tolerated, and progression-free survival at 9 months was 75%.

In addition to the “key theme” of overcoming CAR T-cell therapy obstacles, three other themes have emerged from among the thousands of abstracts submitted for presentation at ASH. These, as presented during the press conference, include new venous thromboembolism (VTE) therapies and approaches to research; inclusive medicine, with abstracts focused on age- and race-related issues in clinical trials; and new advances in the treatment of sickle cell disease. All of these have potentially practice-changing implications, as do the six late-breaking abstracts selected from 93 abstracts submitted for consideration for oral presentation at ASH, Dr. Brodsky said.

One of the “truly practice-changing” late-breakers is a randomized phase 3 trial (Abstract LBA-1) comparing the bispecific antibody blinatumomab to chemotherapy for post-re-induction therapy in high- and intermediate-risk acute lymphoblastic leukemia (ALL) at first relapse in children, adolescents and young adults.

The study demonstrated the superiority of blinatumomab for efficacy and tolerability, which is particularly encouraging given the challenges in getting relapsed ALL patients back into remission so they can undergo bone marrow transplant, Dr. Brodsky said.

Of 208 patients randomized, 73% vs. 45% in the blinatumomab vs. chemotherapy arms were able to get to transplant – and therefore to potential cure, he said.

“Of note, the blinatumomab arm was less toxic and there was marked improvement in disease-free and overall survival, so this is clearly going to become a new standard of care for relapsed and refractory ALL,” he added.

[email protected]

SAN ANTONIO – A wide-area transepithelial sampling (WATS) brush proved superior to standard forceps biopsies for detection of intestinal metaplasia (IM) in the esophagus and gastroesophageal junction in patients with no history of IM who had any visible columnar-lined esophagus on upper endoscopy in a large randomized trial.

Bruce Jancin/MDedge News

“This suggests that WATS should in fact be the preferred method of sampling these patients,” Steven R. DeMeester, MD, commented in presenting the study results at the annual meeting of the American College of Gastroenterology.

With that specific exception, however, the two sampling methods proved similarly effective at detecting IM and dysplasia, suggesting either technology can otherwise reliably be used to detect these conditions, added Dr. DeMeester, a general and thoracic surgeon at the Oregon Clinic, Portland.

This is important new information for clinicians. A prior multicenter, randomized trial by other investigators demonstrated that adding WATS to biopsy sampling improved the detection rate of dysplasia and esophageal adenocarcinoma, compared with biopsies alone (Gastrointest Endosc. 2018 Feb;87[2]:348-55). However, this dual-sampling strategy is too time-consuming for routine use in a busy practice. Given the new evidence that the two sampling methods can reliably be used interchangeably except in patients with no history of IM who have endoscopically visible columnar-lined esophagus, WATS offers a clear advantage in that it’s much quicker, especially in patients with long-segment Barrett’s esophagus, the surgeon said.

Unlike brush cytology, which merely collects surface epithelial cells, the WATS brush collects sheets of esophageal mucosa, which then undergo computer-assisted three-dimensional analysis.

“When done appropriately, a wide area of the esophageal mucosa can be sampled with the WATS brush,” Dr. DeMeester explained.

He reported on 1,002 patients who presented at nine U.S. centers for upper endoscopy for Barrett’s esophagus surveillance or evaluation of foregut symptoms. They were randomized to WATS or forceps biopsies using the Seattle protocol. In the entire group, WATS and forceps biopsies were similarly effective, each finding IM – a potentially premalignant mucosal change – in about 21% of patients, and dysplasia or cancer in 0.8%. Among the 185 patients who underwent endoscopy for follow-up of Barrett’s esophagus or post ablation, the two sampling strategies also performed similarly, detecting IM in roughly 36% of the 151 patients with columnar-lined esophagus shorter than 3 cm and in 56% of those with columnar-lined esophagus of greater length.

However, in the 196 patients with no history of IM who had any length of visible columnar-lined esophagus on endoscopy, the frequency of IM detection was 32.7% with WATS, compared with 15.3% with biopsy.

Dr. DeMeester and coinvestigators were also eager to identify factors associated with detection of IM in the esophagus or gastroesophageal junction in patients undergoing elective endoscopy with no history of IM. They found that whites were at greater risk than blacks, by a margin of 10.1% (17.1% vs. 7%). Moreover, the 23% IM detection rate in patients aged over age 70 years was significantly higher than the 15.5% rate in those under age 70. And to their surprise, there was no significant difference between the IM detection rate in men and women.

Nearly 15% of study participants with no measurable columnar-lined esophagus turned out to have IM. And two patients with low-grade dysplasia and one with adenocarcinoma were found among the group with no history of IM and no visible columnar-lined esophagus on upper endoscopy.

“This demonstrates that the absence of a measurable columnar-lined esophagus does not exclude patients from the risk of having intestinal metaplasia, dysplasia, or cancer at the gastroesophageal junction. Therefore evaluation of the gastroesophageal junction by biopsy or WATS should be considered during upper endoscopy, particularly in patients at increased risk for having intestinal metaplasia,” he concluded.

Dr. DeMeester reported serving as a consultant to BARD and receiving research funding from and serving as a paid speaker for CDx Diagnostics, which funded the trial.

[email protected]

SAN ANTONIO – A wide-area transepithelial sampling (WATS) brush proved superior to standard forceps biopsies for detection of intestinal metaplasia (IM) in the esophagus and gastroesophageal junction in patients with no history of IM who had any visible columnar-lined esophagus on upper endoscopy in a large randomized trial.

Bruce Jancin/MDedge News

“This suggests that WATS should in fact be the preferred method of sampling these patients,” Steven R. DeMeester, MD, commented in presenting the study results at the annual meeting of the American College of Gastroenterology.

With that specific exception, however, the two sampling methods proved similarly effective at detecting IM and dysplasia, suggesting either technology can otherwise reliably be used to detect these conditions, added Dr. DeMeester, a general and thoracic surgeon at the Oregon Clinic, Portland.

This is important new information for clinicians. A prior multicenter, randomized trial by other investigators demonstrated that adding WATS to biopsy sampling improved the detection rate of dysplasia and esophageal adenocarcinoma, compared with biopsies alone (Gastrointest Endosc. 2018 Feb;87[2]:348-55). However, this dual-sampling strategy is too time-consuming for routine use in a busy practice. Given the new evidence that the two sampling methods can reliably be used interchangeably except in patients with no history of IM who have endoscopically visible columnar-lined esophagus, WATS offers a clear advantage in that it’s much quicker, especially in patients with long-segment Barrett’s esophagus, the surgeon said.

Unlike brush cytology, which merely collects surface epithelial cells, the WATS brush collects sheets of esophageal mucosa, which then undergo computer-assisted three-dimensional analysis.

“When done appropriately, a wide area of the esophageal mucosa can be sampled with the WATS brush,” Dr. DeMeester explained.

He reported on 1,002 patients who presented at nine U.S. centers for upper endoscopy for Barrett’s esophagus surveillance or evaluation of foregut symptoms. They were randomized to WATS or forceps biopsies using the Seattle protocol. In the entire group, WATS and forceps biopsies were similarly effective, each finding IM – a potentially premalignant mucosal change – in about 21% of patients, and dysplasia or cancer in 0.8%. Among the 185 patients who underwent endoscopy for follow-up of Barrett’s esophagus or post ablation, the two sampling strategies also performed similarly, detecting IM in roughly 36% of the 151 patients with columnar-lined esophagus shorter than 3 cm and in 56% of those with columnar-lined esophagus of greater length.

However, in the 196 patients with no history of IM who had any length of visible columnar-lined esophagus on endoscopy, the frequency of IM detection was 32.7% with WATS, compared with 15.3% with biopsy.

Dr. DeMeester and coinvestigators were also eager to identify factors associated with detection of IM in the esophagus or gastroesophageal junction in patients undergoing elective endoscopy with no history of IM. They found that whites were at greater risk than blacks, by a margin of 10.1% (17.1% vs. 7%). Moreover, the 23% IM detection rate in patients aged over age 70 years was significantly higher than the 15.5% rate in those under age 70. And to their surprise, there was no significant difference between the IM detection rate in men and women.

Nearly 15% of study participants with no measurable columnar-lined esophagus turned out to have IM. And two patients with low-grade dysplasia and one with adenocarcinoma were found among the group with no history of IM and no visible columnar-lined esophagus on upper endoscopy.

“This demonstrates that the absence of a measurable columnar-lined esophagus does not exclude patients from the risk of having intestinal metaplasia, dysplasia, or cancer at the gastroesophageal junction. Therefore evaluation of the gastroesophageal junction by biopsy or WATS should be considered during upper endoscopy, particularly in patients at increased risk for having intestinal metaplasia,” he concluded.

Dr. DeMeester reported serving as a consultant to BARD and receiving research funding from and serving as a paid speaker for CDx Diagnostics, which funded the trial.

[email protected]

SAN ANTONIO – A wide-area transepithelial sampling (WATS) brush proved superior to standard forceps biopsies for detection of intestinal metaplasia (IM) in the esophagus and gastroesophageal junction in patients with no history of IM who had any visible columnar-lined esophagus on upper endoscopy in a large randomized trial.

Bruce Jancin/MDedge News

“This suggests that WATS should in fact be the preferred method of sampling these patients,” Steven R. DeMeester, MD, commented in presenting the study results at the annual meeting of the American College of Gastroenterology.

With that specific exception, however, the two sampling methods proved similarly effective at detecting IM and dysplasia, suggesting either technology can otherwise reliably be used to detect these conditions, added Dr. DeMeester, a general and thoracic surgeon at the Oregon Clinic, Portland.

This is important new information for clinicians. A prior multicenter, randomized trial by other investigators demonstrated that adding WATS to biopsy sampling improved the detection rate of dysplasia and esophageal adenocarcinoma, compared with biopsies alone (Gastrointest Endosc. 2018 Feb;87[2]:348-55). However, this dual-sampling strategy is too time-consuming for routine use in a busy practice. Given the new evidence that the two sampling methods can reliably be used interchangeably except in patients with no history of IM who have endoscopically visible columnar-lined esophagus, WATS offers a clear advantage in that it’s much quicker, especially in patients with long-segment Barrett’s esophagus, the surgeon said.

Unlike brush cytology, which merely collects surface epithelial cells, the WATS brush collects sheets of esophageal mucosa, which then undergo computer-assisted three-dimensional analysis.

“When done appropriately, a wide area of the esophageal mucosa can be sampled with the WATS brush,” Dr. DeMeester explained.

He reported on 1,002 patients who presented at nine U.S. centers for upper endoscopy for Barrett’s esophagus surveillance or evaluation of foregut symptoms. They were randomized to WATS or forceps biopsies using the Seattle protocol. In the entire group, WATS and forceps biopsies were similarly effective, each finding IM – a potentially premalignant mucosal change – in about 21% of patients, and dysplasia or cancer in 0.8%. Among the 185 patients who underwent endoscopy for follow-up of Barrett’s esophagus or post ablation, the two sampling strategies also performed similarly, detecting IM in roughly 36% of the 151 patients with columnar-lined esophagus shorter than 3 cm and in 56% of those with columnar-lined esophagus of greater length.

However, in the 196 patients with no history of IM who had any length of visible columnar-lined esophagus on endoscopy, the frequency of IM detection was 32.7% with WATS, compared with 15.3% with biopsy.

Dr. DeMeester and coinvestigators were also eager to identify factors associated with detection of IM in the esophagus or gastroesophageal junction in patients undergoing elective endoscopy with no history of IM. They found that whites were at greater risk than blacks, by a margin of 10.1% (17.1% vs. 7%). Moreover, the 23% IM detection rate in patients aged over age 70 years was significantly higher than the 15.5% rate in those under age 70. And to their surprise, there was no significant difference between the IM detection rate in men and women.

Nearly 15% of study participants with no measurable columnar-lined esophagus turned out to have IM. And two patients with low-grade dysplasia and one with adenocarcinoma were found among the group with no history of IM and no visible columnar-lined esophagus on upper endoscopy.

“This demonstrates that the absence of a measurable columnar-lined esophagus does not exclude patients from the risk of having intestinal metaplasia, dysplasia, or cancer at the gastroesophageal junction. Therefore evaluation of the gastroesophageal junction by biopsy or WATS should be considered during upper endoscopy, particularly in patients at increased risk for having intestinal metaplasia,” he concluded.

Dr. DeMeester reported serving as a consultant to BARD and receiving research funding from and serving as a paid speaker for CDx Diagnostics, which funded the trial.

[email protected]

On August 22, 2014, a baby girl was born healthy and at full term. She was discharged on August 24 after a routine hospital stay. A day later, the infant’s mother called the pediatrician’s emergency after-hours hotline, in distress. She was concerned because the infant had not had a bowel movement since August 23. She was also concerned that each feeding was lasting an hour. A nurse told the mother that her concerns would be discussed in a routine follow-up appointment scheduled for the next morning.

At the appointment, the pediatrician noted the infant was having feeding problems and had lost 11% of her at-birth weight. The pediatrician also noted a high respiratory rate and abnormal skin coloring. However, the pediatrician concluded that the infant’s feeding problems had resolved, reassured the parents she was healthy, and discharged her, telling her parents to return in 2 weeks.

On August 29, the mother again called the pediatrician’s office, this time with concerns over a decrease in the infant’s feeding. A nurse told her to bring the infant to the emergency department (ED). At the ED, the infant was found to have lost 12% of her weight since birth and to be severely dehydrated. Due to hypovolemia, health care providers could not complete lab tests on the infant until aggressive resuscitation had been performed for 4 hours. The infant’s lab values showed she had hypernatremia, which put her at risk for brain injury through a decrease in cellular hydration, increased vascular permeability, or elevated intracranial pressure.

The infant did sustain a permanent brain injury from the condition: right-side paralysis. Her multi-organ failure from dehydration also caused significant damage to her left kidney, which stopped functioning altogether in 2017.

The infant sued her pediatrician and his office. Plaintiff’s counsel stated that the infant’s early weight loss was a red flag and that the standard of care required the pediatrician to order in-office follow-up within 24 hours to confirm if the loss had been corrected. Plaintiff’s counsel also alleged the baby’s respiratory rate and poor coloring were also red flags for dehydration. He further alleged that if the infant had returned to the office, her weight loss would have prompted supplementation before the dehydration caused her brain injury.

VERDICT

The case was settled for $1,375,000.

COMMENTARY

This case merits discussion because it involves a type of patient many clinicians see in practice. Complaints of newborn and infant feeding problems are common. Most cases require reassurance and troubleshooting about common feeding problems—but the clinician must be on the lookout for serious issues. Thus, it is helpful to revisit expected newborn feeding, stooling, and weight status.

Continue to: With regard to feeding...

With regard to feeding, breastfed infants should receive between 8-12 feeds per day during the newborn hospitalization.¹ Bottlefed infants should be fed 20 kcal per 30 mL of iron-containing formula. Infants are fed on demand, and the duration of the feeding should not exceed 4 hours. The volume of the feed for the first few days of life should be 15-30 mL per feed.

For breastfed infants, clinicians should be attentive to issues that can impact nutrition, including latching difficulties, pain, mastitis, blocked duct, and engorgement. These can limit nutrition and be extremely upsetting to the mother.

Stooling frequency for newborns varies and depends on whether the infant is bottle fed or breast fed. During the first week of life, infants pass a mean of 4 stools per day.² Breastfed infants may have as few as one stool per day, increasing as mother’s milk production increases.²

With regard to weight loss, term infants may lose up to 10% of their birth weight in the first few days of life, which is typically regained in 10 to 14 days.¹ Infants born via cesarean section lose more weight, with 25% of these babies losing more than 10% by 72 hours. Of them, 76% return to birth weight by 14 days and 92% by 21 days. By contrast, vaginally born infants regain weight faster, with 86% returning to their birth weight by 14 days and 95% by the 21st day.¹

Here, the infant was term and healthy, but we are not told some important details. Was she breast fed or bottle fed? Was she born by cesarean section or vaginally? We do know she was discharged on August 24th, her mother called the hotline on the 25th, and she was seen by the pediatrician on the 26th—at which point the infant had not stooled in 3 days. The mother called the physician’s office again on August 29th and was sent to the ED. We are told only that each feeding lasted an hour and the infant hadn’t stooled.

Continue to: Regarding stool...

Regarding stool—we have all had discussions with patients regarding hypervigilant concerns about stool color. We know there are some big things to look for with stool color (eg, black tarry reveals upper GI bleeding, while clay-colored or pale may reveal the absence of bile). Yet, patients’ expectations of the color-coded diagnostic abilities of their stool knows no bounds. Patients are convinced that we have some color wheel in our jacket pocket corresponding to stool color—and that the nuances between shades have important medical implications. If you ask, “Would you say it is more marigold, butterscotch yellow, or Tuscan sun?” … your patient will have an answer.

Patients reveal stool color hesitantly, reservedly, with nervous expectation. They wait for your response in quivering anticipation that the coming reply will include words to the effect that a boysenberry-purple stool is equivalent to a Death tarot card. A subconjunctival hemorrhage is the only thing that approaches the anxiety level of the oddly hued stool (Oddly Hued Stool Anxiety). Woe be the patient with both. For a patient bearing a subconjunctival hemorrhage who has also passed a jungle-green stool in the past 24 hours fully expects to explode within the next 60 minutes.

I’ve been rather facetious for a reason. My purpose is to acknowledge and to help you recognize that most discussions regarding stooling will not be (forgive me) productive. They are not productive because most stool coloration issues are nonentities—yet they produce patient anxiety that takes some time to address, leaving a busy clinician prone to curtly dismiss such discussions out of hand. Because many patient-initiated stool discussions aren’t productive, there is the risk for stool tune-out. As gross and unproductive as they can be, don’t tune out all stool discussions.

In this case, the appropriate frequency of stooling should have been at least once per day. For newborns, a stool color question is helpful; stool should not be white, pale, or clay-colored, which is suggestive of acholic stools from biliary atresia. Here, despite the absence of stool over a 3-day period, the defendant concluded the feeding problem was resolved and set a return visit for 2 weeks later. The plaintiff’s expert contended that the weight loss and absence of stooling was evidence of inadequate intake and warranted a return check the next day. Rather than risk the case going to trial, the defendant settled for $1,375,000.

IN SUM

Newborn nutrition is important. Understand that parents will be anxious about newborn feeding, although often there is no major medical concern. However, do not be dismissive of feeding concerns because of this expected anxiety. Listen to the parents fully, paying particular attention to quantifying feeding difficulty and stooling frequency matters. Don’t let patients’ rainbow parade of needless stool concerns blind you to considering important information. In other words, don’t be a stool fool.

On August 22, 2014, a baby girl was born healthy and at full term. She was discharged on August 24 after a routine hospital stay. A day later, the infant’s mother called the pediatrician’s emergency after-hours hotline, in distress. She was concerned because the infant had not had a bowel movement since August 23. She was also concerned that each feeding was lasting an hour. A nurse told the mother that her concerns would be discussed in a routine follow-up appointment scheduled for the next morning.

At the appointment, the pediatrician noted the infant was having feeding problems and had lost 11% of her at-birth weight. The pediatrician also noted a high respiratory rate and abnormal skin coloring. However, the pediatrician concluded that the infant’s feeding problems had resolved, reassured the parents she was healthy, and discharged her, telling her parents to return in 2 weeks.

On August 29, the mother again called the pediatrician’s office, this time with concerns over a decrease in the infant’s feeding. A nurse told her to bring the infant to the emergency department (ED). At the ED, the infant was found to have lost 12% of her weight since birth and to be severely dehydrated. Due to hypovolemia, health care providers could not complete lab tests on the infant until aggressive resuscitation had been performed for 4 hours. The infant’s lab values showed she had hypernatremia, which put her at risk for brain injury through a decrease in cellular hydration, increased vascular permeability, or elevated intracranial pressure.

The infant did sustain a permanent brain injury from the condition: right-side paralysis. Her multi-organ failure from dehydration also caused significant damage to her left kidney, which stopped functioning altogether in 2017.

The infant sued her pediatrician and his office. Plaintiff’s counsel stated that the infant’s early weight loss was a red flag and that the standard of care required the pediatrician to order in-office follow-up within 24 hours to confirm if the loss had been corrected. Plaintiff’s counsel also alleged the baby’s respiratory rate and poor coloring were also red flags for dehydration. He further alleged that if the infant had returned to the office, her weight loss would have prompted supplementation before the dehydration caused her brain injury.

VERDICT

The case was settled for $1,375,000.

COMMENTARY

This case merits discussion because it involves a type of patient many clinicians see in practice. Complaints of newborn and infant feeding problems are common. Most cases require reassurance and troubleshooting about common feeding problems—but the clinician must be on the lookout for serious issues. Thus, it is helpful to revisit expected newborn feeding, stooling, and weight status.

Continue to: With regard to feeding...

With regard to feeding, breastfed infants should receive between 8-12 feeds per day during the newborn hospitalization.¹ Bottlefed infants should be fed 20 kcal per 30 mL of iron-containing formula. Infants are fed on demand, and the duration of the feeding should not exceed 4 hours. The volume of the feed for the first few days of life should be 15-30 mL per feed.

For breastfed infants, clinicians should be attentive to issues that can impact nutrition, including latching difficulties, pain, mastitis, blocked duct, and engorgement. These can limit nutrition and be extremely upsetting to the mother.

Stooling frequency for newborns varies and depends on whether the infant is bottle fed or breast fed. During the first week of life, infants pass a mean of 4 stools per day.² Breastfed infants may have as few as one stool per day, increasing as mother’s milk production increases.²

With regard to weight loss, term infants may lose up to 10% of their birth weight in the first few days of life, which is typically regained in 10 to 14 days.¹ Infants born via cesarean section lose more weight, with 25% of these babies losing more than 10% by 72 hours. Of them, 76% return to birth weight by 14 days and 92% by 21 days. By contrast, vaginally born infants regain weight faster, with 86% returning to their birth weight by 14 days and 95% by the 21st day.¹

Here, the infant was term and healthy, but we are not told some important details. Was she breast fed or bottle fed? Was she born by cesarean section or vaginally? We do know she was discharged on August 24th, her mother called the hotline on the 25th, and she was seen by the pediatrician on the 26th—at which point the infant had not stooled in 3 days. The mother called the physician’s office again on August 29th and was sent to the ED. We are told only that each feeding lasted an hour and the infant hadn’t stooled.

Continue to: Regarding stool...

Regarding stool—we have all had discussions with patients regarding hypervigilant concerns about stool color. We know there are some big things to look for with stool color (eg, black tarry reveals upper GI bleeding, while clay-colored or pale may reveal the absence of bile). Yet, patients’ expectations of the color-coded diagnostic abilities of their stool knows no bounds. Patients are convinced that we have some color wheel in our jacket pocket corresponding to stool color—and that the nuances between shades have important medical implications. If you ask, “Would you say it is more marigold, butterscotch yellow, or Tuscan sun?” … your patient will have an answer.

Patients reveal stool color hesitantly, reservedly, with nervous expectation. They wait for your response in quivering anticipation that the coming reply will include words to the effect that a boysenberry-purple stool is equivalent to a Death tarot card. A subconjunctival hemorrhage is the only thing that approaches the anxiety level of the oddly hued stool (Oddly Hued Stool Anxiety). Woe be the patient with both. For a patient bearing a subconjunctival hemorrhage who has also passed a jungle-green stool in the past 24 hours fully expects to explode within the next 60 minutes.

I’ve been rather facetious for a reason. My purpose is to acknowledge and to help you recognize that most discussions regarding stooling will not be (forgive me) productive. They are not productive because most stool coloration issues are nonentities—yet they produce patient anxiety that takes some time to address, leaving a busy clinician prone to curtly dismiss such discussions out of hand. Because many patient-initiated stool discussions aren’t productive, there is the risk for stool tune-out. As gross and unproductive as they can be, don’t tune out all stool discussions.

In this case, the appropriate frequency of stooling should have been at least once per day. For newborns, a stool color question is helpful; stool should not be white, pale, or clay-colored, which is suggestive of acholic stools from biliary atresia. Here, despite the absence of stool over a 3-day period, the defendant concluded the feeding problem was resolved and set a return visit for 2 weeks later. The plaintiff’s expert contended that the weight loss and absence of stooling was evidence of inadequate intake and warranted a return check the next day. Rather than risk the case going to trial, the defendant settled for $1,375,000.

IN SUM

Newborn nutrition is important. Understand that parents will be anxious about newborn feeding, although often there is no major medical concern. However, do not be dismissive of feeding concerns because of this expected anxiety. Listen to the parents fully, paying particular attention to quantifying feeding difficulty and stooling frequency matters. Don’t let patients’ rainbow parade of needless stool concerns blind you to considering important information. In other words, don’t be a stool fool.

On August 22, 2014, a baby girl was born healthy and at full term. She was discharged on August 24 after a routine hospital stay. A day later, the infant’s mother called the pediatrician’s emergency after-hours hotline, in distress. She was concerned because the infant had not had a bowel movement since August 23. She was also concerned that each feeding was lasting an hour. A nurse told the mother that her concerns would be discussed in a routine follow-up appointment scheduled for the next morning.

At the appointment, the pediatrician noted the infant was having feeding problems and had lost 11% of her at-birth weight. The pediatrician also noted a high respiratory rate and abnormal skin coloring. However, the pediatrician concluded that the infant’s feeding problems had resolved, reassured the parents she was healthy, and discharged her, telling her parents to return in 2 weeks.

On August 29, the mother again called the pediatrician’s office, this time with concerns over a decrease in the infant’s feeding. A nurse told her to bring the infant to the emergency department (ED). At the ED, the infant was found to have lost 12% of her weight since birth and to be severely dehydrated. Due to hypovolemia, health care providers could not complete lab tests on the infant until aggressive resuscitation had been performed for 4 hours. The infant’s lab values showed she had hypernatremia, which put her at risk for brain injury through a decrease in cellular hydration, increased vascular permeability, or elevated intracranial pressure.

The infant did sustain a permanent brain injury from the condition: right-side paralysis. Her multi-organ failure from dehydration also caused significant damage to her left kidney, which stopped functioning altogether in 2017.

The infant sued her pediatrician and his office. Plaintiff’s counsel stated that the infant’s early weight loss was a red flag and that the standard of care required the pediatrician to order in-office follow-up within 24 hours to confirm if the loss had been corrected. Plaintiff’s counsel also alleged the baby’s respiratory rate and poor coloring were also red flags for dehydration. He further alleged that if the infant had returned to the office, her weight loss would have prompted supplementation before the dehydration caused her brain injury.

VERDICT

The case was settled for $1,375,000.

COMMENTARY

This case merits discussion because it involves a type of patient many clinicians see in practice. Complaints of newborn and infant feeding problems are common. Most cases require reassurance and troubleshooting about common feeding problems—but the clinician must be on the lookout for serious issues. Thus, it is helpful to revisit expected newborn feeding, stooling, and weight status.

Continue to: With regard to feeding...

With regard to feeding, breastfed infants should receive between 8-12 feeds per day during the newborn hospitalization.¹ Bottlefed infants should be fed 20 kcal per 30 mL of iron-containing formula. Infants are fed on demand, and the duration of the feeding should not exceed 4 hours. The volume of the feed for the first few days of life should be 15-30 mL per feed.

For breastfed infants, clinicians should be attentive to issues that can impact nutrition, including latching difficulties, pain, mastitis, blocked duct, and engorgement. These can limit nutrition and be extremely upsetting to the mother.

Stooling frequency for newborns varies and depends on whether the infant is bottle fed or breast fed. During the first week of life, infants pass a mean of 4 stools per day.² Breastfed infants may have as few as one stool per day, increasing as mother’s milk production increases.²

With regard to weight loss, term infants may lose up to 10% of their birth weight in the first few days of life, which is typically regained in 10 to 14 days.¹ Infants born via cesarean section lose more weight, with 25% of these babies losing more than 10% by 72 hours. Of them, 76% return to birth weight by 14 days and 92% by 21 days. By contrast, vaginally born infants regain weight faster, with 86% returning to their birth weight by 14 days and 95% by the 21st day.¹

Here, the infant was term and healthy, but we are not told some important details. Was she breast fed or bottle fed? Was she born by cesarean section or vaginally? We do know she was discharged on August 24th, her mother called the hotline on the 25th, and she was seen by the pediatrician on the 26th—at which point the infant had not stooled in 3 days. The mother called the physician’s office again on August 29th and was sent to the ED. We are told only that each feeding lasted an hour and the infant hadn’t stooled.

Continue to: Regarding stool...

Regarding stool—we have all had discussions with patients regarding hypervigilant concerns about stool color. We know there are some big things to look for with stool color (eg, black tarry reveals upper GI bleeding, while clay-colored or pale may reveal the absence of bile). Yet, patients’ expectations of the color-coded diagnostic abilities of their stool knows no bounds. Patients are convinced that we have some color wheel in our jacket pocket corresponding to stool color—and that the nuances between shades have important medical implications. If you ask, “Would you say it is more marigold, butterscotch yellow, or Tuscan sun?” … your patient will have an answer.

Patients reveal stool color hesitantly, reservedly, with nervous expectation. They wait for your response in quivering anticipation that the coming reply will include words to the effect that a boysenberry-purple stool is equivalent to a Death tarot card. A subconjunctival hemorrhage is the only thing that approaches the anxiety level of the oddly hued stool (Oddly Hued Stool Anxiety). Woe be the patient with both. For a patient bearing a subconjunctival hemorrhage who has also passed a jungle-green stool in the past 24 hours fully expects to explode within the next 60 minutes.

I’ve been rather facetious for a reason. My purpose is to acknowledge and to help you recognize that most discussions regarding stooling will not be (forgive me) productive. They are not productive because most stool coloration issues are nonentities—yet they produce patient anxiety that takes some time to address, leaving a busy clinician prone to curtly dismiss such discussions out of hand. Because many patient-initiated stool discussions aren’t productive, there is the risk for stool tune-out. As gross and unproductive as they can be, don’t tune out all stool discussions.

In this case, the appropriate frequency of stooling should have been at least once per day. For newborns, a stool color question is helpful; stool should not be white, pale, or clay-colored, which is suggestive of acholic stools from biliary atresia. Here, despite the absence of stool over a 3-day period, the defendant concluded the feeding problem was resolved and set a return visit for 2 weeks later. The plaintiff’s expert contended that the weight loss and absence of stooling was evidence of inadequate intake and warranted a return check the next day. Rather than risk the case going to trial, the defendant settled for $1,375,000.

IN SUM

Newborn nutrition is important. Understand that parents will be anxious about newborn feeding, although often there is no major medical concern. However, do not be dismissive of feeding concerns because of this expected anxiety. Listen to the parents fully, paying particular attention to quantifying feeding difficulty and stooling frequency matters. Don’t let patients’ rainbow parade of needless stool concerns blind you to considering important information. In other words, don’t be a stool fool.

PHILADELPHIA – The substantial benefits from adding dapagliflozin to guideline-directed medical therapy for patients with heart failure with reduced ejection fraction enrolled in the DAPA-HF trial applied to patients regardless of their age or baseline health status, a pair of new post hoc analyses suggest.

These findings emerged a day after a report that more fully delineated dapagliflozin’s consistent safety and efficacy in patients with heart failure with reduced ejection fraction (HFrEF) regardless of whether they also had type 2 diabetes. One of the new, post hoc analyses reported at the American Heart Association scientific sessions suggested that even the most elderly enrolled patients, 75 years and older, had a similar cut in mortality and acute heart failure exacerbations, compared with younger patients. A second post hoc analysis indicated that patients with severe heart failure symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with mild baseline symptoms, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

The primary results from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, first reported in August 2019, showed that among more than 4,700 patients with HFrEF randomized to receive the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) on top of standard HFrEF medications or placebo, those who received dapagliflozin had a statistically significant, 26% decrease in their incidence of the primary study endpoint over a median 18 months, regardless of diabetes status (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

“These benefits were entirely consistent across the range of ages studied,” extending from patients younger than 55 years to those older than 75 years, John McMurray, MD, said at the meeting. “In many parts of the world, particularly North America and Western Europe, we have an increasingly elderly population. Many patients with heart failure are much older than in clinical trials,” he said.

Mitchel L. Zoler/MDedge News

Quality-of-life outcomes

The other new, post hoc analysis showed that patients with severe HF symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with milder baseline symptoms and less impaired function, measured by the KCCQ. Dapagliflozin treatment “improved cardiovascular death and worsening heart failure to a similar extent across the entire range of KCCQ at baseline,” Mikhail N. Kosiborod, MD, said in a separate talk at the meeting. In addition, dapagliflozin treatment increased the rate of small, moderate, and large clinically meaningful improvements in patients’ KCCQ scores across all key domains of the metric, which scores symptom frequency and severity, physical and social limitations, and quality of life, said Dr. Kosiborod, a cardiologist and professor of medicine at the University of Missouri–Kansas City.

Mitchel L. Zoler/MDedge News

After the first 8 months of treatment in the DAPA-HF trial, 58% of the 2,373 patients who received dapagliflozin had a clinically meaningful improvement in their total KCCQ symptom score of at least 5 points, compared with a 51% rate in the 2,371 patients in the control arm, a statistically significant difference. This meant that the number needed to treat with dapagliflozin was 14 patients to produce one additional patient with at least a 5-point KCCQ improvement compared with controls, a “very small” number needed to treat, Dr. Kosiborod said in an interview.

Addition of the KCCQ to the panel of assessments that patients underwent during DAPA-HF reflected an evolved approach to measuring efficacy outcomes in clinical trials by including patient-reported outcomes. Earlier in 2019, the Food and Drug Administration released draft guidance for heart failure drug development that explicitly called for efficacy endpoints in pivotal studies that measure how patients feel and function, and stating that these endpoints can be the basis for new drug approvals.

“To many patients, how they feel matters as much if not more than how long they live,” Dr. Kosiborod noted. The goals of heart failure treatments are not only to extend survival and reduced hospitalizations, but also to improve symptoms, function, and quality of life, he said.

“There is a lot of interest now in having outcomes in heart failure trials that are more meaningful to patients, like feeling better and being able to do more,” noted Dr. Walsh.

The DAPA-HF results also showed that patients had similar rates of reduction in death, heart failure hospitalization, or urgent clinical visits, regardless of how severely they were affected by their heart failure when they began dapagliflozin treatment. The researchers ran an analysis that divided the entire trial population into tertiles based on their KCCQ score on entering the study. Patients in the most severely-affected tertile had a 30% cut in their rate of death or acute heart failure exacerbation on dapagliflozin compared with placebo, while patients in the tertile with the mildest symptoms at baseline had a 38% reduction in their primary outcome incidence compared with controls who received placebo. Concurrently with Dr. Kosiborod’s report, the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138).
 

Outcomes by age

Not surprisingly in DAPA-HF, the older patients were, the sicker, Dr. McMurray observed. Of the study’s 1,149 patients (24% of the study cohort) who were at least 75 years old, 62% had chronic kidney disease, compared with a 14% prevalence among the 636 patients younger than age 55. The 75-and-older group showed a steeper, 32% decline in incidence of the primary endpoint – a composite of cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring intravenous therapy – than in the other studied age groups: a 24% decline in those 65-74 years old, a 29% cut in those 55-64 years old, and a 13% drop in patients younger than 55 years old.

In addition, patients aged 75 years or greater were just as likely as the overall group to show at least a 5-point improvement in their KCCQ Total Symptom Score on dapagliflozin, as well as about the same reduced rate of deterioration compared with placebo as tracked with the KCCQ.

Patients “got as much benefit in terms of symptoms as well as morbidity and mortality,” Dr. McMurray concluded. Concurrently with the meeting report the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044133).

“These data are of critical importance, as improving patient-reported outcomes in heart failure, especially in highly symptomatic patients, is an important goal in drug development,” G. Michael Felker, MD, wrote in an editorial accompanying the two published analyses (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044578). These new analyses also highlight another attractive feature of dapagliflozin and, apparently, the entire class of SGLT2 inhibitors: They “ ‘play well with others’ when it comes to overlapping intolerances that often limit (either in reality or in perception) optimization of GDMT [guideline-directed medical therapy]. Although SGLT2 inhibitor therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2 inhibitors generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive up-titration of GDMT problematic, particularly in older patients or those with more advanced disease,“ wrote Dr. Felker, professor of medicine at Duke University in Durham, N.C. “We stand at the beginning of a new era of ‘quadruple therapy’ for HFrEF with beta-blockers, an angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2 inhibitors,” he concluded.
 

A version of this article also appears on Medscape.com

PHILADELPHIA – The substantial benefits from adding dapagliflozin to guideline-directed medical therapy for patients with heart failure with reduced ejection fraction enrolled in the DAPA-HF trial applied to patients regardless of their age or baseline health status, a pair of new post hoc analyses suggest.

These findings emerged a day after a report that more fully delineated dapagliflozin’s consistent safety and efficacy in patients with heart failure with reduced ejection fraction (HFrEF) regardless of whether they also had type 2 diabetes. One of the new, post hoc analyses reported at the American Heart Association scientific sessions suggested that even the most elderly enrolled patients, 75 years and older, had a similar cut in mortality and acute heart failure exacerbations, compared with younger patients. A second post hoc analysis indicated that patients with severe heart failure symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with mild baseline symptoms, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

The primary results from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, first reported in August 2019, showed that among more than 4,700 patients with HFrEF randomized to receive the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) on top of standard HFrEF medications or placebo, those who received dapagliflozin had a statistically significant, 26% decrease in their incidence of the primary study endpoint over a median 18 months, regardless of diabetes status (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

“These benefits were entirely consistent across the range of ages studied,” extending from patients younger than 55 years to those older than 75 years, John McMurray, MD, said at the meeting. “In many parts of the world, particularly North America and Western Europe, we have an increasingly elderly population. Many patients with heart failure are much older than in clinical trials,” he said.

Mitchel L. Zoler/MDedge News

Quality-of-life outcomes

The other new, post hoc analysis showed that patients with severe HF symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with milder baseline symptoms and less impaired function, measured by the KCCQ. Dapagliflozin treatment “improved cardiovascular death and worsening heart failure to a similar extent across the entire range of KCCQ at baseline,” Mikhail N. Kosiborod, MD, said in a separate talk at the meeting. In addition, dapagliflozin treatment increased the rate of small, moderate, and large clinically meaningful improvements in patients’ KCCQ scores across all key domains of the metric, which scores symptom frequency and severity, physical and social limitations, and quality of life, said Dr. Kosiborod, a cardiologist and professor of medicine at the University of Missouri–Kansas City.

Mitchel L. Zoler/MDedge News

After the first 8 months of treatment in the DAPA-HF trial, 58% of the 2,373 patients who received dapagliflozin had a clinically meaningful improvement in their total KCCQ symptom score of at least 5 points, compared with a 51% rate in the 2,371 patients in the control arm, a statistically significant difference. This meant that the number needed to treat with dapagliflozin was 14 patients to produce one additional patient with at least a 5-point KCCQ improvement compared with controls, a “very small” number needed to treat, Dr. Kosiborod said in an interview.

Addition of the KCCQ to the panel of assessments that patients underwent during DAPA-HF reflected an evolved approach to measuring efficacy outcomes in clinical trials by including patient-reported outcomes. Earlier in 2019, the Food and Drug Administration released draft guidance for heart failure drug development that explicitly called for efficacy endpoints in pivotal studies that measure how patients feel and function, and stating that these endpoints can be the basis for new drug approvals.

“To many patients, how they feel matters as much if not more than how long they live,” Dr. Kosiborod noted. The goals of heart failure treatments are not only to extend survival and reduced hospitalizations, but also to improve symptoms, function, and quality of life, he said.

“There is a lot of interest now in having outcomes in heart failure trials that are more meaningful to patients, like feeling better and being able to do more,” noted Dr. Walsh.

The DAPA-HF results also showed that patients had similar rates of reduction in death, heart failure hospitalization, or urgent clinical visits, regardless of how severely they were affected by their heart failure when they began dapagliflozin treatment. The researchers ran an analysis that divided the entire trial population into tertiles based on their KCCQ score on entering the study. Patients in the most severely-affected tertile had a 30% cut in their rate of death or acute heart failure exacerbation on dapagliflozin compared with placebo, while patients in the tertile with the mildest symptoms at baseline had a 38% reduction in their primary outcome incidence compared with controls who received placebo. Concurrently with Dr. Kosiborod’s report, the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138).
 

Outcomes by age

Not surprisingly in DAPA-HF, the older patients were, the sicker, Dr. McMurray observed. Of the study’s 1,149 patients (24% of the study cohort) who were at least 75 years old, 62% had chronic kidney disease, compared with a 14% prevalence among the 636 patients younger than age 55. The 75-and-older group showed a steeper, 32% decline in incidence of the primary endpoint – a composite of cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring intravenous therapy – than in the other studied age groups: a 24% decline in those 65-74 years old, a 29% cut in those 55-64 years old, and a 13% drop in patients younger than 55 years old.

In addition, patients aged 75 years or greater were just as likely as the overall group to show at least a 5-point improvement in their KCCQ Total Symptom Score on dapagliflozin, as well as about the same reduced rate of deterioration compared with placebo as tracked with the KCCQ.

Patients “got as much benefit in terms of symptoms as well as morbidity and mortality,” Dr. McMurray concluded. Concurrently with the meeting report the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044133).

“These data are of critical importance, as improving patient-reported outcomes in heart failure, especially in highly symptomatic patients, is an important goal in drug development,” G. Michael Felker, MD, wrote in an editorial accompanying the two published analyses (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044578). These new analyses also highlight another attractive feature of dapagliflozin and, apparently, the entire class of SGLT2 inhibitors: They “ ‘play well with others’ when it comes to overlapping intolerances that often limit (either in reality or in perception) optimization of GDMT [guideline-directed medical therapy]. Although SGLT2 inhibitor therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2 inhibitors generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive up-titration of GDMT problematic, particularly in older patients or those with more advanced disease,“ wrote Dr. Felker, professor of medicine at Duke University in Durham, N.C. “We stand at the beginning of a new era of ‘quadruple therapy’ for HFrEF with beta-blockers, an angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2 inhibitors,” he concluded.
 

A version of this article also appears on Medscape.com

PHILADELPHIA – The substantial benefits from adding dapagliflozin to guideline-directed medical therapy for patients with heart failure with reduced ejection fraction enrolled in the DAPA-HF trial applied to patients regardless of their age or baseline health status, a pair of new post hoc analyses suggest.

These findings emerged a day after a report that more fully delineated dapagliflozin’s consistent safety and efficacy in patients with heart failure with reduced ejection fraction (HFrEF) regardless of whether they also had type 2 diabetes. One of the new, post hoc analyses reported at the American Heart Association scientific sessions suggested that even the most elderly enrolled patients, 75 years and older, had a similar cut in mortality and acute heart failure exacerbations, compared with younger patients. A second post hoc analysis indicated that patients with severe heart failure symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with mild baseline symptoms, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).

The primary results from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, first reported in August 2019, showed that among more than 4,700 patients with HFrEF randomized to receive the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (Farxiga) on top of standard HFrEF medications or placebo, those who received dapagliflozin had a statistically significant, 26% decrease in their incidence of the primary study endpoint over a median 18 months, regardless of diabetes status (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

“These benefits were entirely consistent across the range of ages studied,” extending from patients younger than 55 years to those older than 75 years, John McMurray, MD, said at the meeting. “In many parts of the world, particularly North America and Western Europe, we have an increasingly elderly population. Many patients with heart failure are much older than in clinical trials,” he said.

Mitchel L. Zoler/MDedge News

Quality-of-life outcomes

The other new, post hoc analysis showed that patients with severe HF symptoms at entry into the trial received about as much benefit from the addition of dapagliflozin as did patients with milder baseline symptoms and less impaired function, measured by the KCCQ. Dapagliflozin treatment “improved cardiovascular death and worsening heart failure to a similar extent across the entire range of KCCQ at baseline,” Mikhail N. Kosiborod, MD, said in a separate talk at the meeting. In addition, dapagliflozin treatment increased the rate of small, moderate, and large clinically meaningful improvements in patients’ KCCQ scores across all key domains of the metric, which scores symptom frequency and severity, physical and social limitations, and quality of life, said Dr. Kosiborod, a cardiologist and professor of medicine at the University of Missouri–Kansas City.

Mitchel L. Zoler/MDedge News

After the first 8 months of treatment in the DAPA-HF trial, 58% of the 2,373 patients who received dapagliflozin had a clinically meaningful improvement in their total KCCQ symptom score of at least 5 points, compared with a 51% rate in the 2,371 patients in the control arm, a statistically significant difference. This meant that the number needed to treat with dapagliflozin was 14 patients to produce one additional patient with at least a 5-point KCCQ improvement compared with controls, a “very small” number needed to treat, Dr. Kosiborod said in an interview.

Addition of the KCCQ to the panel of assessments that patients underwent during DAPA-HF reflected an evolved approach to measuring efficacy outcomes in clinical trials by including patient-reported outcomes. Earlier in 2019, the Food and Drug Administration released draft guidance for heart failure drug development that explicitly called for efficacy endpoints in pivotal studies that measure how patients feel and function, and stating that these endpoints can be the basis for new drug approvals.

“To many patients, how they feel matters as much if not more than how long they live,” Dr. Kosiborod noted. The goals of heart failure treatments are not only to extend survival and reduced hospitalizations, but also to improve symptoms, function, and quality of life, he said.

“There is a lot of interest now in having outcomes in heart failure trials that are more meaningful to patients, like feeling better and being able to do more,” noted Dr. Walsh.

The DAPA-HF results also showed that patients had similar rates of reduction in death, heart failure hospitalization, or urgent clinical visits, regardless of how severely they were affected by their heart failure when they began dapagliflozin treatment. The researchers ran an analysis that divided the entire trial population into tertiles based on their KCCQ score on entering the study. Patients in the most severely-affected tertile had a 30% cut in their rate of death or acute heart failure exacerbation on dapagliflozin compared with placebo, while patients in the tertile with the mildest symptoms at baseline had a 38% reduction in their primary outcome incidence compared with controls who received placebo. Concurrently with Dr. Kosiborod’s report, the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044138).
 

Outcomes by age

Not surprisingly in DAPA-HF, the older patients were, the sicker, Dr. McMurray observed. Of the study’s 1,149 patients (24% of the study cohort) who were at least 75 years old, 62% had chronic kidney disease, compared with a 14% prevalence among the 636 patients younger than age 55. The 75-and-older group showed a steeper, 32% decline in incidence of the primary endpoint – a composite of cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring intravenous therapy – than in the other studied age groups: a 24% decline in those 65-74 years old, a 29% cut in those 55-64 years old, and a 13% drop in patients younger than 55 years old.

In addition, patients aged 75 years or greater were just as likely as the overall group to show at least a 5-point improvement in their KCCQ Total Symptom Score on dapagliflozin, as well as about the same reduced rate of deterioration compared with placebo as tracked with the KCCQ.

Patients “got as much benefit in terms of symptoms as well as morbidity and mortality,” Dr. McMurray concluded. Concurrently with the meeting report the results appeared in an article online (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044133).

“These data are of critical importance, as improving patient-reported outcomes in heart failure, especially in highly symptomatic patients, is an important goal in drug development,” G. Michael Felker, MD, wrote in an editorial accompanying the two published analyses (Circulation. 2019 Nov 17. doi: 10.1161/CIRCULATIONAHA.119.044578). These new analyses also highlight another attractive feature of dapagliflozin and, apparently, the entire class of SGLT2 inhibitors: They “ ‘play well with others’ when it comes to overlapping intolerances that often limit (either in reality or in perception) optimization of GDMT [guideline-directed medical therapy]. Although SGLT2 inhibitor therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2 inhibitors generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive up-titration of GDMT problematic, particularly in older patients or those with more advanced disease,“ wrote Dr. Felker, professor of medicine at Duke University in Durham, N.C. “We stand at the beginning of a new era of ‘quadruple therapy’ for HFrEF with beta-blockers, an angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2 inhibitors,” he concluded.
 

A version of this article also appears on Medscape.com