Federal Practitioner

Most older women with estrogen receptor–positive (ER+) breast cancer can tolerate and should be offered surgery, and a new tool helps them decide between treatment options, the U.K. Age Gap study suggests. Findings from the study were reported at the 12th European Breast Cancer Conference.

“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).

“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.

Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.

The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.

The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.

The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
 

Prospective cohort study

The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).

In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.

At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.

In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.

The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.

In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.

Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.

None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.

Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
 

Cluster-randomized controlled trial

In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.

The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.

Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.

Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).

The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.

Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.

Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
 

Applying results to practice

“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”

“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.

“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.

In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.

“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”

The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.

SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.

Most older women with estrogen receptor–positive (ER+) breast cancer can tolerate and should be offered surgery, and a new tool helps them decide between treatment options, the U.K. Age Gap study suggests. Findings from the study were reported at the 12th European Breast Cancer Conference.

“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).

“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.

Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.

The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.

The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.

The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
 

Prospective cohort study

The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).

In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.

At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.

In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.

The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.

In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.

Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.

None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.

Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
 

Cluster-randomized controlled trial

In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.

The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.

Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.

Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).

The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.

Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.

Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
 

Applying results to practice

“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”

“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.

“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.

In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.

“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”

The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.

SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.

Most older women with estrogen receptor–positive (ER+) breast cancer can tolerate and should be offered surgery, and a new tool helps them decide between treatment options, the U.K. Age Gap study suggests. Findings from the study were reported at the 12th European Breast Cancer Conference.

“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).

“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.

Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.

The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.

The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.

The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
 

Prospective cohort study

The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).

In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.

At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.

In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.

The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.

In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.

Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.

None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.

Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
 

Cluster-randomized controlled trial

In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.

The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.

Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.

Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).

The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.

Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.

Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
 

Applying results to practice

“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”

“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.

“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.

In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.

“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”

The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.

SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.

Since joining the Food and Drug Administration in 1986, Janet Woodcock, MD, has built a reputation as a stalwart champion of patients and consumers, from helping to usher the approval of the first treatments for cystic fibrosis and multiple sclerosis during her tenure as director of the Office of Therapeutics Research and Review, to introducing the concept of risk management in the agency’s analysis of drug safety during her role as acting director of the Center for Drug Evaluation and Research (CDER).

During an online event on Oct. 9, Dr. Woodcock, who became CDER’s director in 2008, will receive a lifetime achievement award from the National Organization for Rare Disorders*. In this interview, she reflects on the CDER’s accomplishments in the field of rare diseases, from which she draws inspiration, and what it’s like to be overseeing the therapeutics component of Operation Warp Speed amid the COVID-19 pandemic.

Q: In what practical ways can physicians become advocates for patients and their families who are navigating life with a rare disease?

Dr. Woodcock: I advise people to get involved in the association or advocacy group for their rare disease. It’s empowering. They can share stories and information with others who have been suffering from the disease. Also, they would get information about what trials might be available. As for physicians themselves, they have a bewildering variety of jobs they’re supposed to do, so it’s hard to be good in any one of them. People with rare disease often suffer terribly because they don’t get diagnosed for 10 years even though they have classic symptoms of a particular disorder. If physicians have never seen it or never heard of it, they may not know how to treat it. It’s a huge problem.



Q: Who inspires you most in your work today?

Dr. Woodcock: The dedication of the staff at the FDA is unbelievable. When you look at responses to the Federal Employee Viewpoint Survey administered by the Office of Personnel Management, FDA workers consistently express a strong sense of mission and dedication. It’s out of the park, really. They have worked night and day during this pandemic. I’m inspired by everyone who works at the FDA and their incredible dedication to their work.

Q: In what ways do you cope with the pressure that comes with your line of work? Do you have a favorite hobby or that activity that helps keep you grounded?

Dr. Woodcock: I’m an avid gardener, so I have a garden with vegetables, fruits, and flowers, including a large orchid collection. I’m also a hiker and a physical fitness buff, so I feel like there isn’t enough time in the day for all of my hobbies. Formal hiking trails near me are very crowded now, so I’ve been hiking around my neighborhood, taking long walks and going up and down hills quickly. Last November, I went hiking in New Zealand with my daughter. We hiked the Milford Track, which is about 33 miles long. It goes from an inland lake, over a mountain pass, and to the Pacific Ocean. It was fun, with unbelievable scenery.



Q: What novel treatment developments in rare disorders are you most excited about in the next 5 years?

Dr. Woodcock: I think gene therapy will come into its own. I think that could be a game-changer for people with genetic mutations causing rare diseases, and even cancer. We’ll see. It takes the technology a long time to mature. There are also gene-directed therapies such as RNA inhibition. We’ve already approved a couple of products like that for rare diseases, including treatments for the cardiomyopathy and neuropathy associated with ATTR amyloidosis. As our knowledge of biology continues to grow, I think more of these diseases will be amenable to interventions.



Q: In May of 2020 you were asked to temporarily step aside from your post as director of CDER to work on Operation Warp Speed. Please describe what your role is in this effort to accelerate COVID-19 treatments.

Dr. Woodcock: I’m the lead on therapeutics. Operation Warp Speed is mainly focused on developing vaccines for COVID-19. In the meantime, people who don’t respond to vaccines are going to need therapeutics, such as the elderly, or those who refuse to take vaccines, or those who are immunosuppressed and can’t mount a response to a vaccine. If we can develop those therapeutics now, that would be good to get that populous vaccinated. The team identified what we thought were the five highest priority agents to work on, and we’re testing them. We have identified many more in a priority list. We have five master protocols running for different times in the disease, such as when you’re an outpatient, when you’re an inpatient, or when you’re in the ICU. The work is stressful, because we need these treatments as soon as possible, but we have a great team working on this. I feel like I’m making a contribution in this role, because I know people in industry and in the National Institutes of Health. I try to bring everyone together and get things done.

*Correction, 10/22/20: An earlier version of this article misstated the name of the National Organization for Rare Disorders.

[email protected]

Since joining the Food and Drug Administration in 1986, Janet Woodcock, MD, has built a reputation as a stalwart champion of patients and consumers, from helping to usher the approval of the first treatments for cystic fibrosis and multiple sclerosis during her tenure as director of the Office of Therapeutics Research and Review, to introducing the concept of risk management in the agency’s analysis of drug safety during her role as acting director of the Center for Drug Evaluation and Research (CDER).

During an online event on Oct. 9, Dr. Woodcock, who became CDER’s director in 2008, will receive a lifetime achievement award from the National Organization for Rare Disorders*. In this interview, she reflects on the CDER’s accomplishments in the field of rare diseases, from which she draws inspiration, and what it’s like to be overseeing the therapeutics component of Operation Warp Speed amid the COVID-19 pandemic.

Q: In what practical ways can physicians become advocates for patients and their families who are navigating life with a rare disease?

Dr. Woodcock: I advise people to get involved in the association or advocacy group for their rare disease. It’s empowering. They can share stories and information with others who have been suffering from the disease. Also, they would get information about what trials might be available. As for physicians themselves, they have a bewildering variety of jobs they’re supposed to do, so it’s hard to be good in any one of them. People with rare disease often suffer terribly because they don’t get diagnosed for 10 years even though they have classic symptoms of a particular disorder. If physicians have never seen it or never heard of it, they may not know how to treat it. It’s a huge problem.



Q: Who inspires you most in your work today?

Dr. Woodcock: The dedication of the staff at the FDA is unbelievable. When you look at responses to the Federal Employee Viewpoint Survey administered by the Office of Personnel Management, FDA workers consistently express a strong sense of mission and dedication. It’s out of the park, really. They have worked night and day during this pandemic. I’m inspired by everyone who works at the FDA and their incredible dedication to their work.

Q: In what ways do you cope with the pressure that comes with your line of work? Do you have a favorite hobby or that activity that helps keep you grounded?

Dr. Woodcock: I’m an avid gardener, so I have a garden with vegetables, fruits, and flowers, including a large orchid collection. I’m also a hiker and a physical fitness buff, so I feel like there isn’t enough time in the day for all of my hobbies. Formal hiking trails near me are very crowded now, so I’ve been hiking around my neighborhood, taking long walks and going up and down hills quickly. Last November, I went hiking in New Zealand with my daughter. We hiked the Milford Track, which is about 33 miles long. It goes from an inland lake, over a mountain pass, and to the Pacific Ocean. It was fun, with unbelievable scenery.



Q: What novel treatment developments in rare disorders are you most excited about in the next 5 years?

Dr. Woodcock: I think gene therapy will come into its own. I think that could be a game-changer for people with genetic mutations causing rare diseases, and even cancer. We’ll see. It takes the technology a long time to mature. There are also gene-directed therapies such as RNA inhibition. We’ve already approved a couple of products like that for rare diseases, including treatments for the cardiomyopathy and neuropathy associated with ATTR amyloidosis. As our knowledge of biology continues to grow, I think more of these diseases will be amenable to interventions.



Q: In May of 2020 you were asked to temporarily step aside from your post as director of CDER to work on Operation Warp Speed. Please describe what your role is in this effort to accelerate COVID-19 treatments.

Dr. Woodcock: I’m the lead on therapeutics. Operation Warp Speed is mainly focused on developing vaccines for COVID-19. In the meantime, people who don’t respond to vaccines are going to need therapeutics, such as the elderly, or those who refuse to take vaccines, or those who are immunosuppressed and can’t mount a response to a vaccine. If we can develop those therapeutics now, that would be good to get that populous vaccinated. The team identified what we thought were the five highest priority agents to work on, and we’re testing them. We have identified many more in a priority list. We have five master protocols running for different times in the disease, such as when you’re an outpatient, when you’re an inpatient, or when you’re in the ICU. The work is stressful, because we need these treatments as soon as possible, but we have a great team working on this. I feel like I’m making a contribution in this role, because I know people in industry and in the National Institutes of Health. I try to bring everyone together and get things done.

*Correction, 10/22/20: An earlier version of this article misstated the name of the National Organization for Rare Disorders.

[email protected]

Since joining the Food and Drug Administration in 1986, Janet Woodcock, MD, has built a reputation as a stalwart champion of patients and consumers, from helping to usher the approval of the first treatments for cystic fibrosis and multiple sclerosis during her tenure as director of the Office of Therapeutics Research and Review, to introducing the concept of risk management in the agency’s analysis of drug safety during her role as acting director of the Center for Drug Evaluation and Research (CDER).

During an online event on Oct. 9, Dr. Woodcock, who became CDER’s director in 2008, will receive a lifetime achievement award from the National Organization for Rare Disorders*. In this interview, she reflects on the CDER’s accomplishments in the field of rare diseases, from which she draws inspiration, and what it’s like to be overseeing the therapeutics component of Operation Warp Speed amid the COVID-19 pandemic.

Q: In what practical ways can physicians become advocates for patients and their families who are navigating life with a rare disease?

Dr. Woodcock: I advise people to get involved in the association or advocacy group for their rare disease. It’s empowering. They can share stories and information with others who have been suffering from the disease. Also, they would get information about what trials might be available. As for physicians themselves, they have a bewildering variety of jobs they’re supposed to do, so it’s hard to be good in any one of them. People with rare disease often suffer terribly because they don’t get diagnosed for 10 years even though they have classic symptoms of a particular disorder. If physicians have never seen it or never heard of it, they may not know how to treat it. It’s a huge problem.



Q: Who inspires you most in your work today?

Dr. Woodcock: The dedication of the staff at the FDA is unbelievable. When you look at responses to the Federal Employee Viewpoint Survey administered by the Office of Personnel Management, FDA workers consistently express a strong sense of mission and dedication. It’s out of the park, really. They have worked night and day during this pandemic. I’m inspired by everyone who works at the FDA and their incredible dedication to their work.

Q: In what ways do you cope with the pressure that comes with your line of work? Do you have a favorite hobby or that activity that helps keep you grounded?

Dr. Woodcock: I’m an avid gardener, so I have a garden with vegetables, fruits, and flowers, including a large orchid collection. I’m also a hiker and a physical fitness buff, so I feel like there isn’t enough time in the day for all of my hobbies. Formal hiking trails near me are very crowded now, so I’ve been hiking around my neighborhood, taking long walks and going up and down hills quickly. Last November, I went hiking in New Zealand with my daughter. We hiked the Milford Track, which is about 33 miles long. It goes from an inland lake, over a mountain pass, and to the Pacific Ocean. It was fun, with unbelievable scenery.



Q: What novel treatment developments in rare disorders are you most excited about in the next 5 years?

Dr. Woodcock: I think gene therapy will come into its own. I think that could be a game-changer for people with genetic mutations causing rare diseases, and even cancer. We’ll see. It takes the technology a long time to mature. There are also gene-directed therapies such as RNA inhibition. We’ve already approved a couple of products like that for rare diseases, including treatments for the cardiomyopathy and neuropathy associated with ATTR amyloidosis. As our knowledge of biology continues to grow, I think more of these diseases will be amenable to interventions.



Q: In May of 2020 you were asked to temporarily step aside from your post as director of CDER to work on Operation Warp Speed. Please describe what your role is in this effort to accelerate COVID-19 treatments.

Dr. Woodcock: I’m the lead on therapeutics. Operation Warp Speed is mainly focused on developing vaccines for COVID-19. In the meantime, people who don’t respond to vaccines are going to need therapeutics, such as the elderly, or those who refuse to take vaccines, or those who are immunosuppressed and can’t mount a response to a vaccine. If we can develop those therapeutics now, that would be good to get that populous vaccinated. The team identified what we thought were the five highest priority agents to work on, and we’re testing them. We have identified many more in a priority list. We have five master protocols running for different times in the disease, such as when you’re an outpatient, when you’re an inpatient, or when you’re in the ICU. The work is stressful, because we need these treatments as soon as possible, but we have a great team working on this. I feel like I’m making a contribution in this role, because I know people in industry and in the National Institutes of Health. I try to bring everyone together and get things done.

*Correction, 10/22/20: An earlier version of this article misstated the name of the National Organization for Rare Disorders.

[email protected]

Patients receiving even top-notch hospital care for heart failure (HF) are, once discharged to home, at higher short-term risk of another HF hospitalization if home is in a socioeconomically deprived neighborhood. That helps explain why Blacks in the United States have a much higher 30-day HF readmission risk than Whites, a disparity that only worsens with the level of neighborhood deprivation, a new analysis suggests.

Some systemic and entrenched socioeconomic inequities that health care providers have little sway over, and which disproportionately affect Black individuals, are independent and robust predictors of worsened HF outcomes, Alanna A. Morris, MD, MSc, Emory University, Atlanta, said during her presentation at the virtual annual scientific meeting of the Heart Failure Society of America.

In a retrospective cohort study, Blacks had a 45% higher risk of 30-day readmission than Whites (P < .001) independent of cardiovascular risk factors, clinical history, comorbidities, type and location of hospital, and type of third-party payer coverage. The analysis included more than 30,000 patients with at least one HF hospitalization at centers in a major metropolitan health system.

The racial disparity widened with worsening socioeconomic deprivation of patients’ residential neighborhoods, that is, with rising quartiles of neighborhood scores on the Social Deprivation Index (SDI).

The SDI, based on U.S. census data, incorporates seven socioeconomic criteria, including household income, education level, employment, and prevalence of rented housing and households that are without a car, single parent, or overcrowded.

There was a 4–percentage point gap in adjusted 30-day readmission rate between Blacks and Whites in the lowest quartile that widened to more than 8 points by the third quartile; the disparity in both the second and fourth quartiles was the same, at about 5.5 percentage points.

A remaining question, Dr. Morris said in an interview, is why the outcomes disparity between Blacks and Whites peaks in the third SDI quartile but drops a bit in the fourth quartile representing the most severe neighborhood deprivation.

“Our hypothesis is that when you look at patients who are the poorest, who live in the most deprived neighborhoods, race may be less of a factor,” she said. Socioeconomic deprivation may have similar consequences for everyone “regardless of race, ethnicity, gender, or other demographic characteristics if you live in a neighborhood that’s highly deprived.”

Based on the current study, “it does appear that increased heart failure incident rates are related to living in deprived neighborhoods, and it raises important clinical and public health concerns that must be addressed,” Keith C. Ferdinand, MD, Tulane University, New Orleans, said as invited discussant after the presentation from Dr. Morris.

“These findings could serve as an aid to policy makers, going forward, in terms of allocating resources for primary health care,” he said. “And it’s important looking at these data and other [data] that we target heart failure patients who reside in deprived neighborhoods before, during, and [after] hospitalization.”

Dr. Morris agreed that policy makers are in a better position to attack the racial disparity in HF readmission rates identified in the study. “This is not a problem that can be fixed within the health care system.”

If the reported interpretation is correct, it could add a twist to the public health care debate in the United States, observed session moderator Mandeep R. Mehra, MD, Brigham and Woman’s Hospital in Boston.

That debate, he noted, has often focused on insurability, access to coverage, and the merits or shortcomings of a single-payer system. Yet the study suggests outcomes disparities stemming from neighborhood deprivation will not be corrected by improved access to health insurance, a conclusion he finds “startling,” Dr. Mehra said in an interview.

Some proposed explanations for the disparities by race blame unequal access to health care and or variable health insurance coverage, Dr. Morris observed in an interview. But “that may not fully explain the increased risk that we see.”

Black patients followed at Emory University’s advanced HF clinic still have a higher risk of rehospitalization than Whites. “These are patients who have insurance, who are followed by advanced heart failure providers, who are on equal amounts of guideline-recommended medical therapy – and you still see about a 50% higher risk of rehospitalization,” Dr. Morris said, citing data that isn’t part of the current analysis.

“We can say that these patients are certainly able to access care, because they are able to access our emergency room and be taken care of within the hospital setting,” he said. The study controlled for whether health coverage was by private insurance, Medicare, or Medicaid.

Instead, the current analysis points to socioeconomic and environmental factors as a major source of the disparity in 30-day readmissions, Dr. Morris said.

“When patients are discharged from our healthcare systems, they still go back into environments where they don’t have the same resources as patients who live in higher-SDI neighborhoods,” she explained.

For example, “we tell them to eat low-sodium [foods], exercise, eat fresh fruits and vegetables, take their medicines, but the reality is that certain neighborhoods within the United States – and this is much more true for Blacks – make it very difficult to follow those self-care recommendations.”

The analysis included 16,147 Black patients and 14,483 White patients hospitalized with HF within the Emory Healthcare system at least once from 2010-2018, Dr. Morris reported. Compared with Whites, Blacks were younger (63.5 vs 69.1 years) and less likely to be 65 or older (48.9% vs. 66.5%); more likely to be women (53.5% vs. 42.2%), more likely to reside in deprived census tracts and to have diabetes, hypertension, or chronic kidney disease; and had higher comorbidity scores.

In all, 20.6% of Black and 13.5% of White patients were readmitted for HF within 30 days of discharge, for an unadjusted risk ratio of 1.52 (95% CI, 1.44-1.61).

The RR hardly budged, 1.45 (95% CI, 1.37-1.54, P < .001), after adjustment for age, sex, type of insurance, type of HF, vital signs and laboratory values, medical history (diabetes, hypertension, atrial fibrillation, coronary disease, chronic kidney disease, and chronic pulmonary disease), Charlson Comorbidity Index, discharging medical specialty, and hospital location.

The excess in 30-day HF readmissions for Black, compared with White patients climbed from the first to the third neighborhood SDI quartile, the disparity peaking at 8.2 absolute percentage points.

A major criticism of the Hospital Readmissions Reduction Program component of the Affordable Care Act, Dr. Morris said in a Q&A discussion after her presentation, is that it can hold hospitals “responsible for structural inequalities that exist beyond the health care system,” including neighborhood deprivation.

“But public policy makers have to realize that there are certain patients we take care of who don’t have the resources to carry out the therapeutic lifestyle changes that will allow them to live healthy.”

The HRRP’s 30-day HF readmission metric that steers reimbursement “is penalizing health care systems across the United States” with its premise that hospital performance can be measured by 30-day HF readmission rates, Dr. Morris said in an interview.

“The reality is that some of these patients are going to a postdischarge environment that is inherently high risk, and that many of them are going to come back to us within 30 days,” she said. “We would like to make sure that we don’t put excess penalties on health care systems that take care of disproportionate numbers of African Americans in neighborhoods that have fewer resources.”

Dr. Morris and Dr. Ferdinand have disclosed no relevant financial relationships. Dr. Mehra discloses consulting or serving on an advisory board for Abbott, Medtronic, Janssen, Leviticus, NupulseCV, FineHeart, Portola, Bayer, the Baim Institute for Clinical Research, and Mesoblast.

A version of this article originally appeared on Medscape.com.

Patients receiving even top-notch hospital care for heart failure (HF) are, once discharged to home, at higher short-term risk of another HF hospitalization if home is in a socioeconomically deprived neighborhood. That helps explain why Blacks in the United States have a much higher 30-day HF readmission risk than Whites, a disparity that only worsens with the level of neighborhood deprivation, a new analysis suggests.

Some systemic and entrenched socioeconomic inequities that health care providers have little sway over, and which disproportionately affect Black individuals, are independent and robust predictors of worsened HF outcomes, Alanna A. Morris, MD, MSc, Emory University, Atlanta, said during her presentation at the virtual annual scientific meeting of the Heart Failure Society of America.

In a retrospective cohort study, Blacks had a 45% higher risk of 30-day readmission than Whites (P < .001) independent of cardiovascular risk factors, clinical history, comorbidities, type and location of hospital, and type of third-party payer coverage. The analysis included more than 30,000 patients with at least one HF hospitalization at centers in a major metropolitan health system.

The racial disparity widened with worsening socioeconomic deprivation of patients’ residential neighborhoods, that is, with rising quartiles of neighborhood scores on the Social Deprivation Index (SDI).

The SDI, based on U.S. census data, incorporates seven socioeconomic criteria, including household income, education level, employment, and prevalence of rented housing and households that are without a car, single parent, or overcrowded.

There was a 4–percentage point gap in adjusted 30-day readmission rate between Blacks and Whites in the lowest quartile that widened to more than 8 points by the third quartile; the disparity in both the second and fourth quartiles was the same, at about 5.5 percentage points.

A remaining question, Dr. Morris said in an interview, is why the outcomes disparity between Blacks and Whites peaks in the third SDI quartile but drops a bit in the fourth quartile representing the most severe neighborhood deprivation.

“Our hypothesis is that when you look at patients who are the poorest, who live in the most deprived neighborhoods, race may be less of a factor,” she said. Socioeconomic deprivation may have similar consequences for everyone “regardless of race, ethnicity, gender, or other demographic characteristics if you live in a neighborhood that’s highly deprived.”

Based on the current study, “it does appear that increased heart failure incident rates are related to living in deprived neighborhoods, and it raises important clinical and public health concerns that must be addressed,” Keith C. Ferdinand, MD, Tulane University, New Orleans, said as invited discussant after the presentation from Dr. Morris.

“These findings could serve as an aid to policy makers, going forward, in terms of allocating resources for primary health care,” he said. “And it’s important looking at these data and other [data] that we target heart failure patients who reside in deprived neighborhoods before, during, and [after] hospitalization.”

Dr. Morris agreed that policy makers are in a better position to attack the racial disparity in HF readmission rates identified in the study. “This is not a problem that can be fixed within the health care system.”

If the reported interpretation is correct, it could add a twist to the public health care debate in the United States, observed session moderator Mandeep R. Mehra, MD, Brigham and Woman’s Hospital in Boston.

That debate, he noted, has often focused on insurability, access to coverage, and the merits or shortcomings of a single-payer system. Yet the study suggests outcomes disparities stemming from neighborhood deprivation will not be corrected by improved access to health insurance, a conclusion he finds “startling,” Dr. Mehra said in an interview.

Some proposed explanations for the disparities by race blame unequal access to health care and or variable health insurance coverage, Dr. Morris observed in an interview. But “that may not fully explain the increased risk that we see.”

Black patients followed at Emory University’s advanced HF clinic still have a higher risk of rehospitalization than Whites. “These are patients who have insurance, who are followed by advanced heart failure providers, who are on equal amounts of guideline-recommended medical therapy – and you still see about a 50% higher risk of rehospitalization,” Dr. Morris said, citing data that isn’t part of the current analysis.

“We can say that these patients are certainly able to access care, because they are able to access our emergency room and be taken care of within the hospital setting,” he said. The study controlled for whether health coverage was by private insurance, Medicare, or Medicaid.

Instead, the current analysis points to socioeconomic and environmental factors as a major source of the disparity in 30-day readmissions, Dr. Morris said.

“When patients are discharged from our healthcare systems, they still go back into environments where they don’t have the same resources as patients who live in higher-SDI neighborhoods,” she explained.

For example, “we tell them to eat low-sodium [foods], exercise, eat fresh fruits and vegetables, take their medicines, but the reality is that certain neighborhoods within the United States – and this is much more true for Blacks – make it very difficult to follow those self-care recommendations.”

The analysis included 16,147 Black patients and 14,483 White patients hospitalized with HF within the Emory Healthcare system at least once from 2010-2018, Dr. Morris reported. Compared with Whites, Blacks were younger (63.5 vs 69.1 years) and less likely to be 65 or older (48.9% vs. 66.5%); more likely to be women (53.5% vs. 42.2%), more likely to reside in deprived census tracts and to have diabetes, hypertension, or chronic kidney disease; and had higher comorbidity scores.

In all, 20.6% of Black and 13.5% of White patients were readmitted for HF within 30 days of discharge, for an unadjusted risk ratio of 1.52 (95% CI, 1.44-1.61).

The RR hardly budged, 1.45 (95% CI, 1.37-1.54, P < .001), after adjustment for age, sex, type of insurance, type of HF, vital signs and laboratory values, medical history (diabetes, hypertension, atrial fibrillation, coronary disease, chronic kidney disease, and chronic pulmonary disease), Charlson Comorbidity Index, discharging medical specialty, and hospital location.

The excess in 30-day HF readmissions for Black, compared with White patients climbed from the first to the third neighborhood SDI quartile, the disparity peaking at 8.2 absolute percentage points.

A major criticism of the Hospital Readmissions Reduction Program component of the Affordable Care Act, Dr. Morris said in a Q&A discussion after her presentation, is that it can hold hospitals “responsible for structural inequalities that exist beyond the health care system,” including neighborhood deprivation.

“But public policy makers have to realize that there are certain patients we take care of who don’t have the resources to carry out the therapeutic lifestyle changes that will allow them to live healthy.”

The HRRP’s 30-day HF readmission metric that steers reimbursement “is penalizing health care systems across the United States” with its premise that hospital performance can be measured by 30-day HF readmission rates, Dr. Morris said in an interview.

“The reality is that some of these patients are going to a postdischarge environment that is inherently high risk, and that many of them are going to come back to us within 30 days,” she said. “We would like to make sure that we don’t put excess penalties on health care systems that take care of disproportionate numbers of African Americans in neighborhoods that have fewer resources.”

Dr. Morris and Dr. Ferdinand have disclosed no relevant financial relationships. Dr. Mehra discloses consulting or serving on an advisory board for Abbott, Medtronic, Janssen, Leviticus, NupulseCV, FineHeart, Portola, Bayer, the Baim Institute for Clinical Research, and Mesoblast.

A version of this article originally appeared on Medscape.com.

Patients receiving even top-notch hospital care for heart failure (HF) are, once discharged to home, at higher short-term risk of another HF hospitalization if home is in a socioeconomically deprived neighborhood. That helps explain why Blacks in the United States have a much higher 30-day HF readmission risk than Whites, a disparity that only worsens with the level of neighborhood deprivation, a new analysis suggests.

Some systemic and entrenched socioeconomic inequities that health care providers have little sway over, and which disproportionately affect Black individuals, are independent and robust predictors of worsened HF outcomes, Alanna A. Morris, MD, MSc, Emory University, Atlanta, said during her presentation at the virtual annual scientific meeting of the Heart Failure Society of America.

In a retrospective cohort study, Blacks had a 45% higher risk of 30-day readmission than Whites (P < .001) independent of cardiovascular risk factors, clinical history, comorbidities, type and location of hospital, and type of third-party payer coverage. The analysis included more than 30,000 patients with at least one HF hospitalization at centers in a major metropolitan health system.

The racial disparity widened with worsening socioeconomic deprivation of patients’ residential neighborhoods, that is, with rising quartiles of neighborhood scores on the Social Deprivation Index (SDI).

The SDI, based on U.S. census data, incorporates seven socioeconomic criteria, including household income, education level, employment, and prevalence of rented housing and households that are without a car, single parent, or overcrowded.

There was a 4–percentage point gap in adjusted 30-day readmission rate between Blacks and Whites in the lowest quartile that widened to more than 8 points by the third quartile; the disparity in both the second and fourth quartiles was the same, at about 5.5 percentage points.

A remaining question, Dr. Morris said in an interview, is why the outcomes disparity between Blacks and Whites peaks in the third SDI quartile but drops a bit in the fourth quartile representing the most severe neighborhood deprivation.

“Our hypothesis is that when you look at patients who are the poorest, who live in the most deprived neighborhoods, race may be less of a factor,” she said. Socioeconomic deprivation may have similar consequences for everyone “regardless of race, ethnicity, gender, or other demographic characteristics if you live in a neighborhood that’s highly deprived.”

Based on the current study, “it does appear that increased heart failure incident rates are related to living in deprived neighborhoods, and it raises important clinical and public health concerns that must be addressed,” Keith C. Ferdinand, MD, Tulane University, New Orleans, said as invited discussant after the presentation from Dr. Morris.

“These findings could serve as an aid to policy makers, going forward, in terms of allocating resources for primary health care,” he said. “And it’s important looking at these data and other [data] that we target heart failure patients who reside in deprived neighborhoods before, during, and [after] hospitalization.”

Dr. Morris agreed that policy makers are in a better position to attack the racial disparity in HF readmission rates identified in the study. “This is not a problem that can be fixed within the health care system.”

If the reported interpretation is correct, it could add a twist to the public health care debate in the United States, observed session moderator Mandeep R. Mehra, MD, Brigham and Woman’s Hospital in Boston.

That debate, he noted, has often focused on insurability, access to coverage, and the merits or shortcomings of a single-payer system. Yet the study suggests outcomes disparities stemming from neighborhood deprivation will not be corrected by improved access to health insurance, a conclusion he finds “startling,” Dr. Mehra said in an interview.

Some proposed explanations for the disparities by race blame unequal access to health care and or variable health insurance coverage, Dr. Morris observed in an interview. But “that may not fully explain the increased risk that we see.”

Black patients followed at Emory University’s advanced HF clinic still have a higher risk of rehospitalization than Whites. “These are patients who have insurance, who are followed by advanced heart failure providers, who are on equal amounts of guideline-recommended medical therapy – and you still see about a 50% higher risk of rehospitalization,” Dr. Morris said, citing data that isn’t part of the current analysis.

“We can say that these patients are certainly able to access care, because they are able to access our emergency room and be taken care of within the hospital setting,” he said. The study controlled for whether health coverage was by private insurance, Medicare, or Medicaid.

Instead, the current analysis points to socioeconomic and environmental factors as a major source of the disparity in 30-day readmissions, Dr. Morris said.

“When patients are discharged from our healthcare systems, they still go back into environments where they don’t have the same resources as patients who live in higher-SDI neighborhoods,” she explained.

For example, “we tell them to eat low-sodium [foods], exercise, eat fresh fruits and vegetables, take their medicines, but the reality is that certain neighborhoods within the United States – and this is much more true for Blacks – make it very difficult to follow those self-care recommendations.”

The analysis included 16,147 Black patients and 14,483 White patients hospitalized with HF within the Emory Healthcare system at least once from 2010-2018, Dr. Morris reported. Compared with Whites, Blacks were younger (63.5 vs 69.1 years) and less likely to be 65 or older (48.9% vs. 66.5%); more likely to be women (53.5% vs. 42.2%), more likely to reside in deprived census tracts and to have diabetes, hypertension, or chronic kidney disease; and had higher comorbidity scores.

In all, 20.6% of Black and 13.5% of White patients were readmitted for HF within 30 days of discharge, for an unadjusted risk ratio of 1.52 (95% CI, 1.44-1.61).

The RR hardly budged, 1.45 (95% CI, 1.37-1.54, P < .001), after adjustment for age, sex, type of insurance, type of HF, vital signs and laboratory values, medical history (diabetes, hypertension, atrial fibrillation, coronary disease, chronic kidney disease, and chronic pulmonary disease), Charlson Comorbidity Index, discharging medical specialty, and hospital location.

The excess in 30-day HF readmissions for Black, compared with White patients climbed from the first to the third neighborhood SDI quartile, the disparity peaking at 8.2 absolute percentage points.

A major criticism of the Hospital Readmissions Reduction Program component of the Affordable Care Act, Dr. Morris said in a Q&A discussion after her presentation, is that it can hold hospitals “responsible for structural inequalities that exist beyond the health care system,” including neighborhood deprivation.

“But public policy makers have to realize that there are certain patients we take care of who don’t have the resources to carry out the therapeutic lifestyle changes that will allow them to live healthy.”

The HRRP’s 30-day HF readmission metric that steers reimbursement “is penalizing health care systems across the United States” with its premise that hospital performance can be measured by 30-day HF readmission rates, Dr. Morris said in an interview.

“The reality is that some of these patients are going to a postdischarge environment that is inherently high risk, and that many of them are going to come back to us within 30 days,” she said. “We would like to make sure that we don’t put excess penalties on health care systems that take care of disproportionate numbers of African Americans in neighborhoods that have fewer resources.”

Dr. Morris and Dr. Ferdinand have disclosed no relevant financial relationships. Dr. Mehra discloses consulting or serving on an advisory board for Abbott, Medtronic, Janssen, Leviticus, NupulseCV, FineHeart, Portola, Bayer, the Baim Institute for Clinical Research, and Mesoblast.

A version of this article originally appeared on Medscape.com.

Inhaled corticosteroids (ICS) do not protect patients with chronic respiratory conditions against COVID-19-related death, a study of almost 1 million individuals in the United Kingdom has shown.

Patients with chronic obstructive pulmonary disease or asthma who used ICS on a regular basis were more likely to die from COVID-19 than COPD or asthma patients who were prescribed non-ICS therapies, reported co-lead author Anna Schultze, PhD, of London School of Hygiene & Tropical Medicine and colleagues.

Of note, the increased risk of death among ICS users likely stemmed from greater severity of preexisting chronic respiratory conditions, instead of directly from ICS usage, which has little apparent impact on COVID-19 mortality, the investigators wrote in Lancet Respiratory Medicine.

These findings conflict with a hypothesis proposed early in the pandemic: that ICS may protect individuals from SARS-CoV-2 infection and poor outcomes with COVID-19.

According to Megan Conroy, MD, of the department of internal medicine at the Ohio State University Wexner Medical Center, Columbus, this hypothesis was based on some unexpected epidemiological findings.

“In general, we tend to think people with underlying lung disease – like COPD or asthma – to be at higher risk for severe forms of lower respiratory tract infections,” Dr. Conroy said. “Somewhat surprisingly, early data in the pandemic showed patients with COPD and asthma [were] underrepresented [among patients with COVID] when compared to the prevalence of these diseases in the population.”

This raised the possibility of an incidental protective effect from regular ICS therapy, which “had some strong theoretic pathophysiologic basis,” Dr. Conroy said, referring to research that demonstrated ICS-mediated downregulation of SARS-CoV-2 entry receptors ACE2 and TMPRSS2.

Dr. Schultze and colleagues noted that investigators for two ongoing randomized controlled trials (NCT04331054, NCT04330586) are studying ICS as an intervention for COVID-19; but neither trial includes individuals already taking ICS for chronic respiratory disease.

The present observational study therefore aimed to assess mortality risk within this population. Data were drawn from electronic health records and a U.K. national mortality database, with follow-up ranging from March 1 to May 6, 2020. Eligibility required a relevant prescription within 4 months of first follow-up. In the COPD group, patients were prescribed a long-acting beta agonist plus a long-acting muscarinic antagonist (LABA–LAMA), LABA alone, LABA plus ICS, LABA–LAMA plus ICS, or ICS alone (if prescribed LABA within 4 months).

In the asthma group, patients received low/medium-dose ICS, high-dose ICS, or a short-acting beta agonist (SABA) alone. Patients with COPD were at least 35 years of age, while those with asthma were 18 years or older. Hazard ratios were adjusted for a variety of covariates, including respiratory disease–exacerbation history, age, sex, body mass index, hypertension, diabetes, and others.

These eligibility criteria returned 148,557 patients with COPD and 818,490 with asthma.

Patients with COPD who were prescribed ICS plus LABA-LAMA or ICS plus LABA had an increased risk of COVID-19-related death, compared with those who did not receive ICS (adjusted hazard ratio, 1.39; 95% confidence interval, 1.10-1.76). Separate analyses of patients who received a triple combination (LABA–LAMA plus ICS) versus those who took a dual combination (LABA plus ICS) showed that triple-combination therapy was significantly associated with increased COVID-19-related mortality (aHR, 1.43; 95% CI, 1.12-1.83), while dual-combination therapy was less so (aHR, 1.29; 95% CI, 0.96-1.74). Non–COVID-19–related mortality was significantly increased for all COPD patients who were prescribed ICS, with or without adjustment for covariates.

Asthma patients prescribed high-dose ICS instead of SABA alone had a slightly greater risk of COVID-19–related death, based on an adjusted hazard ratio of 1.55 (95% CI, 1.10-2.18). Those with asthma who received low/medium–dose ICS demonstrated a slight trend toward increased mortality risk, but this was not significant (aHR, 1.14; 95% CI, 0.85-1.54). ICS usage in the asthma group was not linked with a significant increase in non–COVID-19–related death.

“In summary, we found no evidence of a beneficial effect of regular ICS use among people with COPD and asthma on COVID-19–related mortality,” the investigators concluded.

In agreement with the investigators, Dr. Conroy said that the increased mortality rate among ICS users should not be misconstrued as a medication-related risk.

“While the study found that those with COPD or asthma taking ICS and high-dose ICS were at an increased risk of death, this could easily be explained by the likelihood that those are the patients who are more likely to have more severe underlying lung disease,” Dr. Conroy said. “While this observational study did attempt to control for exacerbation history, the ability to do so by electronic health records data is certainly imperfect.”

With this in mind, patients with chronic respiratory disease should be encouraged to adhere to their usual treatment regimen, Dr. Conroy added.

“There isn’t evidence to increase or decrease medications just because of the pandemic,” she said. “A patient with asthma or COPD should continue to take the medications that are needed to achieve good control of their lung disease.”

The study was funded by the U.K. Medical Research Council. The investigators reported additional relationships with the Wellcome Trust, the Good Thinking Foundation, the Laura and John Arnold Foundation, and others. Dr. Conroy reported no conflicts of interest.

SOURCE: Schultze A et al. Lancet Respir Med. 2020 Sep 24. doi: 10.1016/ S2213-2600(20)30415-X.

Inhaled corticosteroids (ICS) do not protect patients with chronic respiratory conditions against COVID-19-related death, a study of almost 1 million individuals in the United Kingdom has shown.

Patients with chronic obstructive pulmonary disease or asthma who used ICS on a regular basis were more likely to die from COVID-19 than COPD or asthma patients who were prescribed non-ICS therapies, reported co-lead author Anna Schultze, PhD, of London School of Hygiene & Tropical Medicine and colleagues.

Of note, the increased risk of death among ICS users likely stemmed from greater severity of preexisting chronic respiratory conditions, instead of directly from ICS usage, which has little apparent impact on COVID-19 mortality, the investigators wrote in Lancet Respiratory Medicine.

These findings conflict with a hypothesis proposed early in the pandemic: that ICS may protect individuals from SARS-CoV-2 infection and poor outcomes with COVID-19.

According to Megan Conroy, MD, of the department of internal medicine at the Ohio State University Wexner Medical Center, Columbus, this hypothesis was based on some unexpected epidemiological findings.

“In general, we tend to think people with underlying lung disease – like COPD or asthma – to be at higher risk for severe forms of lower respiratory tract infections,” Dr. Conroy said. “Somewhat surprisingly, early data in the pandemic showed patients with COPD and asthma [were] underrepresented [among patients with COVID] when compared to the prevalence of these diseases in the population.”

This raised the possibility of an incidental protective effect from regular ICS therapy, which “had some strong theoretic pathophysiologic basis,” Dr. Conroy said, referring to research that demonstrated ICS-mediated downregulation of SARS-CoV-2 entry receptors ACE2 and TMPRSS2.

Dr. Schultze and colleagues noted that investigators for two ongoing randomized controlled trials (NCT04331054, NCT04330586) are studying ICS as an intervention for COVID-19; but neither trial includes individuals already taking ICS for chronic respiratory disease.

The present observational study therefore aimed to assess mortality risk within this population. Data were drawn from electronic health records and a U.K. national mortality database, with follow-up ranging from March 1 to May 6, 2020. Eligibility required a relevant prescription within 4 months of first follow-up. In the COPD group, patients were prescribed a long-acting beta agonist plus a long-acting muscarinic antagonist (LABA–LAMA), LABA alone, LABA plus ICS, LABA–LAMA plus ICS, or ICS alone (if prescribed LABA within 4 months).

In the asthma group, patients received low/medium-dose ICS, high-dose ICS, or a short-acting beta agonist (SABA) alone. Patients with COPD were at least 35 years of age, while those with asthma were 18 years or older. Hazard ratios were adjusted for a variety of covariates, including respiratory disease–exacerbation history, age, sex, body mass index, hypertension, diabetes, and others.

These eligibility criteria returned 148,557 patients with COPD and 818,490 with asthma.

Patients with COPD who were prescribed ICS plus LABA-LAMA or ICS plus LABA had an increased risk of COVID-19-related death, compared with those who did not receive ICS (adjusted hazard ratio, 1.39; 95% confidence interval, 1.10-1.76). Separate analyses of patients who received a triple combination (LABA–LAMA plus ICS) versus those who took a dual combination (LABA plus ICS) showed that triple-combination therapy was significantly associated with increased COVID-19-related mortality (aHR, 1.43; 95% CI, 1.12-1.83), while dual-combination therapy was less so (aHR, 1.29; 95% CI, 0.96-1.74). Non–COVID-19–related mortality was significantly increased for all COPD patients who were prescribed ICS, with or without adjustment for covariates.

Asthma patients prescribed high-dose ICS instead of SABA alone had a slightly greater risk of COVID-19–related death, based on an adjusted hazard ratio of 1.55 (95% CI, 1.10-2.18). Those with asthma who received low/medium–dose ICS demonstrated a slight trend toward increased mortality risk, but this was not significant (aHR, 1.14; 95% CI, 0.85-1.54). ICS usage in the asthma group was not linked with a significant increase in non–COVID-19–related death.

“In summary, we found no evidence of a beneficial effect of regular ICS use among people with COPD and asthma on COVID-19–related mortality,” the investigators concluded.

In agreement with the investigators, Dr. Conroy said that the increased mortality rate among ICS users should not be misconstrued as a medication-related risk.

“While the study found that those with COPD or asthma taking ICS and high-dose ICS were at an increased risk of death, this could easily be explained by the likelihood that those are the patients who are more likely to have more severe underlying lung disease,” Dr. Conroy said. “While this observational study did attempt to control for exacerbation history, the ability to do so by electronic health records data is certainly imperfect.”

With this in mind, patients with chronic respiratory disease should be encouraged to adhere to their usual treatment regimen, Dr. Conroy added.

“There isn’t evidence to increase or decrease medications just because of the pandemic,” she said. “A patient with asthma or COPD should continue to take the medications that are needed to achieve good control of their lung disease.”

The study was funded by the U.K. Medical Research Council. The investigators reported additional relationships with the Wellcome Trust, the Good Thinking Foundation, the Laura and John Arnold Foundation, and others. Dr. Conroy reported no conflicts of interest.

SOURCE: Schultze A et al. Lancet Respir Med. 2020 Sep 24. doi: 10.1016/ S2213-2600(20)30415-X.

Inhaled corticosteroids (ICS) do not protect patients with chronic respiratory conditions against COVID-19-related death, a study of almost 1 million individuals in the United Kingdom has shown.

Patients with chronic obstructive pulmonary disease or asthma who used ICS on a regular basis were more likely to die from COVID-19 than COPD or asthma patients who were prescribed non-ICS therapies, reported co-lead author Anna Schultze, PhD, of London School of Hygiene & Tropical Medicine and colleagues.

Of note, the increased risk of death among ICS users likely stemmed from greater severity of preexisting chronic respiratory conditions, instead of directly from ICS usage, which has little apparent impact on COVID-19 mortality, the investigators wrote in Lancet Respiratory Medicine.

These findings conflict with a hypothesis proposed early in the pandemic: that ICS may protect individuals from SARS-CoV-2 infection and poor outcomes with COVID-19.

According to Megan Conroy, MD, of the department of internal medicine at the Ohio State University Wexner Medical Center, Columbus, this hypothesis was based on some unexpected epidemiological findings.

“In general, we tend to think people with underlying lung disease – like COPD or asthma – to be at higher risk for severe forms of lower respiratory tract infections,” Dr. Conroy said. “Somewhat surprisingly, early data in the pandemic showed patients with COPD and asthma [were] underrepresented [among patients with COVID] when compared to the prevalence of these diseases in the population.”

This raised the possibility of an incidental protective effect from regular ICS therapy, which “had some strong theoretic pathophysiologic basis,” Dr. Conroy said, referring to research that demonstrated ICS-mediated downregulation of SARS-CoV-2 entry receptors ACE2 and TMPRSS2.

Dr. Schultze and colleagues noted that investigators for two ongoing randomized controlled trials (NCT04331054, NCT04330586) are studying ICS as an intervention for COVID-19; but neither trial includes individuals already taking ICS for chronic respiratory disease.

The present observational study therefore aimed to assess mortality risk within this population. Data were drawn from electronic health records and a U.K. national mortality database, with follow-up ranging from March 1 to May 6, 2020. Eligibility required a relevant prescription within 4 months of first follow-up. In the COPD group, patients were prescribed a long-acting beta agonist plus a long-acting muscarinic antagonist (LABA–LAMA), LABA alone, LABA plus ICS, LABA–LAMA plus ICS, or ICS alone (if prescribed LABA within 4 months).

In the asthma group, patients received low/medium-dose ICS, high-dose ICS, or a short-acting beta agonist (SABA) alone. Patients with COPD were at least 35 years of age, while those with asthma were 18 years or older. Hazard ratios were adjusted for a variety of covariates, including respiratory disease–exacerbation history, age, sex, body mass index, hypertension, diabetes, and others.

These eligibility criteria returned 148,557 patients with COPD and 818,490 with asthma.

Patients with COPD who were prescribed ICS plus LABA-LAMA or ICS plus LABA had an increased risk of COVID-19-related death, compared with those who did not receive ICS (adjusted hazard ratio, 1.39; 95% confidence interval, 1.10-1.76). Separate analyses of patients who received a triple combination (LABA–LAMA plus ICS) versus those who took a dual combination (LABA plus ICS) showed that triple-combination therapy was significantly associated with increased COVID-19-related mortality (aHR, 1.43; 95% CI, 1.12-1.83), while dual-combination therapy was less so (aHR, 1.29; 95% CI, 0.96-1.74). Non–COVID-19–related mortality was significantly increased for all COPD patients who were prescribed ICS, with or without adjustment for covariates.

Asthma patients prescribed high-dose ICS instead of SABA alone had a slightly greater risk of COVID-19–related death, based on an adjusted hazard ratio of 1.55 (95% CI, 1.10-2.18). Those with asthma who received low/medium–dose ICS demonstrated a slight trend toward increased mortality risk, but this was not significant (aHR, 1.14; 95% CI, 0.85-1.54). ICS usage in the asthma group was not linked with a significant increase in non–COVID-19–related death.

“In summary, we found no evidence of a beneficial effect of regular ICS use among people with COPD and asthma on COVID-19–related mortality,” the investigators concluded.

In agreement with the investigators, Dr. Conroy said that the increased mortality rate among ICS users should not be misconstrued as a medication-related risk.

“While the study found that those with COPD or asthma taking ICS and high-dose ICS were at an increased risk of death, this could easily be explained by the likelihood that those are the patients who are more likely to have more severe underlying lung disease,” Dr. Conroy said. “While this observational study did attempt to control for exacerbation history, the ability to do so by electronic health records data is certainly imperfect.”

With this in mind, patients with chronic respiratory disease should be encouraged to adhere to their usual treatment regimen, Dr. Conroy added.

“There isn’t evidence to increase or decrease medications just because of the pandemic,” she said. “A patient with asthma or COPD should continue to take the medications that are needed to achieve good control of their lung disease.”

The study was funded by the U.K. Medical Research Council. The investigators reported additional relationships with the Wellcome Trust, the Good Thinking Foundation, the Laura and John Arnold Foundation, and others. Dr. Conroy reported no conflicts of interest.

SOURCE: Schultze A et al. Lancet Respir Med. 2020 Sep 24. doi: 10.1016/ S2213-2600(20)30415-X.

Roughly half of American adults have hypertension, and about 71% of these cases are uncontrolled, according to data from the American Heart Association.

If left uncontrolled, hypertension can increase risk for conditions including heart disease, stroke, kidney disease, pregnancy complications, and cognitive decline, surgeon general Vice Adm. Jerome M. Adams, MD, said in a teleconference on Oct. 7. Hispanic and Black individuals are disproportionately affected, he added.

“We cannot wait to deal with this epidemic of uncontrolled high blood pressure,” even in the midst of the ongoing COVID-19 pandemic, said Dr. Adams. “We know what works” to help control hypertension, he added, citing his own use of a blood pressure monitoring device at home.

The Department of Health & Human Services has issued a Call to Action to Control Hypertension based on the latest science and research.

Dr. Adams outlined three goals to improve hypertension control, starting with making it a national priority. The Call to Action supports increasing awareness of the health risks associated with hypertension, recognizing the economic impact, overcoming barriers to controlling hypertension, and promoting health equity.

“In 2020, disparities in the burden of disease – especially among minority populations – have been recognized during the COVID-19 pandemic. A growing body of evidence has shown that people with underlying health conditions, including cardiovascular disease, are at increased risk of worse outcomes related to COVID-19 infection,” according to the Call to Action.

A second goal is to build and sustain communities that support individuals in taking responsibility for their health and blood pressure control, Dr. Adams said. He cited the need to create places for safe physical activity, access to healthy food, and opportunities to connect to resources to support lifestyle changes.

Finally, clinicians should continue to use standardized treatment approaches and promote team-based care to maximize outcomes for patients, Dr. Adams said.

Success starts with making hypertension control a priority across the leadership team, regardless of the size, location, or demographic population at a health care setting, he said. Dr. Adams cited the Million Hearts 2022 program, an ongoing initiative to prevent 1 million heart attacks in the United States over 5 years, as a way that HHS is recognizing and rewarding success stories in hypertension control from across the country.

Empowering patients and equipping them to take charge of their hypertension essential to reducing the epidemic of high blood pressure, especially during the ongoing pandemic, Dr. Adams said. His message to clinicians to extend to patients is that it is safe to visit their doctors. Hospitals have worked to create a safe environment, however, patients can and should monitor their blood pressure regularly at home, using a self-measured blood pressure monitoring (SMBP) device, which may be covered by some insurers.

“I would encourage people to know their numbers,” and that 130/80 mm Hg is considered high and a risk factor for poor health outcomes, Dr. Adams said. Clinicians also should continue to support patients in lifestyle changes such as healthy eating and exercising regularly to help control high blood pressure.

The AHA expressed support for the surgeon general’s Call to Action. “Today’s call to action references updated hypertension guidelines the AHA and the American College of Cardiology issued in 2017 that apply the latest science to help clinicians work with patients to control their blood pressure,” the AHA said in a statement. The AHA also called on the Centers for Medicare & Medicaid Services and other insurance providers “to include coverage of SMBP devices for treatment and management of hypertension.”

The Call to Action was accompanied by a Viewpoint from Dr. Adams and Janet S. Wright, MD, also of the HHS, published in JAMA. Dr. Adams and Dr. Wright emphasized that the timing of the Call to Action recognizes that many of the same social factors that support or impede successful high blood pressure control are factors in worse outcomes from COVID-19 infections as well.

“When coupled with widespread implementation of best practices in clinical settings and empowering individuals to actively manage their blood pressure, acknowledging and addressing a community’s social conditions may generate sustained improvements in control of both hypertension and COVID-19,” they said.

Read and download the full Call to Action here, and read the Executive Summary at hhs.gov.

Roughly half of American adults have hypertension, and about 71% of these cases are uncontrolled, according to data from the American Heart Association.

If left uncontrolled, hypertension can increase risk for conditions including heart disease, stroke, kidney disease, pregnancy complications, and cognitive decline, surgeon general Vice Adm. Jerome M. Adams, MD, said in a teleconference on Oct. 7. Hispanic and Black individuals are disproportionately affected, he added.

“We cannot wait to deal with this epidemic of uncontrolled high blood pressure,” even in the midst of the ongoing COVID-19 pandemic, said Dr. Adams. “We know what works” to help control hypertension, he added, citing his own use of a blood pressure monitoring device at home.

The Department of Health & Human Services has issued a Call to Action to Control Hypertension based on the latest science and research.

Dr. Adams outlined three goals to improve hypertension control, starting with making it a national priority. The Call to Action supports increasing awareness of the health risks associated with hypertension, recognizing the economic impact, overcoming barriers to controlling hypertension, and promoting health equity.

“In 2020, disparities in the burden of disease – especially among minority populations – have been recognized during the COVID-19 pandemic. A growing body of evidence has shown that people with underlying health conditions, including cardiovascular disease, are at increased risk of worse outcomes related to COVID-19 infection,” according to the Call to Action.

A second goal is to build and sustain communities that support individuals in taking responsibility for their health and blood pressure control, Dr. Adams said. He cited the need to create places for safe physical activity, access to healthy food, and opportunities to connect to resources to support lifestyle changes.

Finally, clinicians should continue to use standardized treatment approaches and promote team-based care to maximize outcomes for patients, Dr. Adams said.

Success starts with making hypertension control a priority across the leadership team, regardless of the size, location, or demographic population at a health care setting, he said. Dr. Adams cited the Million Hearts 2022 program, an ongoing initiative to prevent 1 million heart attacks in the United States over 5 years, as a way that HHS is recognizing and rewarding success stories in hypertension control from across the country.

Empowering patients and equipping them to take charge of their hypertension essential to reducing the epidemic of high blood pressure, especially during the ongoing pandemic, Dr. Adams said. His message to clinicians to extend to patients is that it is safe to visit their doctors. Hospitals have worked to create a safe environment, however, patients can and should monitor their blood pressure regularly at home, using a self-measured blood pressure monitoring (SMBP) device, which may be covered by some insurers.

“I would encourage people to know their numbers,” and that 130/80 mm Hg is considered high and a risk factor for poor health outcomes, Dr. Adams said. Clinicians also should continue to support patients in lifestyle changes such as healthy eating and exercising regularly to help control high blood pressure.

The AHA expressed support for the surgeon general’s Call to Action. “Today’s call to action references updated hypertension guidelines the AHA and the American College of Cardiology issued in 2017 that apply the latest science to help clinicians work with patients to control their blood pressure,” the AHA said in a statement. The AHA also called on the Centers for Medicare & Medicaid Services and other insurance providers “to include coverage of SMBP devices for treatment and management of hypertension.”

The Call to Action was accompanied by a Viewpoint from Dr. Adams and Janet S. Wright, MD, also of the HHS, published in JAMA. Dr. Adams and Dr. Wright emphasized that the timing of the Call to Action recognizes that many of the same social factors that support or impede successful high blood pressure control are factors in worse outcomes from COVID-19 infections as well.

“When coupled with widespread implementation of best practices in clinical settings and empowering individuals to actively manage their blood pressure, acknowledging and addressing a community’s social conditions may generate sustained improvements in control of both hypertension and COVID-19,” they said.

Read and download the full Call to Action here, and read the Executive Summary at hhs.gov.

Roughly half of American adults have hypertension, and about 71% of these cases are uncontrolled, according to data from the American Heart Association.

If left uncontrolled, hypertension can increase risk for conditions including heart disease, stroke, kidney disease, pregnancy complications, and cognitive decline, surgeon general Vice Adm. Jerome M. Adams, MD, said in a teleconference on Oct. 7. Hispanic and Black individuals are disproportionately affected, he added.

“We cannot wait to deal with this epidemic of uncontrolled high blood pressure,” even in the midst of the ongoing COVID-19 pandemic, said Dr. Adams. “We know what works” to help control hypertension, he added, citing his own use of a blood pressure monitoring device at home.

The Department of Health & Human Services has issued a Call to Action to Control Hypertension based on the latest science and research.

Dr. Adams outlined three goals to improve hypertension control, starting with making it a national priority. The Call to Action supports increasing awareness of the health risks associated with hypertension, recognizing the economic impact, overcoming barriers to controlling hypertension, and promoting health equity.

“In 2020, disparities in the burden of disease – especially among minority populations – have been recognized during the COVID-19 pandemic. A growing body of evidence has shown that people with underlying health conditions, including cardiovascular disease, are at increased risk of worse outcomes related to COVID-19 infection,” according to the Call to Action.

A second goal is to build and sustain communities that support individuals in taking responsibility for their health and blood pressure control, Dr. Adams said. He cited the need to create places for safe physical activity, access to healthy food, and opportunities to connect to resources to support lifestyle changes.

Finally, clinicians should continue to use standardized treatment approaches and promote team-based care to maximize outcomes for patients, Dr. Adams said.

Success starts with making hypertension control a priority across the leadership team, regardless of the size, location, or demographic population at a health care setting, he said. Dr. Adams cited the Million Hearts 2022 program, an ongoing initiative to prevent 1 million heart attacks in the United States over 5 years, as a way that HHS is recognizing and rewarding success stories in hypertension control from across the country.

Empowering patients and equipping them to take charge of their hypertension essential to reducing the epidemic of high blood pressure, especially during the ongoing pandemic, Dr. Adams said. His message to clinicians to extend to patients is that it is safe to visit their doctors. Hospitals have worked to create a safe environment, however, patients can and should monitor their blood pressure regularly at home, using a self-measured blood pressure monitoring (SMBP) device, which may be covered by some insurers.

“I would encourage people to know their numbers,” and that 130/80 mm Hg is considered high and a risk factor for poor health outcomes, Dr. Adams said. Clinicians also should continue to support patients in lifestyle changes such as healthy eating and exercising regularly to help control high blood pressure.

The AHA expressed support for the surgeon general’s Call to Action. “Today’s call to action references updated hypertension guidelines the AHA and the American College of Cardiology issued in 2017 that apply the latest science to help clinicians work with patients to control their blood pressure,” the AHA said in a statement. The AHA also called on the Centers for Medicare & Medicaid Services and other insurance providers “to include coverage of SMBP devices for treatment and management of hypertension.”

The Call to Action was accompanied by a Viewpoint from Dr. Adams and Janet S. Wright, MD, also of the HHS, published in JAMA. Dr. Adams and Dr. Wright emphasized that the timing of the Call to Action recognizes that many of the same social factors that support or impede successful high blood pressure control are factors in worse outcomes from COVID-19 infections as well.

“When coupled with widespread implementation of best practices in clinical settings and empowering individuals to actively manage their blood pressure, acknowledging and addressing a community’s social conditions may generate sustained improvements in control of both hypertension and COVID-19,” they said.

Read and download the full Call to Action here, and read the Executive Summary at hhs.gov.

Coagulation in patients with cirrhosis is a complicated area of evolving research. Patients with cirrhosis were originally thought to be naturally anticoagulated due to the decreased production of clotting factors and platelets, combined with an increased international normalized ratio (INR).¹ New data have shown that patients with cirrhosis are at a concomitant risk of bleeding and thrombosis due to increased platelet aggregation, decreased fibrinolysis, and decreased production of natural anticoagulants such as protein C and antithrombin.¹ Traditionally, patients with cirrhosis needing anticoagulation therapy for comorbid conditions, such as nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE) were placed on warfarin therapy. Managing warfarin in patients with cirrhosis poses a challenge to clinicians due to the many food and drug interactions, narrow therapeutic index, and complications with maintaining a therapeutic INR.¹

Direct oral anticoagulants (DOACs) have several benefits over warfarin therapy, including convenience, decreased monitoring, decreased drug and dietary restrictions, and faster onset of action.² Conversely, DOACs undergo extensive hepatic metabolism giving rise to concerns about supratherapeutic drug levels and increased bleeding rates in patients with liver dysfunction.¹ Consequently, patients with cirrhosis were excluded from the pivotal trials establishing DOACs for NVAF and VTE treatment. Exclusion of these patients in major clinical trials alongside the challenges of managing warfarin warrant an evaluation of the efficacy and safety of DOACs in patients with cirrhosis.

Recent retrospective studies have examined the use of DOACs in patients with cirrhosis and found favorable results. A retrospective chart review by Intagliata and colleagues consisting of 39 patients with cirrhosis using either a DOAC or warfarin found similar rates of all-cause bleeding and major bleeding between the 2 groups.³ A retrospective cohort study by Hum and colleagues consisting of 45 patients with cirrhosis compared the use of DOACs with warfarin or low-molecular weight heparin (LMWH).⁴ Hum and colleagues found patients prescribed a DOAC had significantly fewer major bleeding events than did patients using warfarin or LMWH.⁴ The largest retrospective cohort study consisted of 233 patients with chronic liver disease and found no differences among all-cause bleeding and major bleeding rates between patients using DOACs compared with those of patients using warfarin.⁵

The purpose of this research is to evaluate the safety and efficacy of DOACs in veteran patients with cirrhosis compared with patients using warfarin.

Methods

A retrospective single-center chart review was conducted at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas, between October 31, 2014 and October 31, 2018. Patients included in the study were adults aged ≥ 18 years with a diagnosis of cirrhosis and prescribed any of the following oral anticoagulants: apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin. Patients prescribed apixaban, dabigatran, edoxaban, or rivaroxaban were collectively grouped into the DOAC group, while patients prescribed warfarin were classified as the standard of care comparator group.

A diagnosis of cirrhosis was confirmed using a combination of the codes from the ninth and tenth editions of the International Classification of Diseases (ICD) for cirrhosis, documentation of diagnostic confirmation by clinicians from the gastroenterology or hepatology services, and positive liver biopsy result. Liver function tests, liver ultrasound results, and FibroSure biomarker assays were used to aid in confirming the diagnosis of cirrhosis but were not considered definitive. Patients were excluded from the trial if they had indications for anticoagulation other than NVAF and VTE and/or were prescribed triple antithrombotic therapy (dual antiplatelet therapy plus an anticoagulant). Patients who switched anticoagulant therapy during the trial period (ie, switched from warfarin to a DOAC) were also excluded from the analysis.

Patient demographic characteristics that were collected included weight; body mass index (BMI); etiology of cirrhosis; Child-Turcotte-Pugh, Model for End-Stage Liver Disease (MELD), and CHA₂DS₂-VASc score; concomitant antiplatelet, nonsteroidal anti-inflammatory drug (NSAID), proton pump inhibitor (PPI), and histamine-2 receptor antagonist (H2RA) medications; presence of gastric and/or esophageal varices; active malignancies; albumin, total bilirubin, serum creatinine, INR, and platelet laboratory values; and indication and duration of anticoagulation therapy.

Two patient lists were used to identify patients for inclusion in the warfarin arm. The first patient list was generated using the US Department of Veterans Affairs (VA) Cirrhosis Tracker, which identified patients with an ICD-9/10 code for cirrhosis and an INR laboratory value. Patients generated from the VA Cirrhosis Tracker with an INR > 1.5 were screened for a warfarin prescription and then evaluated for full study inclusion. The second patient list was generated using the VA Advanced Liver Disease Dashboard which identified patients with ICD-9/10 codes for advanced liver disease and an active warfarin prescription. Patients with an active warfarin prescription were then evaluated for full study inclusion. A single patient list was generated to identify patients for inclusion in the DOAC arm. This patient list was generated using the VA DOAC dashboard, which identified patients with an active DOAC prescription and an ICD-9/10 code for cirrhosis. Patients with an ICD-9/10 code for cirrhosis and prescribed a DOAC were screened for full study inclusion. Patient data were collected from the MEDVAMC Computerized Patient Record System (CPRS) electronic health record (EHR). The research study was approved by the Baylor College of Medicine Institutional Review Board and the VA Office of Research and Development.

Outcomes

The primary endpoint for the study was all-cause bleeding. The secondary endpoints for the study were major bleeding and failed efficacy. Major bleeding was defined using the International Society on Thrombosis and Haemostasis (ISTH) 2005 definition: fatal bleeding, symptomatic bleeding in a critical organ area (ie, intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome), or bleeding causing a fall in hemoglobin level of > 2 g/dL or leading to the transfusion of ≥ 2 units of red cells.⁶ Failed efficacy was a combination endpoint that included development of VTE, stroke, myocardial infarction (MI), and/or death. A prespecified subgroup analysis was conducted at the end of the study period to analyze trends in the DOAC and warfarin groups with respect to all-cause bleeding. All-cause bleeding risk was stratified by weight, BMI, Child-Turcotte-Pugh score, MELD score, presence of gastric and/or esophageal varices, active malignancies, percentage of time within therapeutic INR range in the warfarin group, indications for anticoagulation, and antiplatelet, NSAID, PPI, and H2RA therapy.

Statistical Analysis

Data were analyzed using descriptive and inferential statistics. Continuous data were analyzed using the Student t test, and categorical data were analyzed using the Fisher exact test. Previous studies determined an all-cause bleeding rate of 10 to 17% for warfarin compared with 5% for DOACs.^7,8 To detect a 12% difference in the all-cause bleeding rate between DOACs and warfarin, 212 patients would be needed to achieve 80% power at an α level of 0.05.

Results

A total of 170 patients were screened, and after applying inclusion and exclusion criteria, 79 patients were enrolled in the study (Figure). The DOAC group included 42 patients, and the warfarin group included 37 patients. In the DOAC group, 69.1% (n = 29) of patients were taking apixaban, 21.4% (n = 9) rivaroxaban, and 9.5% (n = 4) dabigatran. There were no patients prescribed edoxaban during the study period.

Baseline characteristics were similar between the 2 groups except for Child-Turcotte-Pugh score, MELD score, mean INR, and number of days on anticoagulation therapy (Table 1). Most of the patients were male (98.7%), and the mean age was 71 years. The most common causes of cirrhosis were viral (29.1%), nonalcoholic fatty liver disease (NAFLD) (24.1%), multiple causes (22.8%), and alcohol (21.5%). Sixty-two patients (78.5%) had a NVAF indication for anticoagulation. The average CHA₂DS₂-VASc score was 3.7. Aspirin was prescribed in 51.9% (n = 41) of patients, and PPIs were prescribed in 48.1% (n = 38) of patients. At inclusion, esophageal varices were present in 13 patients and active malignancies were present in 6 patients.

Safety Outcome

The primary outcome comparing all-cause bleeding rates between patients on DOACs compared with warfarin are listed in Table 2. With respect to the primary outcome, 7 (16.7%) patients on DOACs experienced a bleeding event compared with 8 (21.6%) patients on warfarin (P = .77). No statistically significant differences were detected between the DOAC and warfarin groups with respect to all-cause bleeding. Seven bleeding events occurred in the DOAC group; 1 met the qualification for major bleeding with a suspected gastrointestinal (GI) bleed.⁶ The other 6 bleeding episodes in the DOAC group consisted of hematoma, epistaxis, hematuria, and hematochezia. Eight bleeding events occurred in the warfarin group; 2 met the qualification for major bleeding with an intracranial hemorrhage and upper GI bleed.⁶ The other 6 bleeding episodes in the warfarin group consisted of epistaxis, bleeding gums, hematuria, and hematochezia. There were no statistically significant differences between the rates of major bleeding and nonmajor bleeding between the DOAC and warfarin groups.

Efficacy Outcomes

There were 3 events in the DOAC group and 3 events in the warfarin group (P = .99). In the DOAC group, 2 patients experienced a pulmonary embolism, and 1 patient experienced a MI. In the warfarin group, 3 patients died (end-stage heart failure, unknown cause due to death at an outside hospital, and sepsis/organ failure). There were no statistically significant differences between the composite endpoint of failed efficacy or the individual endpoints of VTE, stroke, MI, and death.

Subgroup Analysis

A prespecified subgroup analysis was conducted to determine risk factors for all-cause bleeding within each treatment group (Table 3). No significant trends were observed in the following risk factors: Child-Turcotte-Pugh score, indication for anticoagulation, use of NSAIDs, PPIs or H2RAs, presence of gastric or esophageal varices, active malignancies, and time within therapeutic INR range in the warfarin group. Patients with bleeding events had slightly increased weight and BMI vs patients without bleeding events. Within the warfarin group, patients with bleeding events had slightly elevated MELD scores compared to patients without bleeding events. There was an equal balance of patients prescribed aspirin therapy between the groups with and without bleeding events. Overall, no significant risk factors were identified for all-cause bleeding.

Discussion

Initially, patients with cirrhosis were excluded from DOAC trials due to concerns for increased bleeding risk with hepatically eliminated medications. New retrospective research has concluded that in patients with cirrhosis, DOACs have similar or lower bleeding rates when compared directly to warfarin.^9,10

In this study, no statistically significant differences were detected between the primary and secondary outcomes of all-cause bleeding, major bleeding, or failed efficacy. Subgroup analysis did not identify any significant risk factors with respect to all-cause bleeding among patients in the DOAC and warfarin groups. To meet 80% power, 212 patients needed to be enrolled in the study; however, only 79 patients were enrolled, and power was not met. The results of this study should be interpreted cautiously as hypothesis-generating due to the small sample size. Strengths of this study include similar baseline characteristics between the DOAC and warfarin groups, 4-year length of retrospective data review, and availability of both inpatient and outpatient EHR limiting the amount of missing data points.

Baseline characteristics were similar between the groups except for mean INR, Child-Turcotte-Pugh score, MELD score, and number of days on anticoagulation therapy. The difference in mean INR between groups is expected as patients in the warfarin group have a goal INR of 2 to 3 to maintain therapeutic efficacy and safety. INR is not used as a marker of efficacy or safety with DOACs; therefore, a consistent elevation in INR is not expected. Child- Turcotte-Pugh scores are calculated using INR levels.¹¹ When calculating the score, patients with an INR < 1.7 receive 1 point; patients with an INR between 1.7 and 2.3 receive 2 points.¹¹ Therefore, patients in the warfarin group will have artificially inflated Child-Turcotte-Pugh scores as this group has goal INR levels of 2 to 3. This makes Child-Turcotte-Pugh scores unreliable markers of disease severity in patients using warfarin therapy. When the INR scores for patients prescribed warfarin were replaced with values < 1.7, the statistical difference disappeared between the warfarin and DOAC groups. The same effect is seen on MELD scores for patients prescribed warfarin therapy. The MELD score is calculated using INR levels.¹² MELD scores also will be artificially elevated in patients prescribed warfarin therapy due to the INR elevation to between 2 and 3. When MELD scores for patients prescribed warfarin were replaced with values similar to those in the DOAC group, the statistical difference disappeared between the warfarin and DOAC groups.

The last statistically significant difference was found in number of days on anticoagulant therapy. This difference was expected as warfarin is the standard of care for anticoagulation treatment in patients with cirrhosis. The first DOAC, dabigatran, was not approved by the US Food and Drug Administration until 2010.¹³ DOACs have only recently been used in patients with cirrhosis accounting for the statistically significant difference in days on anticoagulation therapy between the warfarin and DOAC groups.

Limitations

The inability to meet power or evaluate adherence and appropriate renal dose adjustments for DOACs limited this study. This study was conducted at a single center in a predominantly male veteran population and therefore may not be generalizable to other populations. A majority of patients in the DOAC group were prescribed apixaban (69.1%), which may have affected the overall rate of major bleeding in the DOAC group. Pivotal trials of apixaban have shown a consistent decreased risk of major bleeding in patients with NVAF or VTE when compared with warfarin.^14,15 Therefore, the results of this study may not be generalizable to all DOACs.

An inherent limitation of this study was the inability to collect data verifying adherence in the DOAC group. However, in the warfarin group, percentage of time within the therapeutic INR range of 2 to 3 was collected. While not a direct marker of adherence, this does allow for limited evaluation of therapeutic efficacy and safety within the warfarin group. Last, proper dosing of DOACs in patients with and without adequate renal function was not evaluated in this study.

Conclusions

The results of this study are consistent with other retrospective research and literature reviews. There were no statistically significant differences identified between the rates of all-cause bleeding, major bleeding, and failed efficacy between the DOAC and warfarin groups. DOACs may be a safe alternative to warfarin in patients with cirrhosis requiring anticoagulation for NVAF or VTE, but large randomized trials are required to confirm these results.

Coagulation in patients with cirrhosis is a complicated area of evolving research. Patients with cirrhosis were originally thought to be naturally anticoagulated due to the decreased production of clotting factors and platelets, combined with an increased international normalized ratio (INR).¹ New data have shown that patients with cirrhosis are at a concomitant risk of bleeding and thrombosis due to increased platelet aggregation, decreased fibrinolysis, and decreased production of natural anticoagulants such as protein C and antithrombin.¹ Traditionally, patients with cirrhosis needing anticoagulation therapy for comorbid conditions, such as nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE) were placed on warfarin therapy. Managing warfarin in patients with cirrhosis poses a challenge to clinicians due to the many food and drug interactions, narrow therapeutic index, and complications with maintaining a therapeutic INR.¹

Direct oral anticoagulants (DOACs) have several benefits over warfarin therapy, including convenience, decreased monitoring, decreased drug and dietary restrictions, and faster onset of action.² Conversely, DOACs undergo extensive hepatic metabolism giving rise to concerns about supratherapeutic drug levels and increased bleeding rates in patients with liver dysfunction.¹ Consequently, patients with cirrhosis were excluded from the pivotal trials establishing DOACs for NVAF and VTE treatment. Exclusion of these patients in major clinical trials alongside the challenges of managing warfarin warrant an evaluation of the efficacy and safety of DOACs in patients with cirrhosis.

Recent retrospective studies have examined the use of DOACs in patients with cirrhosis and found favorable results. A retrospective chart review by Intagliata and colleagues consisting of 39 patients with cirrhosis using either a DOAC or warfarin found similar rates of all-cause bleeding and major bleeding between the 2 groups.³ A retrospective cohort study by Hum and colleagues consisting of 45 patients with cirrhosis compared the use of DOACs with warfarin or low-molecular weight heparin (LMWH).⁴ Hum and colleagues found patients prescribed a DOAC had significantly fewer major bleeding events than did patients using warfarin or LMWH.⁴ The largest retrospective cohort study consisted of 233 patients with chronic liver disease and found no differences among all-cause bleeding and major bleeding rates between patients using DOACs compared with those of patients using warfarin.⁵

The purpose of this research is to evaluate the safety and efficacy of DOACs in veteran patients with cirrhosis compared with patients using warfarin.

Methods

A retrospective single-center chart review was conducted at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas, between October 31, 2014 and October 31, 2018. Patients included in the study were adults aged ≥ 18 years with a diagnosis of cirrhosis and prescribed any of the following oral anticoagulants: apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin. Patients prescribed apixaban, dabigatran, edoxaban, or rivaroxaban were collectively grouped into the DOAC group, while patients prescribed warfarin were classified as the standard of care comparator group.

A diagnosis of cirrhosis was confirmed using a combination of the codes from the ninth and tenth editions of the International Classification of Diseases (ICD) for cirrhosis, documentation of diagnostic confirmation by clinicians from the gastroenterology or hepatology services, and positive liver biopsy result. Liver function tests, liver ultrasound results, and FibroSure biomarker assays were used to aid in confirming the diagnosis of cirrhosis but were not considered definitive. Patients were excluded from the trial if they had indications for anticoagulation other than NVAF and VTE and/or were prescribed triple antithrombotic therapy (dual antiplatelet therapy plus an anticoagulant). Patients who switched anticoagulant therapy during the trial period (ie, switched from warfarin to a DOAC) were also excluded from the analysis.

Patient demographic characteristics that were collected included weight; body mass index (BMI); etiology of cirrhosis; Child-Turcotte-Pugh, Model for End-Stage Liver Disease (MELD), and CHA₂DS₂-VASc score; concomitant antiplatelet, nonsteroidal anti-inflammatory drug (NSAID), proton pump inhibitor (PPI), and histamine-2 receptor antagonist (H2RA) medications; presence of gastric and/or esophageal varices; active malignancies; albumin, total bilirubin, serum creatinine, INR, and platelet laboratory values; and indication and duration of anticoagulation therapy.

Two patient lists were used to identify patients for inclusion in the warfarin arm. The first patient list was generated using the US Department of Veterans Affairs (VA) Cirrhosis Tracker, which identified patients with an ICD-9/10 code for cirrhosis and an INR laboratory value. Patients generated from the VA Cirrhosis Tracker with an INR > 1.5 were screened for a warfarin prescription and then evaluated for full study inclusion. The second patient list was generated using the VA Advanced Liver Disease Dashboard which identified patients with ICD-9/10 codes for advanced liver disease and an active warfarin prescription. Patients with an active warfarin prescription were then evaluated for full study inclusion. A single patient list was generated to identify patients for inclusion in the DOAC arm. This patient list was generated using the VA DOAC dashboard, which identified patients with an active DOAC prescription and an ICD-9/10 code for cirrhosis. Patients with an ICD-9/10 code for cirrhosis and prescribed a DOAC were screened for full study inclusion. Patient data were collected from the MEDVAMC Computerized Patient Record System (CPRS) electronic health record (EHR). The research study was approved by the Baylor College of Medicine Institutional Review Board and the VA Office of Research and Development.

Outcomes

The primary endpoint for the study was all-cause bleeding. The secondary endpoints for the study were major bleeding and failed efficacy. Major bleeding was defined using the International Society on Thrombosis and Haemostasis (ISTH) 2005 definition: fatal bleeding, symptomatic bleeding in a critical organ area (ie, intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome), or bleeding causing a fall in hemoglobin level of > 2 g/dL or leading to the transfusion of ≥ 2 units of red cells.⁶ Failed efficacy was a combination endpoint that included development of VTE, stroke, myocardial infarction (MI), and/or death. A prespecified subgroup analysis was conducted at the end of the study period to analyze trends in the DOAC and warfarin groups with respect to all-cause bleeding. All-cause bleeding risk was stratified by weight, BMI, Child-Turcotte-Pugh score, MELD score, presence of gastric and/or esophageal varices, active malignancies, percentage of time within therapeutic INR range in the warfarin group, indications for anticoagulation, and antiplatelet, NSAID, PPI, and H2RA therapy.

Statistical Analysis

Data were analyzed using descriptive and inferential statistics. Continuous data were analyzed using the Student t test, and categorical data were analyzed using the Fisher exact test. Previous studies determined an all-cause bleeding rate of 10 to 17% for warfarin compared with 5% for DOACs.^7,8 To detect a 12% difference in the all-cause bleeding rate between DOACs and warfarin, 212 patients would be needed to achieve 80% power at an α level of 0.05.

Results

A total of 170 patients were screened, and after applying inclusion and exclusion criteria, 79 patients were enrolled in the study (Figure). The DOAC group included 42 patients, and the warfarin group included 37 patients. In the DOAC group, 69.1% (n = 29) of patients were taking apixaban, 21.4% (n = 9) rivaroxaban, and 9.5% (n = 4) dabigatran. There were no patients prescribed edoxaban during the study period.

Baseline characteristics were similar between the 2 groups except for Child-Turcotte-Pugh score, MELD score, mean INR, and number of days on anticoagulation therapy (Table 1). Most of the patients were male (98.7%), and the mean age was 71 years. The most common causes of cirrhosis were viral (29.1%), nonalcoholic fatty liver disease (NAFLD) (24.1%), multiple causes (22.8%), and alcohol (21.5%). Sixty-two patients (78.5%) had a NVAF indication for anticoagulation. The average CHA₂DS₂-VASc score was 3.7. Aspirin was prescribed in 51.9% (n = 41) of patients, and PPIs were prescribed in 48.1% (n = 38) of patients. At inclusion, esophageal varices were present in 13 patients and active malignancies were present in 6 patients.

Safety Outcome

The primary outcome comparing all-cause bleeding rates between patients on DOACs compared with warfarin are listed in Table 2. With respect to the primary outcome, 7 (16.7%) patients on DOACs experienced a bleeding event compared with 8 (21.6%) patients on warfarin (P = .77). No statistically significant differences were detected between the DOAC and warfarin groups with respect to all-cause bleeding. Seven bleeding events occurred in the DOAC group; 1 met the qualification for major bleeding with a suspected gastrointestinal (GI) bleed.⁶ The other 6 bleeding episodes in the DOAC group consisted of hematoma, epistaxis, hematuria, and hematochezia. Eight bleeding events occurred in the warfarin group; 2 met the qualification for major bleeding with an intracranial hemorrhage and upper GI bleed.⁶ The other 6 bleeding episodes in the warfarin group consisted of epistaxis, bleeding gums, hematuria, and hematochezia. There were no statistically significant differences between the rates of major bleeding and nonmajor bleeding between the DOAC and warfarin groups.

Efficacy Outcomes

There were 3 events in the DOAC group and 3 events in the warfarin group (P = .99). In the DOAC group, 2 patients experienced a pulmonary embolism, and 1 patient experienced a MI. In the warfarin group, 3 patients died (end-stage heart failure, unknown cause due to death at an outside hospital, and sepsis/organ failure). There were no statistically significant differences between the composite endpoint of failed efficacy or the individual endpoints of VTE, stroke, MI, and death.

Subgroup Analysis

A prespecified subgroup analysis was conducted to determine risk factors for all-cause bleeding within each treatment group (Table 3). No significant trends were observed in the following risk factors: Child-Turcotte-Pugh score, indication for anticoagulation, use of NSAIDs, PPIs or H2RAs, presence of gastric or esophageal varices, active malignancies, and time within therapeutic INR range in the warfarin group. Patients with bleeding events had slightly increased weight and BMI vs patients without bleeding events. Within the warfarin group, patients with bleeding events had slightly elevated MELD scores compared to patients without bleeding events. There was an equal balance of patients prescribed aspirin therapy between the groups with and without bleeding events. Overall, no significant risk factors were identified for all-cause bleeding.

Discussion

Initially, patients with cirrhosis were excluded from DOAC trials due to concerns for increased bleeding risk with hepatically eliminated medications. New retrospective research has concluded that in patients with cirrhosis, DOACs have similar or lower bleeding rates when compared directly to warfarin.^9,10

In this study, no statistically significant differences were detected between the primary and secondary outcomes of all-cause bleeding, major bleeding, or failed efficacy. Subgroup analysis did not identify any significant risk factors with respect to all-cause bleeding among patients in the DOAC and warfarin groups. To meet 80% power, 212 patients needed to be enrolled in the study; however, only 79 patients were enrolled, and power was not met. The results of this study should be interpreted cautiously as hypothesis-generating due to the small sample size. Strengths of this study include similar baseline characteristics between the DOAC and warfarin groups, 4-year length of retrospective data review, and availability of both inpatient and outpatient EHR limiting the amount of missing data points.

Baseline characteristics were similar between the groups except for mean INR, Child-Turcotte-Pugh score, MELD score, and number of days on anticoagulation therapy. The difference in mean INR between groups is expected as patients in the warfarin group have a goal INR of 2 to 3 to maintain therapeutic efficacy and safety. INR is not used as a marker of efficacy or safety with DOACs; therefore, a consistent elevation in INR is not expected. Child- Turcotte-Pugh scores are calculated using INR levels.¹¹ When calculating the score, patients with an INR < 1.7 receive 1 point; patients with an INR between 1.7 and 2.3 receive 2 points.¹¹ Therefore, patients in the warfarin group will have artificially inflated Child-Turcotte-Pugh scores as this group has goal INR levels of 2 to 3. This makes Child-Turcotte-Pugh scores unreliable markers of disease severity in patients using warfarin therapy. When the INR scores for patients prescribed warfarin were replaced with values < 1.7, the statistical difference disappeared between the warfarin and DOAC groups. The same effect is seen on MELD scores for patients prescribed warfarin therapy. The MELD score is calculated using INR levels.¹² MELD scores also will be artificially elevated in patients prescribed warfarin therapy due to the INR elevation to between 2 and 3. When MELD scores for patients prescribed warfarin were replaced with values similar to those in the DOAC group, the statistical difference disappeared between the warfarin and DOAC groups.

The last statistically significant difference was found in number of days on anticoagulant therapy. This difference was expected as warfarin is the standard of care for anticoagulation treatment in patients with cirrhosis. The first DOAC, dabigatran, was not approved by the US Food and Drug Administration until 2010.¹³ DOACs have only recently been used in patients with cirrhosis accounting for the statistically significant difference in days on anticoagulation therapy between the warfarin and DOAC groups.

Limitations

The inability to meet power or evaluate adherence and appropriate renal dose adjustments for DOACs limited this study. This study was conducted at a single center in a predominantly male veteran population and therefore may not be generalizable to other populations. A majority of patients in the DOAC group were prescribed apixaban (69.1%), which may have affected the overall rate of major bleeding in the DOAC group. Pivotal trials of apixaban have shown a consistent decreased risk of major bleeding in patients with NVAF or VTE when compared with warfarin.^14,15 Therefore, the results of this study may not be generalizable to all DOACs.

An inherent limitation of this study was the inability to collect data verifying adherence in the DOAC group. However, in the warfarin group, percentage of time within the therapeutic INR range of 2 to 3 was collected. While not a direct marker of adherence, this does allow for limited evaluation of therapeutic efficacy and safety within the warfarin group. Last, proper dosing of DOACs in patients with and without adequate renal function was not evaluated in this study.

Conclusions

The results of this study are consistent with other retrospective research and literature reviews. There were no statistically significant differences identified between the rates of all-cause bleeding, major bleeding, and failed efficacy between the DOAC and warfarin groups. DOACs may be a safe alternative to warfarin in patients with cirrhosis requiring anticoagulation for NVAF or VTE, but large randomized trials are required to confirm these results.

Coagulation in patients with cirrhosis is a complicated area of evolving research. Patients with cirrhosis were originally thought to be naturally anticoagulated due to the decreased production of clotting factors and platelets, combined with an increased international normalized ratio (INR).¹ New data have shown that patients with cirrhosis are at a concomitant risk of bleeding and thrombosis due to increased platelet aggregation, decreased fibrinolysis, and decreased production of natural anticoagulants such as protein C and antithrombin.¹ Traditionally, patients with cirrhosis needing anticoagulation therapy for comorbid conditions, such as nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE) were placed on warfarin therapy. Managing warfarin in patients with cirrhosis poses a challenge to clinicians due to the many food and drug interactions, narrow therapeutic index, and complications with maintaining a therapeutic INR.¹

Direct oral anticoagulants (DOACs) have several benefits over warfarin therapy, including convenience, decreased monitoring, decreased drug and dietary restrictions, and faster onset of action.² Conversely, DOACs undergo extensive hepatic metabolism giving rise to concerns about supratherapeutic drug levels and increased bleeding rates in patients with liver dysfunction.¹ Consequently, patients with cirrhosis were excluded from the pivotal trials establishing DOACs for NVAF and VTE treatment. Exclusion of these patients in major clinical trials alongside the challenges of managing warfarin warrant an evaluation of the efficacy and safety of DOACs in patients with cirrhosis.

Recent retrospective studies have examined the use of DOACs in patients with cirrhosis and found favorable results. A retrospective chart review by Intagliata and colleagues consisting of 39 patients with cirrhosis using either a DOAC or warfarin found similar rates of all-cause bleeding and major bleeding between the 2 groups.³ A retrospective cohort study by Hum and colleagues consisting of 45 patients with cirrhosis compared the use of DOACs with warfarin or low-molecular weight heparin (LMWH).⁴ Hum and colleagues found patients prescribed a DOAC had significantly fewer major bleeding events than did patients using warfarin or LMWH.⁴ The largest retrospective cohort study consisted of 233 patients with chronic liver disease and found no differences among all-cause bleeding and major bleeding rates between patients using DOACs compared with those of patients using warfarin.⁵

The purpose of this research is to evaluate the safety and efficacy of DOACs in veteran patients with cirrhosis compared with patients using warfarin.

Methods

A retrospective single-center chart review was conducted at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) in Houston, Texas, between October 31, 2014 and October 31, 2018. Patients included in the study were adults aged ≥ 18 years with a diagnosis of cirrhosis and prescribed any of the following oral anticoagulants: apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin. Patients prescribed apixaban, dabigatran, edoxaban, or rivaroxaban were collectively grouped into the DOAC group, while patients prescribed warfarin were classified as the standard of care comparator group.

A diagnosis of cirrhosis was confirmed using a combination of the codes from the ninth and tenth editions of the International Classification of Diseases (ICD) for cirrhosis, documentation of diagnostic confirmation by clinicians from the gastroenterology or hepatology services, and positive liver biopsy result. Liver function tests, liver ultrasound results, and FibroSure biomarker assays were used to aid in confirming the diagnosis of cirrhosis but were not considered definitive. Patients were excluded from the trial if they had indications for anticoagulation other than NVAF and VTE and/or were prescribed triple antithrombotic therapy (dual antiplatelet therapy plus an anticoagulant). Patients who switched anticoagulant therapy during the trial period (ie, switched from warfarin to a DOAC) were also excluded from the analysis.

Patient demographic characteristics that were collected included weight; body mass index (BMI); etiology of cirrhosis; Child-Turcotte-Pugh, Model for End-Stage Liver Disease (MELD), and CHA₂DS₂-VASc score; concomitant antiplatelet, nonsteroidal anti-inflammatory drug (NSAID), proton pump inhibitor (PPI), and histamine-2 receptor antagonist (H2RA) medications; presence of gastric and/or esophageal varices; active malignancies; albumin, total bilirubin, serum creatinine, INR, and platelet laboratory values; and indication and duration of anticoagulation therapy.

Two patient lists were used to identify patients for inclusion in the warfarin arm. The first patient list was generated using the US Department of Veterans Affairs (VA) Cirrhosis Tracker, which identified patients with an ICD-9/10 code for cirrhosis and an INR laboratory value. Patients generated from the VA Cirrhosis Tracker with an INR > 1.5 were screened for a warfarin prescription and then evaluated for full study inclusion. The second patient list was generated using the VA Advanced Liver Disease Dashboard which identified patients with ICD-9/10 codes for advanced liver disease and an active warfarin prescription. Patients with an active warfarin prescription were then evaluated for full study inclusion. A single patient list was generated to identify patients for inclusion in the DOAC arm. This patient list was generated using the VA DOAC dashboard, which identified patients with an active DOAC prescription and an ICD-9/10 code for cirrhosis. Patients with an ICD-9/10 code for cirrhosis and prescribed a DOAC were screened for full study inclusion. Patient data were collected from the MEDVAMC Computerized Patient Record System (CPRS) electronic health record (EHR). The research study was approved by the Baylor College of Medicine Institutional Review Board and the VA Office of Research and Development.

Outcomes

The primary endpoint for the study was all-cause bleeding. The secondary endpoints for the study were major bleeding and failed efficacy. Major bleeding was defined using the International Society on Thrombosis and Haemostasis (ISTH) 2005 definition: fatal bleeding, symptomatic bleeding in a critical organ area (ie, intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, pericardial, or intramuscular with compartment syndrome), or bleeding causing a fall in hemoglobin level of > 2 g/dL or leading to the transfusion of ≥ 2 units of red cells.⁶ Failed efficacy was a combination endpoint that included development of VTE, stroke, myocardial infarction (MI), and/or death. A prespecified subgroup analysis was conducted at the end of the study period to analyze trends in the DOAC and warfarin groups with respect to all-cause bleeding. All-cause bleeding risk was stratified by weight, BMI, Child-Turcotte-Pugh score, MELD score, presence of gastric and/or esophageal varices, active malignancies, percentage of time within therapeutic INR range in the warfarin group, indications for anticoagulation, and antiplatelet, NSAID, PPI, and H2RA therapy.

Statistical Analysis

Data were analyzed using descriptive and inferential statistics. Continuous data were analyzed using the Student t test, and categorical data were analyzed using the Fisher exact test. Previous studies determined an all-cause bleeding rate of 10 to 17% for warfarin compared with 5% for DOACs.^7,8 To detect a 12% difference in the all-cause bleeding rate between DOACs and warfarin, 212 patients would be needed to achieve 80% power at an α level of 0.05.

Results

A total of 170 patients were screened, and after applying inclusion and exclusion criteria, 79 patients were enrolled in the study (Figure). The DOAC group included 42 patients, and the warfarin group included 37 patients. In the DOAC group, 69.1% (n = 29) of patients were taking apixaban, 21.4% (n = 9) rivaroxaban, and 9.5% (n = 4) dabigatran. There were no patients prescribed edoxaban during the study period.

Baseline characteristics were similar between the 2 groups except for Child-Turcotte-Pugh score, MELD score, mean INR, and number of days on anticoagulation therapy (Table 1). Most of the patients were male (98.7%), and the mean age was 71 years. The most common causes of cirrhosis were viral (29.1%), nonalcoholic fatty liver disease (NAFLD) (24.1%), multiple causes (22.8%), and alcohol (21.5%). Sixty-two patients (78.5%) had a NVAF indication for anticoagulation. The average CHA₂DS₂-VASc score was 3.7. Aspirin was prescribed in 51.9% (n = 41) of patients, and PPIs were prescribed in 48.1% (n = 38) of patients. At inclusion, esophageal varices were present in 13 patients and active malignancies were present in 6 patients.

Safety Outcome

The primary outcome comparing all-cause bleeding rates between patients on DOACs compared with warfarin are listed in Table 2. With respect to the primary outcome, 7 (16.7%) patients on DOACs experienced a bleeding event compared with 8 (21.6%) patients on warfarin (P = .77). No statistically significant differences were detected between the DOAC and warfarin groups with respect to all-cause bleeding. Seven bleeding events occurred in the DOAC group; 1 met the qualification for major bleeding with a suspected gastrointestinal (GI) bleed.⁶ The other 6 bleeding episodes in the DOAC group consisted of hematoma, epistaxis, hematuria, and hematochezia. Eight bleeding events occurred in the warfarin group; 2 met the qualification for major bleeding with an intracranial hemorrhage and upper GI bleed.⁶ The other 6 bleeding episodes in the warfarin group consisted of epistaxis, bleeding gums, hematuria, and hematochezia. There were no statistically significant differences between the rates of major bleeding and nonmajor bleeding between the DOAC and warfarin groups.

Efficacy Outcomes

There were 3 events in the DOAC group and 3 events in the warfarin group (P = .99). In the DOAC group, 2 patients experienced a pulmonary embolism, and 1 patient experienced a MI. In the warfarin group, 3 patients died (end-stage heart failure, unknown cause due to death at an outside hospital, and sepsis/organ failure). There were no statistically significant differences between the composite endpoint of failed efficacy or the individual endpoints of VTE, stroke, MI, and death.

Subgroup Analysis

A prespecified subgroup analysis was conducted to determine risk factors for all-cause bleeding within each treatment group (Table 3). No significant trends were observed in the following risk factors: Child-Turcotte-Pugh score, indication for anticoagulation, use of NSAIDs, PPIs or H2RAs, presence of gastric or esophageal varices, active malignancies, and time within therapeutic INR range in the warfarin group. Patients with bleeding events had slightly increased weight and BMI vs patients without bleeding events. Within the warfarin group, patients with bleeding events had slightly elevated MELD scores compared to patients without bleeding events. There was an equal balance of patients prescribed aspirin therapy between the groups with and without bleeding events. Overall, no significant risk factors were identified for all-cause bleeding.

Discussion

Initially, patients with cirrhosis were excluded from DOAC trials due to concerns for increased bleeding risk with hepatically eliminated medications. New retrospective research has concluded that in patients with cirrhosis, DOACs have similar or lower bleeding rates when compared directly to warfarin.^9,10

In this study, no statistically significant differences were detected between the primary and secondary outcomes of all-cause bleeding, major bleeding, or failed efficacy. Subgroup analysis did not identify any significant risk factors with respect to all-cause bleeding among patients in the DOAC and warfarin groups. To meet 80% power, 212 patients needed to be enrolled in the study; however, only 79 patients were enrolled, and power was not met. The results of this study should be interpreted cautiously as hypothesis-generating due to the small sample size. Strengths of this study include similar baseline characteristics between the DOAC and warfarin groups, 4-year length of retrospective data review, and availability of both inpatient and outpatient EHR limiting the amount of missing data points.

Baseline characteristics were similar between the groups except for mean INR, Child-Turcotte-Pugh score, MELD score, and number of days on anticoagulation therapy. The difference in mean INR between groups is expected as patients in the warfarin group have a goal INR of 2 to 3 to maintain therapeutic efficacy and safety. INR is not used as a marker of efficacy or safety with DOACs; therefore, a consistent elevation in INR is not expected. Child- Turcotte-Pugh scores are calculated using INR levels.¹¹ When calculating the score, patients with an INR < 1.7 receive 1 point; patients with an INR between 1.7 and 2.3 receive 2 points.¹¹ Therefore, patients in the warfarin group will have artificially inflated Child-Turcotte-Pugh scores as this group has goal INR levels of 2 to 3. This makes Child-Turcotte-Pugh scores unreliable markers of disease severity in patients using warfarin therapy. When the INR scores for patients prescribed warfarin were replaced with values < 1.7, the statistical difference disappeared between the warfarin and DOAC groups. The same effect is seen on MELD scores for patients prescribed warfarin therapy. The MELD score is calculated using INR levels.¹² MELD scores also will be artificially elevated in patients prescribed warfarin therapy due to the INR elevation to between 2 and 3. When MELD scores for patients prescribed warfarin were replaced with values similar to those in the DOAC group, the statistical difference disappeared between the warfarin and DOAC groups.

The last statistically significant difference was found in number of days on anticoagulant therapy. This difference was expected as warfarin is the standard of care for anticoagulation treatment in patients with cirrhosis. The first DOAC, dabigatran, was not approved by the US Food and Drug Administration until 2010.¹³ DOACs have only recently been used in patients with cirrhosis accounting for the statistically significant difference in days on anticoagulation therapy between the warfarin and DOAC groups.

Limitations

The inability to meet power or evaluate adherence and appropriate renal dose adjustments for DOACs limited this study. This study was conducted at a single center in a predominantly male veteran population and therefore may not be generalizable to other populations. A majority of patients in the DOAC group were prescribed apixaban (69.1%), which may have affected the overall rate of major bleeding in the DOAC group. Pivotal trials of apixaban have shown a consistent decreased risk of major bleeding in patients with NVAF or VTE when compared with warfarin.^14,15 Therefore, the results of this study may not be generalizable to all DOACs.

An inherent limitation of this study was the inability to collect data verifying adherence in the DOAC group. However, in the warfarin group, percentage of time within the therapeutic INR range of 2 to 3 was collected. While not a direct marker of adherence, this does allow for limited evaluation of therapeutic efficacy and safety within the warfarin group. Last, proper dosing of DOACs in patients with and without adequate renal function was not evaluated in this study.

Conclusions

The results of this study are consistent with other retrospective research and literature reviews. There were no statistically significant differences identified between the rates of all-cause bleeding, major bleeding, and failed efficacy between the DOAC and warfarin groups. DOACs may be a safe alternative to warfarin in patients with cirrhosis requiring anticoagulation for NVAF or VTE, but large randomized trials are required to confirm these results.

Despite advancements in techniques, postsurgical pain continues to be a prominent part of the patient experience. Often this experience can lead to developing chronic postsurgical pain that interferes with quality of life after the expected time to recovery.^1-3 As many as 14% of patients who undergo surgery without any history of opioid use develop chronic opioid use that persists after recovery from their operation.^4-8 For patients with existing chronic opioid use or a history of substance use disorder (SUD), surgeons, primary care providers, or addiction providers often do not provide sufficient presurgical planning or postsurgical coordination of care. This lack of pain care coordination can increase the risk of inadequate pain control, opioid use escalation, or SUD relapse after surgery.

Convincing arguments have been made that a perioperative surgical home can improve significantly the quality of perioperative care.^9-14 This report describes our experience implementing a perioperative surgical home at the US Department of Veterans Affairs (VA) Salt Lake City VA Medical Center (SLCVAMC), focusing on pain management extending from the preoperative period until 6 months or more after surgery. This type of Transitional Pain Service (TPS) has been described previously.^15-17 Our service differs from those described previously by enrolling all patients before surgery rather than select postsurgical enrollment of only patients with a history of opioid use or SUD or patients who struggle with persistent postsurgical pain.

Methods

In January 2018, we developed and implemented a new TPS at the SLCVAMC. The transitional pain team consisted of an anesthesiologist with specialization in acute pain management, a nurse practitioner (NP) with experience in both acute and chronic pain management, 2 nurse care coordinators, and a psychologist (Figure 1). Before implementation, a needs assessment took place with these key stakeholders and others at SLCVAMC to identify the following specific goals of the TPS: (1) reduce pain through pharmacologic and nonpharmacologic interventions; (2) eliminate new chronic opioid use in previously nonopioid user (NOU) patients; (3) address chronic opioid use in previous chronic opioid users (COUs) by providing support for opioid taper and alternative analgesic therapies for their chronic pain conditions; and (4) improve continuity of care by close coordination with the surgical team, primary care providers (PCPs), and mental health or chronic pain providers as needed.

Once these TPS goals were defined, the Consolidated Framework for Implementation Research (CFIR) guided the implementation. CFIR is a theory-based implementation framework consisting of 5 domains: intervention characteristics, inner setting, outer setting, characteristics of individuals, and process. These domains were used to identify barriers and facilitators during the early implementation process and helped refine TPS as it was put into clinical practice.

Patient Selection

During the initial implementation of TPS, enrollment was limited to patients scheduled for elective primary or revision knee, hip, or shoulder replacement as well as rotator cuff repair surgery. But as the TPS workflow became established after iterative refinement, we expanded the program to enroll patients with established risk factors for OUD having other types of surgery (Table 1). The diagnosis of risk factors, such as history of SUD, chronic opioid use, or significant mental health disorders (ie, history of suicidal ideation or attempt, posttraumatic stress disorder, and inpatient psychiatric care) were confirmed through both in-person interviews and electronic health record (EHR) documentation. The overall goal was to identify all at-risk patients as soon as they were indicated for surgery, to allow time for evaluation, education, developing an individualized pain plan, and opioid taper prior to surgery if indicated.

Preoperative Procedures

Once identified, patients were contacted by a TPS team member and invited to attend a onetime 90-minute presurgical expectations class held at SLCVAMC. The education curriculum was developed by the whole team, and classes were taught primarily by the TPS psychologist. The class included education about expectations for postoperative pain, available analgesic therapies, opioid education, appropriate use of opioids, and the effect of psychological factors on pain. Pain coping strategies were introduced using a mindfulness-based intervention (MBI) and the Acceptance and Commitment Therapy (ACT) matrix. Classes were offered multiple times a week to help maximize convenience for patients and were separate from the anesthesia preoperative evaluation. Patients attended class only once. High-risk patients (patients with chronic opioid therapy, recent history of or current SUDs, significant comorbid mental health issues) were encouraged to attend this class one-on-one with the TPS psychologist rather than in the group setting, so individual attention to mental health and SUD issues could be addressed directly. For patients who were unable to or who chose not to attend the class, the basic education component of the class without the MBI and ACT matrix was provided by nurse care coordinators and/or the anesthesiologist/NP individually before surgery either during the anesthesia preoperative visit or in the same-day surgery unit on the day of surgery.

Baseline history, morphine equivalent daily dose (MEDD), and patient-reported outcomes using measures from the Patient-Reported Outcome Measurement System (PROMIS) for pain intensity (PROMIS 3a), pain interference (PROMIS 6b), and physical function (PROMIS 8b), and a pain-catastrophizing scale (PCS) score were obtained on all patients.¹⁸ PROMIS measures are validated questionnaires developed with the National Institutes of Health to standardize and quantify patient-reported outcomes in many domains.¹⁹ Patients with a history of SUD or COU met with the anesthesiologist and/or NP, and a personalized pain plan was developed that included preoperative opioid taper, buprenorphine use strategy, or opioid-free strategies.

Hospital Procedures

On the day of surgery, the TPS team met with the patient preoperatively and implemented an individualized pain plan that included multimodal analgesic techniques with nonsteroidal anti-inflammatory drugs, acetaminophen, gabapentinoids, and regional anesthesia, where appropriate (Table 2). Enhanced recovery after surgery protocols were developed in conjunction with the surgeons to include local infiltration analgesia by the surgeon, postoperative multimodal analgesic strategies, and intensive physical therapy starting the day of surgery for inpatient procedures.

After surgery, the TPS team followed up with patients daily and provided recommendations for analgesic therapies. Patients were offered daily sessions with the psychologist to reinforce and practice nonpharmacologic pain-coping strategies, such as meditation and relaxation. Prior to patient discharge, the TPS team provided recommendations for discharge medications and an opioid taper plan. For some patients taking buprenorphine before surgery who had stopped this therapy prior to or during their hospital stay, TPS providers transitioned them back to buprenorphine before discharge.

Postoperative Procedures

Patients were called by the nurse care coordinators at postdischarge days 2, 7, 10, 14, 21, 28, and then monthly for ≥ 6 months. For patients who had not stopped opioid use or returned to their preoperative baseline opioid dose, weekly calls were made until opioid taper goals were achieved. At each call, nurses collected PROMIS scores for the previous 24 hours, the most recent 24-hour MEDD, the date of last opioid use, and the number of remaining opioid tablets after opioid cessation. In addition, nurses provided active listening and supportive care and encouragement as well as care coordination for issues related to rehabilitation facilities, physical therapy, transportation, medication questions, and wound questions. Nurses notified the anesthesiologist or NP when patients were unable to taper opioid use or had poor pain control as indicated by their PROMIS scores, opioid use, or directly expressed by the patient.

The TPS team prescribed alternative analgesic therapies, opioid taper plans, and communicated with surgeons and primary care providers if limited continued opioid therapy was recommended. Individual sessions with the psychologist were available to patients after discharge with a focus on ACT-matrix therapy and consultation with long-term mental health and/or substance abuse providers as indicated. Frequent communication and care coordination were maintained with the surgical team, the PCP, and other providers on the mental health or chronic pain services. This care coordination often included postsurgical joint clinic appointments in which TPS providers and nurses would be present with the surgeon or the PCP.

For patients with inadequately treated chronic pain conditions or who required long-term opioid tapers, we developed a combined clinic with the TPS and Anesthesia Chronic Pain group. This clinic allows patients to be seen by both services in the same setting, allowing a warm handoff by TPS to the chronic pain team.

Heath and Decision Support Tools 

An electronic dashboard registry of surgical episodes managed by TPS was developed to achieve clinical, administrative, and quality improvement goals. The dashboard registry consists of surgical episode data, opioid doses, patient-reported outcomes, and clinical decision-making processes. Custom-built note templates capture pertinent data through embedded data labels, called health factors. Data are captured as part of routine clinical care, recorded in Computerized Patient Record System as health factors. They are available in the VA Corporate Data Warehouse as structured data. Workflows are executed daily to keep the dashboard registry current, clean, and able to process new data. Information displays direct daily clinical workflow and support point-of-care clinical decision making (Figures 2, 3, and 4). Data are aggregated across patient-care encounters and allow nurse care coordinators to concisely review pertinent patient data prior to delivering care. These data include surgical history, comorbidities, timeline of opioid use, and PROMIS scores during their course of recovery. This system allows TPS to optimize care delivery by providing longitudinal data across the surgical episode, thereby reducing the time needed to review records. Secondary purposes of captured data include measuring clinic performance and quality improvement to improve care delivery.

Results

The TPS intervention was implemented January 1, 2018. Two-hundred thirteen patients were enrolled between January and December 2018, which included 60 (28%) patients with a history of chronic opioid use and 153 (72%) patients who were considered opioid naïve. A total of 99% of patients had ≥ 1 successful follow-up within 14 days after discharge, 96% had ≥ 1 follow-up between 14 and 30 days after surgery, and 72% had completed personal follow-up 90 days after discharge (Table 3). For patients who TPS was unable to contact in person or by phone, 90-day MEDD was obtained using prescription and Controlled Substance Database reviews. The protocol for this retrospective analysis was approved by the University of Utah Institutional Review Board and the VA Research Review Committee.

By 90 days after surgery, 26 (43.3%) COUs were off opioids completely, 17 (28.3%) had decreased their opioid dose from their preoperative baseline MEDD (120 [SD, 108] vs 55 [SD, 45]), 14 (23.3%) returned to their baseline dose, and 3 (5%) increased from their baseline dose. Of the 153 patients who were NOUs before surgery, only 1 (0.7%) was taking opioids after 90 days. TPS continued to work closely with the patient and their PCP and that patient was finally able to stop opioid use 262 days after discharge. Ten patients had an additional surgery within 90 days of the initial surgery. Of these, 6 were COU, of whom 3 stopped all opioids by 90 days from their original surgery, 2 had no change in MEDD at 90 days, and 1 had a lower MEDD at 90 days. Of the 4 NOU who had additional surgery, all were off opioids by 90 days from the original surgery.

Discussion

With any new clinical service, there are obstacles and challenges. TPS requires a considerable investment in personnel, and currently no mechanism is in place for obtaining payment for many of the provided services. We were fortunate the VA Whole Health Initiative, the VA Office of Rural Health, and the VA Centers of Innovation provided support for the development, implementation, and pilot evaluation of TPS. After we presented our initial results to hospital leadership, we also received hospital support to expand TPS service to include a total of 4 nurse care coordinators and 2 psychologists. We are currently performing a cost analysis of the service but recognize that this model may be difficult to reproduce at other institutions without a change in reimbursement standards.

Developing a working relationship with the surgical and primary care services required a concerted effort from the TPS team and a number of months to become effective. As most veterans receive primary care, mental health care, and surgical care within the VA system, this model lends itself to close care coordination. Initially there was skepticism about TPS recommendations to reduce opioid use, especially from PCPs who had cared for complex patients over many years. But this uncertainty went away as we showed evidence of close patient follow-up and detailed communication. TPS soon became the designated service for both primary care and surgical providers who were otherwise uncomfortable with how to approach opioid tapers and nonopioid pain strategies. In fact, a substantial portion of our referrals now come directly from the PCP who is referring a high-risk patient for evaluation for surgery rather than from the surgeons, and joint visits with TPS and primary care have become commonplace.

Challenges abound when working with patients with substance abuse history, opioid use history, high anxiety, significant pain catastrophizing, and those who have had previous negative experiences with surgery. We have found that the most important facet of our service comes from the amount of time and effort team members, especially the nurses, spend helping patients. Much of the nurses' work focuses on nonpain-related issues, such as assisting patients with finding transportation, housing issues, questions about medications, help scheduling appointments, etc. Through this concerted effort, patients gain trust in TPS providers and are willing to listen to and experiment with our recommendations. Many patients who were initially extremely unreceptive to the presurgery education asked for our support weeks after surgery to help with postsurgery pain.

Another challenge we continue to experience comes from the success of the program. We receive many requests from PCPs to help with opioid tapers and pain management for nonsurgical patients. Although we are happy that they look to TPS for assistance, the pressure to expand threatens our ability to maintain the expected quality of work we are trying to provide for surgical patients.

Conclusions

The multidisciplinary TPS supports greater preoperative to postoperative longitudinal care for surgical patients. This endeavor has resulted in better patient preparation before surgery and improved care coordination after surgery, with specific improvements in appropriate use of opioid medications and smooth transitions of care for patients with ongoing and complex needs. Development of sophisticated note templates and customized health information technology allows for accurate follow-through and data gathering for quality improvement, facilitating data-driven improvements and proving value to the facility.

Given that TPS is a multidisciplinary program with multiple interventions, it is difficult to pinpoint which specific aspects of TPS are most effective in achieving success. For example, although we have little doubt that the work our psychologists do with our patients is beneficial and even essential for the success we have had with some of our most difficult patients, it is less clear whether it matters if they use mindfulness, ACT matrix, or cognitive behavioral therapy. We think that an important part of TPS is the frequent human interaction with a caring individual. Therefore, as TPS continues to grow, maintaining the ability to provide frequent personal interaction is a priority.

The role of opioids in acute pain deserves further scrutiny. In 2018, with TPS use of opioids after orthopedic surgery decreased by > 40% from the previous year. Despite this more restricted use of opioids, pain interference and physical function scores indicated that surgical patients do not seem to experience increased pain or reduced physical function. In addition, stopping opioid use for COUs did not seem to affect the quality of recovery, pain, or physical function. Future prospective controlled studies of TPS are needed to confirm these findings and identify which aspects of TPS are most effective in improving functional recovery of patients. Also, more evidence is needed to determine the appropriateness or need for opioids in acute postsurgical pain.

TPS has expanded to include all surgical specialties. Given the high burden and limited resources, we have chosen to focus on patients at higher risk for chronic postsurgical pain by type of surgery (eg, thoracotomy, open abdominal, limb amputation, major joint surgery) and/or history of substance abuse or chronic opioid use. To better direct scarce resources where it would be of most benefit, we are now enrolling only NOUs without other risk factors postoperatively if they request a refill of opioids or are otherwise struggling with pain control after surgery. Whether this approach affects the success we had in the first year in preventing new COUs after surgery remains to be seen.

It is unlikely that any single model of a perioperative surgical home will fit the needs of the many different types of medical systems that exist. The TPS model fits well in large hospital systems, like the VA, where patients receive most of their care within the same system. However, it seems to us that the optimal TPS program in any health system will provide education, support, and care coordination beginning preoperatively to prepare the patient for surgery and then to facilitate care coordination to transition patients back to their PCPs or on to specialized chronic care.

Acknowledgments

We would like to acknowledge the contributions of Candice Harmon, RN; David Merrill, RN; Amy Beckstead, RN, who have provided invaluable assistance with establishing the TPS program at the VA Salt Lake City and helping with the evaluation process.

Funding for the implementation and evaluation of the TPS was received from the VA Whole Health Initiative, the VA Center of Innovation, the VA Office of Rural Health, and National Institutes of Health Grant UL1TR002538.