ILLUSTRATIVE CASE

Ms. M is a 76-year-old woman with well-­controlled type 2 diabetes mellitus for 10 years and well-controlled mild hypertension. She is otherwise healthy, and her mother lived to age 95. Ms. M has never smoked, has no previous history of vascular/cardiovascular disease, and drinks 1 glass of wine 2 to 3 times per week. Based on the American College of Cardiology (ACC) calculator, she was started on atorvastatin years ago. Is continued use of the medication of any benefit at her current age?

The 2018 American Heart Association (AHA)/ACC/Multi-Society cholesterol guidelines do not provide primary prevention recommendations for those older than age 75 years.³ Up to age 75, the guidelines recommend that patients with type 2 diabetes and a low-density lipoprotein cholesterol (LDL-C) level ≥ 70 mg/dL, as well as those without diabetes but with an LDL-C ≥ 70 mg/dL and a 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 10%, be started on medium-intensity statin therapy.

A 2018 consensus panel review of the current literature, sponsored by the National Institute on Aging and the National Heart, Lung, and Blood Institute, concluded that there was insufficient evidence regarding the benefits and harms of statins in older adults, especially those with comorbidities, and that there was a paucity of evidence about statin therapy outcomes (both adverse and beneficial) relevant to older adults.⁴

A review of all guidelines published since 2013 revealed that only the United Kingdom’s 2014 National Institute for Health and Care Excellence (NICE) guideline provides a strong, risk-based recommendation for initiating primary prevention with statins in patients > 75 years old.⁵ These recommendations are based on the QRISK2 calculator (which has since been updated to the QRISK3), which assigns everyone ages > 75 years a > 10% 10-year risk score. This provides a universal statin indication for anyone in the 76-to-84 age range.⁶

Both the ACC/AHA and US Preventive Services Task Force guidelines clearly state that there are too few data and inadequate evidence in people older than 75 for a strong, risk-based statin recommendation.⁵ The Canadian Cardiovascular Society guideline takes a similar stance, emphasizing that the recommended Framingham risk model is not well validated in people > 75 years.⁵

STUDY SUMMARIES

Two different looks at statin use in the elderly

A retrospective cohort study (N = 46,864; median follow-up, 5.6 years) examined whether statin treatment is associated with a reduction in atherosclerotic disease and mortality in old and very old adults with and without type 2 diabetes.¹ Patients were enrolled from a large, anonymized national database in Spain. The researchers looked only at first-time users of statins and those without a statin prescription within the past 18 months.

Statin therapy seems to provide no benefit to patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Patients with previous ASCVD, type 1 diabetes, previous lipid-lowering treatment, dementia, cancer, or paralysis were excluded, as were those who were in residential care, were on dialysis, or had received an organ transplant. Patients were stratified by age (75-84 years and ≥ 85 years), diabetes status (with or without type 2 diabetes), and statin use (nonuser or new user).

Continue to: Results

Results. For patients with type 2 diabetes, the risk of ASCVD (a composite of coronary heart disease and stroke) was lower among those who took statins than among those who did not in the 75-to-84 group (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.65-0.89; 1-year number needed to treat [NNT] = 164). Among those who took statins, there was also lower all-cause mortality (HR = 0.84; 95% CI, 0.75-0.94; 1-year NNT = 306). In those ages ≥ 85 years with diabetes, the statin group did not have a lower risk of ASCVD (HR = 0.82; 95% CI, 0.53-1.26) or all-cause mortality (HR = 1.05; 95% CI, 0.86-1.28).

For patients ages 75 to 84 years without diabetes, there was no difference in risk between groups for ASCVD (HR = 0.94; 95% CI, 0.86–1.04) or all-cause mortality (HR = 0.98; 95% CI, 0.91-1.05). In those ages ≥ 85 years without diabetes, there was also no difference between groups for ASCVD (HR = 1; 95% CI, 0.80-1.24) or for all-cause mortality (HR = 1; 95% CI, 0.90-1.11).

A 2019 meta-analysis of randomized controlled trials (RCTs) (n = 134,537) and RCT summary data (n = 12,705) evaluated the safety and efficacy of statin therapy in patients ages ≥ 55 years.² In the group of patients ages > 75 years (n = 14,483; median follow-up, 4.9 years), each 1 mmol/L reduction in LDL-C was associated with significant decreased risk for major vascular events (risk ratio [RR] = 0.82; 95% CI, 0.70-0.95) and for major coronary events (RR = 0.82; 95% CI, 0.70-0.96).

In subgroup analysis by the presence or absence of previous vascular disease, there was a decreased risk per 1 mmol/L LDL-C reduction of major vascular events in patients with previous vascular disease (RR = 0.85; 95% CI, 0.73-0.98); however, there was not a significant effect in patients without previous vascular disease (RR = 0.92; 95% CI, 0.73-1.16).

WHAT’S NEW

Statins may be unnecessary in older adults without ASCVD or T2DM

Statin therapy reduces the risk of ASCVD and mortality in patients ages 75 to 84 with type 2 diabetes and in patients > 75 years with known vascular disease. However, statin therapy seems to provide no benefit in patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Continue to: CAVEATS

CAVEATS

Retrospective cohort design leaves cause and effect equivocal

Even though the first study was large (with more than 46,000 patients) and the median follow-up was 5.6 years, it was a retrospective cohort study. While there is clearly an association between statin therapy and reduced ASCVD and all-cause mortality in patients with diabetes ages 75 to 84 years, cause and effect cannot be unequivocally stated. However, the meta-analysis, which included RCTs, confirms the benefit of statins in secondary prevention for older patients.

The cohort study did not look at adverse effects from statin therapy in this age group, but the data from the 2019 meta-analysis did not reveal any significant risk of myopathy.

CHALLENGES TO IMPLEMENTATION

Guidelines are lacking and discontinuing meds requires discussion

The lack of supporting guidelines to treat this age group with statins remains the largest barrier to implementation. Many patients may already be taking a statin, so a discussion about discontinuing medication will need to be initiated.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 76-year-old woman with well-­controlled type 2 diabetes mellitus for 10 years and well-controlled mild hypertension. She is otherwise healthy, and her mother lived to age 95. Ms. M has never smoked, has no previous history of vascular/cardiovascular disease, and drinks 1 glass of wine 2 to 3 times per week. Based on the American College of Cardiology (ACC) calculator, she was started on atorvastatin years ago. Is continued use of the medication of any benefit at her current age?

The 2018 American Heart Association (AHA)/ACC/Multi-Society cholesterol guidelines do not provide primary prevention recommendations for those older than age 75 years.³ Up to age 75, the guidelines recommend that patients with type 2 diabetes and a low-density lipoprotein cholesterol (LDL-C) level ≥ 70 mg/dL, as well as those without diabetes but with an LDL-C ≥ 70 mg/dL and a 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 10%, be started on medium-intensity statin therapy.

A 2018 consensus panel review of the current literature, sponsored by the National Institute on Aging and the National Heart, Lung, and Blood Institute, concluded that there was insufficient evidence regarding the benefits and harms of statins in older adults, especially those with comorbidities, and that there was a paucity of evidence about statin therapy outcomes (both adverse and beneficial) relevant to older adults.⁴

A review of all guidelines published since 2013 revealed that only the United Kingdom’s 2014 National Institute for Health and Care Excellence (NICE) guideline provides a strong, risk-based recommendation for initiating primary prevention with statins in patients > 75 years old.⁵ These recommendations are based on the QRISK2 calculator (which has since been updated to the QRISK3), which assigns everyone ages > 75 years a > 10% 10-year risk score. This provides a universal statin indication for anyone in the 76-to-84 age range.⁶

Both the ACC/AHA and US Preventive Services Task Force guidelines clearly state that there are too few data and inadequate evidence in people older than 75 for a strong, risk-based statin recommendation.⁵ The Canadian Cardiovascular Society guideline takes a similar stance, emphasizing that the recommended Framingham risk model is not well validated in people > 75 years.⁵

STUDY SUMMARIES

Two different looks at statin use in the elderly

A retrospective cohort study (N = 46,864; median follow-up, 5.6 years) examined whether statin treatment is associated with a reduction in atherosclerotic disease and mortality in old and very old adults with and without type 2 diabetes.¹ Patients were enrolled from a large, anonymized national database in Spain. The researchers looked only at first-time users of statins and those without a statin prescription within the past 18 months.

Statin therapy seems to provide no benefit to patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Patients with previous ASCVD, type 1 diabetes, previous lipid-lowering treatment, dementia, cancer, or paralysis were excluded, as were those who were in residential care, were on dialysis, or had received an organ transplant. Patients were stratified by age (75-84 years and ≥ 85 years), diabetes status (with or without type 2 diabetes), and statin use (nonuser or new user).

Continue to: Results

Results. For patients with type 2 diabetes, the risk of ASCVD (a composite of coronary heart disease and stroke) was lower among those who took statins than among those who did not in the 75-to-84 group (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.65-0.89; 1-year number needed to treat [NNT] = 164). Among those who took statins, there was also lower all-cause mortality (HR = 0.84; 95% CI, 0.75-0.94; 1-year NNT = 306). In those ages ≥ 85 years with diabetes, the statin group did not have a lower risk of ASCVD (HR = 0.82; 95% CI, 0.53-1.26) or all-cause mortality (HR = 1.05; 95% CI, 0.86-1.28).

For patients ages 75 to 84 years without diabetes, there was no difference in risk between groups for ASCVD (HR = 0.94; 95% CI, 0.86–1.04) or all-cause mortality (HR = 0.98; 95% CI, 0.91-1.05). In those ages ≥ 85 years without diabetes, there was also no difference between groups for ASCVD (HR = 1; 95% CI, 0.80-1.24) or for all-cause mortality (HR = 1; 95% CI, 0.90-1.11).

A 2019 meta-analysis of randomized controlled trials (RCTs) (n = 134,537) and RCT summary data (n = 12,705) evaluated the safety and efficacy of statin therapy in patients ages ≥ 55 years.² In the group of patients ages > 75 years (n = 14,483; median follow-up, 4.9 years), each 1 mmol/L reduction in LDL-C was associated with significant decreased risk for major vascular events (risk ratio [RR] = 0.82; 95% CI, 0.70-0.95) and for major coronary events (RR = 0.82; 95% CI, 0.70-0.96).

In subgroup analysis by the presence or absence of previous vascular disease, there was a decreased risk per 1 mmol/L LDL-C reduction of major vascular events in patients with previous vascular disease (RR = 0.85; 95% CI, 0.73-0.98); however, there was not a significant effect in patients without previous vascular disease (RR = 0.92; 95% CI, 0.73-1.16).

WHAT’S NEW

Statins may be unnecessary in older adults without ASCVD or T2DM

Statin therapy reduces the risk of ASCVD and mortality in patients ages 75 to 84 with type 2 diabetes and in patients > 75 years with known vascular disease. However, statin therapy seems to provide no benefit in patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Continue to: CAVEATS

CAVEATS

Retrospective cohort design leaves cause and effect equivocal

Even though the first study was large (with more than 46,000 patients) and the median follow-up was 5.6 years, it was a retrospective cohort study. While there is clearly an association between statin therapy and reduced ASCVD and all-cause mortality in patients with diabetes ages 75 to 84 years, cause and effect cannot be unequivocally stated. However, the meta-analysis, which included RCTs, confirms the benefit of statins in secondary prevention for older patients.

The cohort study did not look at adverse effects from statin therapy in this age group, but the data from the 2019 meta-analysis did not reveal any significant risk of myopathy.

CHALLENGES TO IMPLEMENTATION

Guidelines are lacking and discontinuing meds requires discussion

The lack of supporting guidelines to treat this age group with statins remains the largest barrier to implementation. Many patients may already be taking a statin, so a discussion about discontinuing medication will need to be initiated.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 76-year-old woman with well-­controlled type 2 diabetes mellitus for 10 years and well-controlled mild hypertension. She is otherwise healthy, and her mother lived to age 95. Ms. M has never smoked, has no previous history of vascular/cardiovascular disease, and drinks 1 glass of wine 2 to 3 times per week. Based on the American College of Cardiology (ACC) calculator, she was started on atorvastatin years ago. Is continued use of the medication of any benefit at her current age?

The 2018 American Heart Association (AHA)/ACC/Multi-Society cholesterol guidelines do not provide primary prevention recommendations for those older than age 75 years.³ Up to age 75, the guidelines recommend that patients with type 2 diabetes and a low-density lipoprotein cholesterol (LDL-C) level ≥ 70 mg/dL, as well as those without diabetes but with an LDL-C ≥ 70 mg/dL and a 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 10%, be started on medium-intensity statin therapy.

A 2018 consensus panel review of the current literature, sponsored by the National Institute on Aging and the National Heart, Lung, and Blood Institute, concluded that there was insufficient evidence regarding the benefits and harms of statins in older adults, especially those with comorbidities, and that there was a paucity of evidence about statin therapy outcomes (both adverse and beneficial) relevant to older adults.⁴

A review of all guidelines published since 2013 revealed that only the United Kingdom’s 2014 National Institute for Health and Care Excellence (NICE) guideline provides a strong, risk-based recommendation for initiating primary prevention with statins in patients > 75 years old.⁵ These recommendations are based on the QRISK2 calculator (which has since been updated to the QRISK3), which assigns everyone ages > 75 years a > 10% 10-year risk score. This provides a universal statin indication for anyone in the 76-to-84 age range.⁶

Both the ACC/AHA and US Preventive Services Task Force guidelines clearly state that there are too few data and inadequate evidence in people older than 75 for a strong, risk-based statin recommendation.⁵ The Canadian Cardiovascular Society guideline takes a similar stance, emphasizing that the recommended Framingham risk model is not well validated in people > 75 years.⁵

STUDY SUMMARIES

Two different looks at statin use in the elderly

A retrospective cohort study (N = 46,864; median follow-up, 5.6 years) examined whether statin treatment is associated with a reduction in atherosclerotic disease and mortality in old and very old adults with and without type 2 diabetes.¹ Patients were enrolled from a large, anonymized national database in Spain. The researchers looked only at first-time users of statins and those without a statin prescription within the past 18 months.

Statin therapy seems to provide no benefit to patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Patients with previous ASCVD, type 1 diabetes, previous lipid-lowering treatment, dementia, cancer, or paralysis were excluded, as were those who were in residential care, were on dialysis, or had received an organ transplant. Patients were stratified by age (75-84 years and ≥ 85 years), diabetes status (with or without type 2 diabetes), and statin use (nonuser or new user).

Continue to: Results

Results. For patients with type 2 diabetes, the risk of ASCVD (a composite of coronary heart disease and stroke) was lower among those who took statins than among those who did not in the 75-to-84 group (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.65-0.89; 1-year number needed to treat [NNT] = 164). Among those who took statins, there was also lower all-cause mortality (HR = 0.84; 95% CI, 0.75-0.94; 1-year NNT = 306). In those ages ≥ 85 years with diabetes, the statin group did not have a lower risk of ASCVD (HR = 0.82; 95% CI, 0.53-1.26) or all-cause mortality (HR = 1.05; 95% CI, 0.86-1.28).

For patients ages 75 to 84 years without diabetes, there was no difference in risk between groups for ASCVD (HR = 0.94; 95% CI, 0.86–1.04) or all-cause mortality (HR = 0.98; 95% CI, 0.91-1.05). In those ages ≥ 85 years without diabetes, there was also no difference between groups for ASCVD (HR = 1; 95% CI, 0.80-1.24) or for all-cause mortality (HR = 1; 95% CI, 0.90-1.11).

A 2019 meta-analysis of randomized controlled trials (RCTs) (n = 134,537) and RCT summary data (n = 12,705) evaluated the safety and efficacy of statin therapy in patients ages ≥ 55 years.² In the group of patients ages > 75 years (n = 14,483; median follow-up, 4.9 years), each 1 mmol/L reduction in LDL-C was associated with significant decreased risk for major vascular events (risk ratio [RR] = 0.82; 95% CI, 0.70-0.95) and for major coronary events (RR = 0.82; 95% CI, 0.70-0.96).

In subgroup analysis by the presence or absence of previous vascular disease, there was a decreased risk per 1 mmol/L LDL-C reduction of major vascular events in patients with previous vascular disease (RR = 0.85; 95% CI, 0.73-0.98); however, there was not a significant effect in patients without previous vascular disease (RR = 0.92; 95% CI, 0.73-1.16).

WHAT’S NEW

Statins may be unnecessary in older adults without ASCVD or T2DM

Statin therapy reduces the risk of ASCVD and mortality in patients ages 75 to 84 with type 2 diabetes and in patients > 75 years with known vascular disease. However, statin therapy seems to provide no benefit in patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Continue to: CAVEATS

CAVEATS

Retrospective cohort design leaves cause and effect equivocal

Even though the first study was large (with more than 46,000 patients) and the median follow-up was 5.6 years, it was a retrospective cohort study. While there is clearly an association between statin therapy and reduced ASCVD and all-cause mortality in patients with diabetes ages 75 to 84 years, cause and effect cannot be unequivocally stated. However, the meta-analysis, which included RCTs, confirms the benefit of statins in secondary prevention for older patients.

The cohort study did not look at adverse effects from statin therapy in this age group, but the data from the 2019 meta-analysis did not reveal any significant risk of myopathy.

CHALLENGES TO IMPLEMENTATION

Guidelines are lacking and discontinuing meds requires discussion

The lack of supporting guidelines to treat this age group with statins remains the largest barrier to implementation. Many patients may already be taking a statin, so a discussion about discontinuing medication will need to be initiated.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

The death of George Floyd and other African Americans spurred the Association of Black Cardiologists, the American Heart Association, and the American College of Cardiology to join forces and issue an urgent letter denouncing recent and ongoing events.

Starting off by acknowledging that these are “difficult and disturbing times,” the presidents of the three societies tied the violence into the bigger public health picture. “Like cardiovascular disease, acts of violence and racism are core causes of psychosocial stress that promote poor well-being and cardiovascular health, especially for communities of color.”

“It’s not just one quick solution, one quick letter. It’s more of an ongoing project to raise awareness and have really defined projects. We want to have goals, tactics, and measurable outcomes. We want to make sure it’s not just a banner on the wall,” Athena Poppas, MD, president of the American College of Cardiology and one of three physicians signing the letter, said in an interview.

The Association of Black Cardiologists drafted the statement and asked the AHA and ACC if they wanted to sign on. “It felt important to join them and follow their lead,” she said. “There is a clear link between psychosocial stress and discrimination and health equity in the communities.”

Interestingly, the ABC and ACC have an existing partnership, one that included creating a “Campaign for the Future” a little more than a year ago. One of the focuses is on reducing health disparities and starting a diversity and inclusion task force that later became a committee. The groups held a joint board of trustees meeting at Morehouse University, Atlanta, in January 2020. Thinking about that time, Dr. Poppas added, “who knew what was about to transpire over the next few months?”

The letter is only one component of an ongoing effort to “find concrete ways to make change, both within the college and within our profession,” added Dr. Poppas, chief of cardiology and professor of medicine at Brown University, Providence, R.I., and director of the Lifespan Cardiovascular Institute of Rhode Island, Miriam Hospitals, and Newport Hospitals. “Thereby, there is good data that you affect health equity in the population as well.”

“We DENOUNCE incidents of racism and violence that continue to ravage our communities,” the society leaders wrote in the letter. “Given that heart disease and stroke are the leading causes of death for communities of color, particularly African Americans who have the lowest life expectancy of all racial/ethnic groups living in the United States, we are extremely disturbed by violent acts that cut to the core of the lives of our community.”

Other societies released similar statements. For example, the American College of Physicians expressed “grave concern” about recent events and the American Medical Association released a statement entitled “Police brutality must stop.”

A cardiologist speaks out

“Thank you to my organizations, the Association of Black Cardiologists and the American College of Cardiology, for taking a stand,” Travis C. Batts, MD, said in a video statement posted to YouTube on June 2, 2020.

“As an African American male who has sons, brothers, and friends who are also African American, I oftentimes have angst, particularly with my sons. Despite what I do to create an environment that cultivates education and puts them in the right position, there are some people who would stop just at how they look when they approach them,” Dr. Batts said.

“I always have that fear as a father that at some point they may engage with law enforcement – and it may not turn out the way we want it to,” said Dr. Batts, chairman of medical sub-specialties and medical director of the cardiology clinic at Wilford Hall Ambulatory Surgical Center at Lackland Air Force Base, Tex. He also is an associate professor of cardiovascular medicine for the Uniformed Services University of the Health Sciences, Bethesda, Md., and is an adjunct assistant professor at Texas A&M University. He went on in the video to describe how a personal encounter with police years ago changed his life.

The urgent letter from the cardiology societies speaks to health care disparities, Dr. Batts said, “but it doesn’t stop there. It talks about their goals to balance these issues that we see as a pervasive problem in our community.”

The societies point out that George Floyd’s death is not an isolated incident. “Mr. Floyd’s death comes on the heels of other recent incidents caught on camera. In another 2020 incident, Ahmaud Arbery was shot and killed while jogging in his hometown of Brunswick, Ga. Christian Cooper is fortunately alive and well to speak to the Memorial Day incident in New York’s Central Park where he was accused of threatening the life of a woman while bird watching.” They added that “another senseless death involves officers entering the Louisville, Kent., home of emergency medical technician Breonna Taylor.”

Dr. Batts said this portion of the statement was particularly poignant: “We stand and link arms in solidarity with efforts to dismantle systems that maintain excess morbidity and mortality, especially among vulnerable populations and those historically oppressed. Indeed, our collective vast membership, many of whom are at the front lines of clinical health care, has taken an oath to decisively and with kindness, compassion and grace act to relieve suffering related to ‘I can’t breathe’ in order to preserve life.”

A Positive Response

The response to the urgent letter has been “overwhelmingly positive,” Dr. Poppas said. “This isn’t political, per se. This is really about justice, about health equity, and about being moral and conscious human beings. People I hadn’t heard from in years said, ‘thank you for doing this.’ ” The comments on social media were “almost uniformly positive,” she added. “There is always one or two people who feel this isn’t what cardiology is about.”

“Although making a statement is important, so is doing the hard work to make change,” Dr. Poppas said. The goal involves “rolling up our sleeves and spending the time, the money and the energy to make changes – so 5-10 years from now, it looks different.”

In addition to Dr. Poppas, Michelle A. Albert, MD, MPH, president of the Association of Black Cardiologists and Robert A. Harrington, MD, president of the American Heart Association, signed the letter. Dr. Pappas and Dr. Batts had no relevant disclosures.

The death of George Floyd and other African Americans spurred the Association of Black Cardiologists, the American Heart Association, and the American College of Cardiology to join forces and issue an urgent letter denouncing recent and ongoing events.

Starting off by acknowledging that these are “difficult and disturbing times,” the presidents of the three societies tied the violence into the bigger public health picture. “Like cardiovascular disease, acts of violence and racism are core causes of psychosocial stress that promote poor well-being and cardiovascular health, especially for communities of color.”

“It’s not just one quick solution, one quick letter. It’s more of an ongoing project to raise awareness and have really defined projects. We want to have goals, tactics, and measurable outcomes. We want to make sure it’s not just a banner on the wall,” Athena Poppas, MD, president of the American College of Cardiology and one of three physicians signing the letter, said in an interview.

The Association of Black Cardiologists drafted the statement and asked the AHA and ACC if they wanted to sign on. “It felt important to join them and follow their lead,” she said. “There is a clear link between psychosocial stress and discrimination and health equity in the communities.”

Interestingly, the ABC and ACC have an existing partnership, one that included creating a “Campaign for the Future” a little more than a year ago. One of the focuses is on reducing health disparities and starting a diversity and inclusion task force that later became a committee. The groups held a joint board of trustees meeting at Morehouse University, Atlanta, in January 2020. Thinking about that time, Dr. Poppas added, “who knew what was about to transpire over the next few months?”

The letter is only one component of an ongoing effort to “find concrete ways to make change, both within the college and within our profession,” added Dr. Poppas, chief of cardiology and professor of medicine at Brown University, Providence, R.I., and director of the Lifespan Cardiovascular Institute of Rhode Island, Miriam Hospitals, and Newport Hospitals. “Thereby, there is good data that you affect health equity in the population as well.”

“We DENOUNCE incidents of racism and violence that continue to ravage our communities,” the society leaders wrote in the letter. “Given that heart disease and stroke are the leading causes of death for communities of color, particularly African Americans who have the lowest life expectancy of all racial/ethnic groups living in the United States, we are extremely disturbed by violent acts that cut to the core of the lives of our community.”

Other societies released similar statements. For example, the American College of Physicians expressed “grave concern” about recent events and the American Medical Association released a statement entitled “Police brutality must stop.”

A cardiologist speaks out

“Thank you to my organizations, the Association of Black Cardiologists and the American College of Cardiology, for taking a stand,” Travis C. Batts, MD, said in a video statement posted to YouTube on June 2, 2020.

“As an African American male who has sons, brothers, and friends who are also African American, I oftentimes have angst, particularly with my sons. Despite what I do to create an environment that cultivates education and puts them in the right position, there are some people who would stop just at how they look when they approach them,” Dr. Batts said.

“I always have that fear as a father that at some point they may engage with law enforcement – and it may not turn out the way we want it to,” said Dr. Batts, chairman of medical sub-specialties and medical director of the cardiology clinic at Wilford Hall Ambulatory Surgical Center at Lackland Air Force Base, Tex. He also is an associate professor of cardiovascular medicine for the Uniformed Services University of the Health Sciences, Bethesda, Md., and is an adjunct assistant professor at Texas A&M University. He went on in the video to describe how a personal encounter with police years ago changed his life.

The urgent letter from the cardiology societies speaks to health care disparities, Dr. Batts said, “but it doesn’t stop there. It talks about their goals to balance these issues that we see as a pervasive problem in our community.”

The societies point out that George Floyd’s death is not an isolated incident. “Mr. Floyd’s death comes on the heels of other recent incidents caught on camera. In another 2020 incident, Ahmaud Arbery was shot and killed while jogging in his hometown of Brunswick, Ga. Christian Cooper is fortunately alive and well to speak to the Memorial Day incident in New York’s Central Park where he was accused of threatening the life of a woman while bird watching.” They added that “another senseless death involves officers entering the Louisville, Kent., home of emergency medical technician Breonna Taylor.”

Dr. Batts said this portion of the statement was particularly poignant: “We stand and link arms in solidarity with efforts to dismantle systems that maintain excess morbidity and mortality, especially among vulnerable populations and those historically oppressed. Indeed, our collective vast membership, many of whom are at the front lines of clinical health care, has taken an oath to decisively and with kindness, compassion and grace act to relieve suffering related to ‘I can’t breathe’ in order to preserve life.”

A Positive Response

The response to the urgent letter has been “overwhelmingly positive,” Dr. Poppas said. “This isn’t political, per se. This is really about justice, about health equity, and about being moral and conscious human beings. People I hadn’t heard from in years said, ‘thank you for doing this.’ ” The comments on social media were “almost uniformly positive,” she added. “There is always one or two people who feel this isn’t what cardiology is about.”

“Although making a statement is important, so is doing the hard work to make change,” Dr. Poppas said. The goal involves “rolling up our sleeves and spending the time, the money and the energy to make changes – so 5-10 years from now, it looks different.”

In addition to Dr. Poppas, Michelle A. Albert, MD, MPH, president of the Association of Black Cardiologists and Robert A. Harrington, MD, president of the American Heart Association, signed the letter. Dr. Pappas and Dr. Batts had no relevant disclosures.

The death of George Floyd and other African Americans spurred the Association of Black Cardiologists, the American Heart Association, and the American College of Cardiology to join forces and issue an urgent letter denouncing recent and ongoing events.

Starting off by acknowledging that these are “difficult and disturbing times,” the presidents of the three societies tied the violence into the bigger public health picture. “Like cardiovascular disease, acts of violence and racism are core causes of psychosocial stress that promote poor well-being and cardiovascular health, especially for communities of color.”

“It’s not just one quick solution, one quick letter. It’s more of an ongoing project to raise awareness and have really defined projects. We want to have goals, tactics, and measurable outcomes. We want to make sure it’s not just a banner on the wall,” Athena Poppas, MD, president of the American College of Cardiology and one of three physicians signing the letter, said in an interview.

The Association of Black Cardiologists drafted the statement and asked the AHA and ACC if they wanted to sign on. “It felt important to join them and follow their lead,” she said. “There is a clear link between psychosocial stress and discrimination and health equity in the communities.”

Interestingly, the ABC and ACC have an existing partnership, one that included creating a “Campaign for the Future” a little more than a year ago. One of the focuses is on reducing health disparities and starting a diversity and inclusion task force that later became a committee. The groups held a joint board of trustees meeting at Morehouse University, Atlanta, in January 2020. Thinking about that time, Dr. Poppas added, “who knew what was about to transpire over the next few months?”

The letter is only one component of an ongoing effort to “find concrete ways to make change, both within the college and within our profession,” added Dr. Poppas, chief of cardiology and professor of medicine at Brown University, Providence, R.I., and director of the Lifespan Cardiovascular Institute of Rhode Island, Miriam Hospitals, and Newport Hospitals. “Thereby, there is good data that you affect health equity in the population as well.”

“We DENOUNCE incidents of racism and violence that continue to ravage our communities,” the society leaders wrote in the letter. “Given that heart disease and stroke are the leading causes of death for communities of color, particularly African Americans who have the lowest life expectancy of all racial/ethnic groups living in the United States, we are extremely disturbed by violent acts that cut to the core of the lives of our community.”

Other societies released similar statements. For example, the American College of Physicians expressed “grave concern” about recent events and the American Medical Association released a statement entitled “Police brutality must stop.”

A cardiologist speaks out

“Thank you to my organizations, the Association of Black Cardiologists and the American College of Cardiology, for taking a stand,” Travis C. Batts, MD, said in a video statement posted to YouTube on June 2, 2020.

“As an African American male who has sons, brothers, and friends who are also African American, I oftentimes have angst, particularly with my sons. Despite what I do to create an environment that cultivates education and puts them in the right position, there are some people who would stop just at how they look when they approach them,” Dr. Batts said.

“I always have that fear as a father that at some point they may engage with law enforcement – and it may not turn out the way we want it to,” said Dr. Batts, chairman of medical sub-specialties and medical director of the cardiology clinic at Wilford Hall Ambulatory Surgical Center at Lackland Air Force Base, Tex. He also is an associate professor of cardiovascular medicine for the Uniformed Services University of the Health Sciences, Bethesda, Md., and is an adjunct assistant professor at Texas A&M University. He went on in the video to describe how a personal encounter with police years ago changed his life.

The urgent letter from the cardiology societies speaks to health care disparities, Dr. Batts said, “but it doesn’t stop there. It talks about their goals to balance these issues that we see as a pervasive problem in our community.”

The societies point out that George Floyd’s death is not an isolated incident. “Mr. Floyd’s death comes on the heels of other recent incidents caught on camera. In another 2020 incident, Ahmaud Arbery was shot and killed while jogging in his hometown of Brunswick, Ga. Christian Cooper is fortunately alive and well to speak to the Memorial Day incident in New York’s Central Park where he was accused of threatening the life of a woman while bird watching.” They added that “another senseless death involves officers entering the Louisville, Kent., home of emergency medical technician Breonna Taylor.”

Dr. Batts said this portion of the statement was particularly poignant: “We stand and link arms in solidarity with efforts to dismantle systems that maintain excess morbidity and mortality, especially among vulnerable populations and those historically oppressed. Indeed, our collective vast membership, many of whom are at the front lines of clinical health care, has taken an oath to decisively and with kindness, compassion and grace act to relieve suffering related to ‘I can’t breathe’ in order to preserve life.”

A Positive Response

The response to the urgent letter has been “overwhelmingly positive,” Dr. Poppas said. “This isn’t political, per se. This is really about justice, about health equity, and about being moral and conscious human beings. People I hadn’t heard from in years said, ‘thank you for doing this.’ ” The comments on social media were “almost uniformly positive,” she added. “There is always one or two people who feel this isn’t what cardiology is about.”

“Although making a statement is important, so is doing the hard work to make change,” Dr. Poppas said. The goal involves “rolling up our sleeves and spending the time, the money and the energy to make changes – so 5-10 years from now, it looks different.”

In addition to Dr. Poppas, Michelle A. Albert, MD, MPH, president of the Association of Black Cardiologists and Robert A. Harrington, MD, president of the American Heart Association, signed the letter. Dr. Pappas and Dr. Batts had no relevant disclosures.

THE CASE

A 36-year-old nonsmoking white man presented with an episodic 3-month history of dry cough and nasal allergy symptoms. He reported a past history of sinus allergies but no history of asthma. His illness began with a flu-like syndrome, and he had been treated with antibiotics (amoxicillin and azithromycin) and oral steroids (methylprednisolone) by 2 other physicians for “viral syndrome” and “bronchitis.”

The patient reported some tactile fever initially but none thereafter. Symptoms included episodic wheezing but no overt shortness of breath. In addition to the persistent dry cough, he complained of frequent sinus congestion, post-nasal drip, and sneezing. He became concerned when he noticed a fleck of blood in his phlegm.

Physical exam was unimpressive, except for nasal congestion. His breath sounds were clear. Chest x-ray showed a benign-appearing granuloma in the right lower lobe (no previous films available for comparison). Peak-flow measurements taken in the office were persistently low (58%-70%) but improved with steroids and inhaled albuterol.

Over the following 7 weeks, the patient experienced waxing and waning symptoms. At his follow-up visit, he appeared well; chest auscultation revealed normal breath sounds. He was treated with an additional round of antibiotics (levofloxacin), oral steroids, nasal steroids, and inhaled albuterol.

At 13 weeks from his initial presentation, he developed frank hemoptysis and was diagnosed with a right lower-lobe pneumonia in the emergency department. While hospitalized, his clinical status deteriorated, requiring chest tube placement for a large pleural effusion.

Shortly thereafter, he underwent right middle and lower lobectomies and decortication. Multiple organisms were cultured from the pleural fluid. Tuberculosis testing and acid-fast bacilli stains were negative. No malignant cells were identified. Pathologic examination of the resected lung tissue confirmed the chest x-ray finding of a benign calcified granuloma. Additional testing, including a thin barium esophagram, was performed.

THE DIAGNOSIS

Results of the esophagram revealed a congenital bronchoesophageal fistula (C-BEF) between the patient’s esophagus and right mainstem bronchus, located 15 cm distal to his trachea.

Continue to: DISCUSSION

 

 

DISCUSSION

Fistulous connections between the esophagus and bronchi are rare but may arise in the setting of malignancy, trauma, inflammation, or congenital malformation.¹ While the precise etiology of C-BEF remains unknown, it is believed to be a consequence of failed tracheoesophageal separation during the early stages of embryonic development.

Prevalence and epidemiology. C-BEF has been reported to occur in 1 in 3000 to 4000 live births, often with concomitant esophageal atresia.² Infants with esophageal atresia demonstrate clinically significant respiratory symptoms and failure to thrive. However, C-BEF without esophageal atresia may be asymptomatic for years to decades.

Age at diagnosis ranges from 9 days to 83 years.³ Several explanations exist for the prolonged asymptomatic phase of this disease: (1) presence of a membrane overlying the fistula during childhood that subsequently ruptures; (2) presence of a proximal fold of esophageal mucosa overlapping the orifice; (3) antigravitational or upward extension of the fistulous tract from the esophagus; and (4) spasm of the smooth muscle of the fistula.⁴

Congenital bronchoesophageal fistula without esophageal atresia may be asymptomatic for years to decades.

Four subtypes. Type I fistulas are associated with a wide-necked congenital diverticulum of the esophagus, which may become inflamed and allow perforation into the nearby lung. Type II fistulas (most common) consist of a short tract running directly from the esophagus to a nearby lobar or segmental bronchus. Type III fistulas involve a communication between the esophagus and a cystic structure within the lung parenchyma. Type IV fistulas run from the esophagus into a sequestered pulmonary segment.¹ Our patient had a type II fistula.

Is there a nonspecific cough? The most common signs and symptoms of C-BEF are nonspecific cough, cough after ingestion of fluids or meals, and hemoptysis.^5,6 Symptoms may persist for decades prior to diagnosis, and the indolent course of C-BEF may lead to fatal complications such as recalcitrant pneumonia, bronchiectasis, and abscess formation.

Continue to: One test bests others for diagnosis

One test bests others for diagnosis. Plain chest x-ray may indicate enlarged lymph nodes or surrounding airspace disease but will not be able to identify a C-BEF. Computed tomography (CT) of the chest may detect the presence of a C-BEF but does not rule it out. Barium esophagram is the most sensitive test for BEF. Esophagoscopy and bronchoscopy may be helpful once the BEF has been identified, but neither has demonstrated reliability as a first-line test. In this particular case, the C-BEF was not seen on chest CT but was later detected on a thin barium esophagram.

To confirm the congenital nature of the fistula, histopathology should be examined. C-BEFs will have a mucosal layer and definitive muscularis layer within the fistulous tract.^3,5

Treatment. The preferred method of treatment for C-BEF is thoracotomy with resection of the fistula and insertion of a pleural or muscular flap graft to close the defects in the bronchus and esophagus.⁷ Alternatively, obliteration of the esophageal defect can be performed using biological glue or silver nitrate. Prognosis after surgical repair is excellent.

Our patient

Two weeks after hospital discharge, the patient was re-admitted for hydropneumothorax and underwent additional surgeries. Unfortunately, he died in the ICU due to a tension pneumothorax while intubated.

THE TAKEAWAY

C-BEF is a rare, insidious condition that may remain asymptomatic into adulthood. After common causes are ruled out, patients with adult-onset nonspecific cough, episodes of coughing after eating/drinking, and hemoptysis should be evaluated for BEF. The most useful diagnostic investigation is barium esophagram. Once C-BEF is identified, prompt surgical management is warranted. Because C-BEF persisting into adulthood is so rare, recommendations regarding diagnosis and treatment are based on expert opinion.

CORRESPONDENCE
Rade N. Pejic, MD, MMM, Department of Family Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, Mailbox #8033, New Orleans, LA 70112; rpejic@tulane.edu.

THE CASE

A 36-year-old nonsmoking white man presented with an episodic 3-month history of dry cough and nasal allergy symptoms. He reported a past history of sinus allergies but no history of asthma. His illness began with a flu-like syndrome, and he had been treated with antibiotics (amoxicillin and azithromycin) and oral steroids (methylprednisolone) by 2 other physicians for “viral syndrome” and “bronchitis.”

The patient reported some tactile fever initially but none thereafter. Symptoms included episodic wheezing but no overt shortness of breath. In addition to the persistent dry cough, he complained of frequent sinus congestion, post-nasal drip, and sneezing. He became concerned when he noticed a fleck of blood in his phlegm.

Physical exam was unimpressive, except for nasal congestion. His breath sounds were clear. Chest x-ray showed a benign-appearing granuloma in the right lower lobe (no previous films available for comparison). Peak-flow measurements taken in the office were persistently low (58%-70%) but improved with steroids and inhaled albuterol.

Over the following 7 weeks, the patient experienced waxing and waning symptoms. At his follow-up visit, he appeared well; chest auscultation revealed normal breath sounds. He was treated with an additional round of antibiotics (levofloxacin), oral steroids, nasal steroids, and inhaled albuterol.

At 13 weeks from his initial presentation, he developed frank hemoptysis and was diagnosed with a right lower-lobe pneumonia in the emergency department. While hospitalized, his clinical status deteriorated, requiring chest tube placement for a large pleural effusion.

Shortly thereafter, he underwent right middle and lower lobectomies and decortication. Multiple organisms were cultured from the pleural fluid. Tuberculosis testing and acid-fast bacilli stains were negative. No malignant cells were identified. Pathologic examination of the resected lung tissue confirmed the chest x-ray finding of a benign calcified granuloma. Additional testing, including a thin barium esophagram, was performed.

THE DIAGNOSIS

Results of the esophagram revealed a congenital bronchoesophageal fistula (C-BEF) between the patient’s esophagus and right mainstem bronchus, located 15 cm distal to his trachea.

Continue to: DISCUSSION

 

 

DISCUSSION

Fistulous connections between the esophagus and bronchi are rare but may arise in the setting of malignancy, trauma, inflammation, or congenital malformation.¹ While the precise etiology of C-BEF remains unknown, it is believed to be a consequence of failed tracheoesophageal separation during the early stages of embryonic development.

Prevalence and epidemiology. C-BEF has been reported to occur in 1 in 3000 to 4000 live births, often with concomitant esophageal atresia.² Infants with esophageal atresia demonstrate clinically significant respiratory symptoms and failure to thrive. However, C-BEF without esophageal atresia may be asymptomatic for years to decades.

Age at diagnosis ranges from 9 days to 83 years.³ Several explanations exist for the prolonged asymptomatic phase of this disease: (1) presence of a membrane overlying the fistula during childhood that subsequently ruptures; (2) presence of a proximal fold of esophageal mucosa overlapping the orifice; (3) antigravitational or upward extension of the fistulous tract from the esophagus; and (4) spasm of the smooth muscle of the fistula.⁴

Congenital bronchoesophageal fistula without esophageal atresia may be asymptomatic for years to decades.

Four subtypes. Type I fistulas are associated with a wide-necked congenital diverticulum of the esophagus, which may become inflamed and allow perforation into the nearby lung. Type II fistulas (most common) consist of a short tract running directly from the esophagus to a nearby lobar or segmental bronchus. Type III fistulas involve a communication between the esophagus and a cystic structure within the lung parenchyma. Type IV fistulas run from the esophagus into a sequestered pulmonary segment.¹ Our patient had a type II fistula.

Is there a nonspecific cough? The most common signs and symptoms of C-BEF are nonspecific cough, cough after ingestion of fluids or meals, and hemoptysis.^5,6 Symptoms may persist for decades prior to diagnosis, and the indolent course of C-BEF may lead to fatal complications such as recalcitrant pneumonia, bronchiectasis, and abscess formation.

Continue to: One test bests others for diagnosis

One test bests others for diagnosis. Plain chest x-ray may indicate enlarged lymph nodes or surrounding airspace disease but will not be able to identify a C-BEF. Computed tomography (CT) of the chest may detect the presence of a C-BEF but does not rule it out. Barium esophagram is the most sensitive test for BEF. Esophagoscopy and bronchoscopy may be helpful once the BEF has been identified, but neither has demonstrated reliability as a first-line test. In this particular case, the C-BEF was not seen on chest CT but was later detected on a thin barium esophagram.

To confirm the congenital nature of the fistula, histopathology should be examined. C-BEFs will have a mucosal layer and definitive muscularis layer within the fistulous tract.^3,5

Treatment. The preferred method of treatment for C-BEF is thoracotomy with resection of the fistula and insertion of a pleural or muscular flap graft to close the defects in the bronchus and esophagus.⁷ Alternatively, obliteration of the esophageal defect can be performed using biological glue or silver nitrate. Prognosis after surgical repair is excellent.

Our patient

Two weeks after hospital discharge, the patient was re-admitted for hydropneumothorax and underwent additional surgeries. Unfortunately, he died in the ICU due to a tension pneumothorax while intubated.

THE TAKEAWAY

C-BEF is a rare, insidious condition that may remain asymptomatic into adulthood. After common causes are ruled out, patients with adult-onset nonspecific cough, episodes of coughing after eating/drinking, and hemoptysis should be evaluated for BEF. The most useful diagnostic investigation is barium esophagram. Once C-BEF is identified, prompt surgical management is warranted. Because C-BEF persisting into adulthood is so rare, recommendations regarding diagnosis and treatment are based on expert opinion.

CORRESPONDENCE
Rade N. Pejic, MD, MMM, Department of Family Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, Mailbox #8033, New Orleans, LA 70112; rpejic@tulane.edu.

THE CASE

A 36-year-old nonsmoking white man presented with an episodic 3-month history of dry cough and nasal allergy symptoms. He reported a past history of sinus allergies but no history of asthma. His illness began with a flu-like syndrome, and he had been treated with antibiotics (amoxicillin and azithromycin) and oral steroids (methylprednisolone) by 2 other physicians for “viral syndrome” and “bronchitis.”

The patient reported some tactile fever initially but none thereafter. Symptoms included episodic wheezing but no overt shortness of breath. In addition to the persistent dry cough, he complained of frequent sinus congestion, post-nasal drip, and sneezing. He became concerned when he noticed a fleck of blood in his phlegm.

Physical exam was unimpressive, except for nasal congestion. His breath sounds were clear. Chest x-ray showed a benign-appearing granuloma in the right lower lobe (no previous films available for comparison). Peak-flow measurements taken in the office were persistently low (58%-70%) but improved with steroids and inhaled albuterol.

Over the following 7 weeks, the patient experienced waxing and waning symptoms. At his follow-up visit, he appeared well; chest auscultation revealed normal breath sounds. He was treated with an additional round of antibiotics (levofloxacin), oral steroids, nasal steroids, and inhaled albuterol.

At 13 weeks from his initial presentation, he developed frank hemoptysis and was diagnosed with a right lower-lobe pneumonia in the emergency department. While hospitalized, his clinical status deteriorated, requiring chest tube placement for a large pleural effusion.

Shortly thereafter, he underwent right middle and lower lobectomies and decortication. Multiple organisms were cultured from the pleural fluid. Tuberculosis testing and acid-fast bacilli stains were negative. No malignant cells were identified. Pathologic examination of the resected lung tissue confirmed the chest x-ray finding of a benign calcified granuloma. Additional testing, including a thin barium esophagram, was performed.

THE DIAGNOSIS

Results of the esophagram revealed a congenital bronchoesophageal fistula (C-BEF) between the patient’s esophagus and right mainstem bronchus, located 15 cm distal to his trachea.

Continue to: DISCUSSION

 

 

DISCUSSION

Fistulous connections between the esophagus and bronchi are rare but may arise in the setting of malignancy, trauma, inflammation, or congenital malformation.¹ While the precise etiology of C-BEF remains unknown, it is believed to be a consequence of failed tracheoesophageal separation during the early stages of embryonic development.

Prevalence and epidemiology. C-BEF has been reported to occur in 1 in 3000 to 4000 live births, often with concomitant esophageal atresia.² Infants with esophageal atresia demonstrate clinically significant respiratory symptoms and failure to thrive. However, C-BEF without esophageal atresia may be asymptomatic for years to decades.

Age at diagnosis ranges from 9 days to 83 years.³ Several explanations exist for the prolonged asymptomatic phase of this disease: (1) presence of a membrane overlying the fistula during childhood that subsequently ruptures; (2) presence of a proximal fold of esophageal mucosa overlapping the orifice; (3) antigravitational or upward extension of the fistulous tract from the esophagus; and (4) spasm of the smooth muscle of the fistula.⁴

Congenital bronchoesophageal fistula without esophageal atresia may be asymptomatic for years to decades.

Four subtypes. Type I fistulas are associated with a wide-necked congenital diverticulum of the esophagus, which may become inflamed and allow perforation into the nearby lung. Type II fistulas (most common) consist of a short tract running directly from the esophagus to a nearby lobar or segmental bronchus. Type III fistulas involve a communication between the esophagus and a cystic structure within the lung parenchyma. Type IV fistulas run from the esophagus into a sequestered pulmonary segment.¹ Our patient had a type II fistula.

Is there a nonspecific cough? The most common signs and symptoms of C-BEF are nonspecific cough, cough after ingestion of fluids or meals, and hemoptysis.^5,6 Symptoms may persist for decades prior to diagnosis, and the indolent course of C-BEF may lead to fatal complications such as recalcitrant pneumonia, bronchiectasis, and abscess formation.

Continue to: One test bests others for diagnosis

One test bests others for diagnosis. Plain chest x-ray may indicate enlarged lymph nodes or surrounding airspace disease but will not be able to identify a C-BEF. Computed tomography (CT) of the chest may detect the presence of a C-BEF but does not rule it out. Barium esophagram is the most sensitive test for BEF. Esophagoscopy and bronchoscopy may be helpful once the BEF has been identified, but neither has demonstrated reliability as a first-line test. In this particular case, the C-BEF was not seen on chest CT but was later detected on a thin barium esophagram.

To confirm the congenital nature of the fistula, histopathology should be examined. C-BEFs will have a mucosal layer and definitive muscularis layer within the fistulous tract.^3,5

Treatment. The preferred method of treatment for C-BEF is thoracotomy with resection of the fistula and insertion of a pleural or muscular flap graft to close the defects in the bronchus and esophagus.⁷ Alternatively, obliteration of the esophageal defect can be performed using biological glue or silver nitrate. Prognosis after surgical repair is excellent.

Our patient

Two weeks after hospital discharge, the patient was re-admitted for hydropneumothorax and underwent additional surgeries. Unfortunately, he died in the ICU due to a tension pneumothorax while intubated.

THE TAKEAWAY

C-BEF is a rare, insidious condition that may remain asymptomatic into adulthood. After common causes are ruled out, patients with adult-onset nonspecific cough, episodes of coughing after eating/drinking, and hemoptysis should be evaluated for BEF. The most useful diagnostic investigation is barium esophagram. Once C-BEF is identified, prompt surgical management is warranted. Because C-BEF persisting into adulthood is so rare, recommendations regarding diagnosis and treatment are based on expert opinion.

CORRESPONDENCE
Rade N. Pejic, MD, MMM, Department of Family Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, Mailbox #8033, New Orleans, LA 70112; rpejic@tulane.edu.

The variability in functional performance within and between levels of disability measured by the Expanded Disability Status Scale (EDSS) call into question the reliability of the EDSS itself, according to researchers.

Preferred walking speed, for example, may vary by as much as 20% among patients with the same EDSS score. “Even though it is considered a walking scale, your scale defined groups of homogeneous disability are not even homogeneous for quantified measurement of walking ability,” said Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y. “That’s a problem.”

Dr. Gudesblatt’s study was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

John F. Kurtzke, MD, developed the EDSS in 1967. The scale has become a standard outcome of clinical trials, alongside MRI measures and annualized relapse rates. More than 15 therapies for MS have received regulatory approval in part based on their effects on EDSS outcomes. Furthermore, the recently proposed treatment goal of no evidence of disease activity includes the EDSS among its criteria.

Functional ability, however, which the EDSS measures, depends on various factors such as cognitive function, manual dexterity, and ambulation. If the degree of variability of these factors is greater than 20% within groups defined as having similar disability, this scale would no longer be valid, according to Dr. Gudesblatt.

To analyze the variability in functional performance in groups of patients with similar disability, Dr. Gudesblatt and colleagues retrospectively reviewed data from a prospective MS registry. Participants underwent multidimensional computerized cognitive testing and digital gait analysis. They also submitted patient-reported outcomes for hand function while undergoing simultaneous measurements of Patient-Determined Disease Steps (PDDS) or EDSS. For the analysis, Dr. Gudesblatt and colleagues defined groups of “adjacent” EDSS scores as follows: from 0 to 2.5, from 3 to 4.5, from 5 to 6.5, and greater than 7.

In all, 258 patients with MS underwent cognitive testing. Of this group, 73% of patients were women, and mean age was 46 years. The proportion of overlap in multidomain computerized cognitive testing global summary score of 7 domains among patients with adjacent EDSS scores was 65%. The researchers found 42% overlap among patients at the extremes of the EDSS scale. The proportion of overlap in accumulative cognitive impairment (i.e., the number of cognitive domains impaired by greater than one standard deviation) was 72% across adjacent EDSS groups and 38% across extreme EDSS groups.

Among 254 patients with MS who underwent evaluation of walking, 72% were women, and mean age was 46 years. The mean normalized velocity of preferred walking speed varied by more than 20% within EDSS groups and overlapped by more than 20% between groups.

A total of 783 patients underwent evaluation of hand function and tremor. About 74% of these participants were women, and mean age was 49 years. The variability across all PDDS groups (i.e., 0 to 1, 2 to 4, and greater than 4) was greater than 50%. Adjacent PDDS groups had overlap of more than 50%, and the extremes had an overlap of greater than 32%.

“The criteria for the diagnosis [of MS] have undergone multiple revisions, but the scale to define the disability remains unchanged,” said Dr. Gudesblatt. “It’s all about trying to do the right thing for the right patient at the right time for the right reason. We cannot go by our own perceptions. You need to have objective not subjective information to appropriately improve measurements of disease trajectory. The neurologist must move beyond the hammer and tuning fork, must move to objective, quantitative, examiner-independent, multidimensional measures of important aspects of disease to enhance identification of critical disease impact along a continuum so as to improved shared decision making with patient centric objective data to improve outcomes and reduce disability.”

Dr. Gudesblatt has served on speakers bureaus for Acorda, Amgen, Medtronic, and Saol Therapeutics. He has performed contracted research for Biogen, EMD Serono, Novartis, Sanofi, and Teva. The study was conducted without external funding.

egreb@mdedge.com

SOURCE: Gudesblatt M et al. CMSC 2020. Abstract QOL15.

The variability in functional performance within and between levels of disability measured by the Expanded Disability Status Scale (EDSS) call into question the reliability of the EDSS itself, according to researchers.

Preferred walking speed, for example, may vary by as much as 20% among patients with the same EDSS score. “Even though it is considered a walking scale, your scale defined groups of homogeneous disability are not even homogeneous for quantified measurement of walking ability,” said Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y. “That’s a problem.”

Dr. Gudesblatt’s study was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

John F. Kurtzke, MD, developed the EDSS in 1967. The scale has become a standard outcome of clinical trials, alongside MRI measures and annualized relapse rates. More than 15 therapies for MS have received regulatory approval in part based on their effects on EDSS outcomes. Furthermore, the recently proposed treatment goal of no evidence of disease activity includes the EDSS among its criteria.

Functional ability, however, which the EDSS measures, depends on various factors such as cognitive function, manual dexterity, and ambulation. If the degree of variability of these factors is greater than 20% within groups defined as having similar disability, this scale would no longer be valid, according to Dr. Gudesblatt.

To analyze the variability in functional performance in groups of patients with similar disability, Dr. Gudesblatt and colleagues retrospectively reviewed data from a prospective MS registry. Participants underwent multidimensional computerized cognitive testing and digital gait analysis. They also submitted patient-reported outcomes for hand function while undergoing simultaneous measurements of Patient-Determined Disease Steps (PDDS) or EDSS. For the analysis, Dr. Gudesblatt and colleagues defined groups of “adjacent” EDSS scores as follows: from 0 to 2.5, from 3 to 4.5, from 5 to 6.5, and greater than 7.

In all, 258 patients with MS underwent cognitive testing. Of this group, 73% of patients were women, and mean age was 46 years. The proportion of overlap in multidomain computerized cognitive testing global summary score of 7 domains among patients with adjacent EDSS scores was 65%. The researchers found 42% overlap among patients at the extremes of the EDSS scale. The proportion of overlap in accumulative cognitive impairment (i.e., the number of cognitive domains impaired by greater than one standard deviation) was 72% across adjacent EDSS groups and 38% across extreme EDSS groups.

Among 254 patients with MS who underwent evaluation of walking, 72% were women, and mean age was 46 years. The mean normalized velocity of preferred walking speed varied by more than 20% within EDSS groups and overlapped by more than 20% between groups.

A total of 783 patients underwent evaluation of hand function and tremor. About 74% of these participants were women, and mean age was 49 years. The variability across all PDDS groups (i.e., 0 to 1, 2 to 4, and greater than 4) was greater than 50%. Adjacent PDDS groups had overlap of more than 50%, and the extremes had an overlap of greater than 32%.

“The criteria for the diagnosis [of MS] have undergone multiple revisions, but the scale to define the disability remains unchanged,” said Dr. Gudesblatt. “It’s all about trying to do the right thing for the right patient at the right time for the right reason. We cannot go by our own perceptions. You need to have objective not subjective information to appropriately improve measurements of disease trajectory. The neurologist must move beyond the hammer and tuning fork, must move to objective, quantitative, examiner-independent, multidimensional measures of important aspects of disease to enhance identification of critical disease impact along a continuum so as to improved shared decision making with patient centric objective data to improve outcomes and reduce disability.”

Dr. Gudesblatt has served on speakers bureaus for Acorda, Amgen, Medtronic, and Saol Therapeutics. He has performed contracted research for Biogen, EMD Serono, Novartis, Sanofi, and Teva. The study was conducted without external funding.

egreb@mdedge.com

SOURCE: Gudesblatt M et al. CMSC 2020. Abstract QOL15.

The variability in functional performance within and between levels of disability measured by the Expanded Disability Status Scale (EDSS) call into question the reliability of the EDSS itself, according to researchers.

Preferred walking speed, for example, may vary by as much as 20% among patients with the same EDSS score. “Even though it is considered a walking scale, your scale defined groups of homogeneous disability are not even homogeneous for quantified measurement of walking ability,” said Mark Gudesblatt, MD, medical director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Patchogue, N.Y. “That’s a problem.”

Dr. Gudesblatt’s study was presented at the virtual meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

John F. Kurtzke, MD, developed the EDSS in 1967. The scale has become a standard outcome of clinical trials, alongside MRI measures and annualized relapse rates. More than 15 therapies for MS have received regulatory approval in part based on their effects on EDSS outcomes. Furthermore, the recently proposed treatment goal of no evidence of disease activity includes the EDSS among its criteria.

Functional ability, however, which the EDSS measures, depends on various factors such as cognitive function, manual dexterity, and ambulation. If the degree of variability of these factors is greater than 20% within groups defined as having similar disability, this scale would no longer be valid, according to Dr. Gudesblatt.

To analyze the variability in functional performance in groups of patients with similar disability, Dr. Gudesblatt and colleagues retrospectively reviewed data from a prospective MS registry. Participants underwent multidimensional computerized cognitive testing and digital gait analysis. They also submitted patient-reported outcomes for hand function while undergoing simultaneous measurements of Patient-Determined Disease Steps (PDDS) or EDSS. For the analysis, Dr. Gudesblatt and colleagues defined groups of “adjacent” EDSS scores as follows: from 0 to 2.5, from 3 to 4.5, from 5 to 6.5, and greater than 7.

In all, 258 patients with MS underwent cognitive testing. Of this group, 73% of patients were women, and mean age was 46 years. The proportion of overlap in multidomain computerized cognitive testing global summary score of 7 domains among patients with adjacent EDSS scores was 65%. The researchers found 42% overlap among patients at the extremes of the EDSS scale. The proportion of overlap in accumulative cognitive impairment (i.e., the number of cognitive domains impaired by greater than one standard deviation) was 72% across adjacent EDSS groups and 38% across extreme EDSS groups.

Among 254 patients with MS who underwent evaluation of walking, 72% were women, and mean age was 46 years. The mean normalized velocity of preferred walking speed varied by more than 20% within EDSS groups and overlapped by more than 20% between groups.

A total of 783 patients underwent evaluation of hand function and tremor. About 74% of these participants were women, and mean age was 49 years. The variability across all PDDS groups (i.e., 0 to 1, 2 to 4, and greater than 4) was greater than 50%. Adjacent PDDS groups had overlap of more than 50%, and the extremes had an overlap of greater than 32%.

“The criteria for the diagnosis [of MS] have undergone multiple revisions, but the scale to define the disability remains unchanged,” said Dr. Gudesblatt. “It’s all about trying to do the right thing for the right patient at the right time for the right reason. We cannot go by our own perceptions. You need to have objective not subjective information to appropriately improve measurements of disease trajectory. The neurologist must move beyond the hammer and tuning fork, must move to objective, quantitative, examiner-independent, multidimensional measures of important aspects of disease to enhance identification of critical disease impact along a continuum so as to improved shared decision making with patient centric objective data to improve outcomes and reduce disability.”

Dr. Gudesblatt has served on speakers bureaus for Acorda, Amgen, Medtronic, and Saol Therapeutics. He has performed contracted research for Biogen, EMD Serono, Novartis, Sanofi, and Teva. The study was conducted without external funding.

egreb@mdedge.com

SOURCE: Gudesblatt M et al. CMSC 2020. Abstract QOL15.

Key clinical point: Patients with relapsing-remitting multiple sclerosis (RRMS) having poor prognostic factors at baseline who were initiated with induction therapy have a lower risk for disability in the long term.

Major finding: After propensity matching, the proportion of patients reaching the primary outcome (Expanded Disability Status Scale [EDSS], ≥6.0) was lower in the induction group (28.0%) than the escalation group (38.7%). The median final EDSS scores were 5.0 and 4.5 after escalation and induction, respectively (P less than .001).

Study details: This study evaluated the long-term effectiveness of initial treatment with induction (n=75) or escalation (n=738) approach in patients with RRMS identified from a multicenter, retrospective registry database in Italy.

Disclosures: The authors declared no conflicts of interest.

Citation: Prosperini et al. Neurotherapeutics. 2020 Mar 31. doi: 10.1007/s13311-020-00847-0.

Key clinical point: Patients with relapsing-remitting multiple sclerosis (RRMS) having poor prognostic factors at baseline who were initiated with induction therapy have a lower risk for disability in the long term.

Major finding: After propensity matching, the proportion of patients reaching the primary outcome (Expanded Disability Status Scale [EDSS], ≥6.0) was lower in the induction group (28.0%) than the escalation group (38.7%). The median final EDSS scores were 5.0 and 4.5 after escalation and induction, respectively (P less than .001).

Study details: This study evaluated the long-term effectiveness of initial treatment with induction (n=75) or escalation (n=738) approach in patients with RRMS identified from a multicenter, retrospective registry database in Italy.

Disclosures: The authors declared no conflicts of interest.

Citation: Prosperini et al. Neurotherapeutics. 2020 Mar 31. doi: 10.1007/s13311-020-00847-0.

Key clinical point: Patients with relapsing-remitting multiple sclerosis (RRMS) having poor prognostic factors at baseline who were initiated with induction therapy have a lower risk for disability in the long term.

Major finding: After propensity matching, the proportion of patients reaching the primary outcome (Expanded Disability Status Scale [EDSS], ≥6.0) was lower in the induction group (28.0%) than the escalation group (38.7%). The median final EDSS scores were 5.0 and 4.5 after escalation and induction, respectively (P less than .001).

Study details: This study evaluated the long-term effectiveness of initial treatment with induction (n=75) or escalation (n=738) approach in patients with RRMS identified from a multicenter, retrospective registry database in Italy.

Disclosures: The authors declared no conflicts of interest.

Citation: Prosperini et al. Neurotherapeutics. 2020 Mar 31. doi: 10.1007/s13311-020-00847-0.

Key clinical point: A pro-inflammatory diet characterized by higher dietary inflammatory index (DII) and energy-adjusted DII (E-DII) during adolescence is a significant risk factor for the onset of multiple sclerosis (MS).

Major finding: The risks for MS increased significantly when E-DII was used as a continuous variable (adjusted odds ratio [aOR], 1.53; P = .001) and categorical variable (fourth vs. first quartile: aOR, 7.01; P less than .001). A similar pattern was seen for DII as both continuous and categorical variables.

Study details: This large population-based incident case-control study conducted in Iran included 547 patients with incident MS and 1057 individuals from the general population.

Disclosures: Dr Hébert owns controlling interest in Connecting Health Innovations LLC (CHI), a company planning to license the DII from the University of South Carolina to develop computer and mobile applications. Dr Shivappa is an employee of CHI.

Citation: Abdollahpour I et al. Clin Nutr. 2020 Mar 6. doi: 10.1016/j.clnu.2020.02.033.

Key clinical point: A pro-inflammatory diet characterized by higher dietary inflammatory index (DII) and energy-adjusted DII (E-DII) during adolescence is a significant risk factor for the onset of multiple sclerosis (MS).

Major finding: The risks for MS increased significantly when E-DII was used as a continuous variable (adjusted odds ratio [aOR], 1.53; P = .001) and categorical variable (fourth vs. first quartile: aOR, 7.01; P less than .001). A similar pattern was seen for DII as both continuous and categorical variables.

Study details: This large population-based incident case-control study conducted in Iran included 547 patients with incident MS and 1057 individuals from the general population.

Disclosures: Dr Hébert owns controlling interest in Connecting Health Innovations LLC (CHI), a company planning to license the DII from the University of South Carolina to develop computer and mobile applications. Dr Shivappa is an employee of CHI.

Citation: Abdollahpour I et al. Clin Nutr. 2020 Mar 6. doi: 10.1016/j.clnu.2020.02.033.

Key clinical point: A pro-inflammatory diet characterized by higher dietary inflammatory index (DII) and energy-adjusted DII (E-DII) during adolescence is a significant risk factor for the onset of multiple sclerosis (MS).

Major finding: The risks for MS increased significantly when E-DII was used as a continuous variable (adjusted odds ratio [aOR], 1.53; P = .001) and categorical variable (fourth vs. first quartile: aOR, 7.01; P less than .001). A similar pattern was seen for DII as both continuous and categorical variables.

Study details: This large population-based incident case-control study conducted in Iran included 547 patients with incident MS and 1057 individuals from the general population.

Disclosures: Dr Hébert owns controlling interest in Connecting Health Innovations LLC (CHI), a company planning to license the DII from the University of South Carolina to develop computer and mobile applications. Dr Shivappa is an employee of CHI.

Citation: Abdollahpour I et al. Clin Nutr. 2020 Mar 6. doi: 10.1016/j.clnu.2020.02.033.

Key clinical point: In patients with multiple sclerosis (MS), protein concentrations of inflammatory cytokines, interleukin (IL)-27, transforming growth factor beta-1 (TGF-β1), and IL-10 are upregulated after 8 weeks of vitamin D₃ supplementation.

Major finding: In patients with MS, 8 weeks of vitamin D₃ administration upregulated the levels of IL-27 (P = .001), TGF-β1 (P less than .001), and IL-10 (P less than .001), whereas levels of IL-17A (P = .024) and IL-6 (P less than .001) were downregulated.

Study details: The study assessed venous blood samples drawn from individuals with MS (n=25) and control participants including first-degree relative (n=25) and healthy participants (n=25) before and after vitamin D₃ supplementation of 50,000 IU.

Disclosures: Dr SR Arefhosseini received financial support from Nutrition Research Center and Tabriz University of Medical Sciences, Tabriz, Iran.

Citation: Hashemi R et al. PLoS One. 2020 Apr 6. doi: 10.1371/journal.pone.0231145.

Key clinical point: In patients with multiple sclerosis (MS), protein concentrations of inflammatory cytokines, interleukin (IL)-27, transforming growth factor beta-1 (TGF-β1), and IL-10 are upregulated after 8 weeks of vitamin D₃ supplementation.

Major finding: In patients with MS, 8 weeks of vitamin D₃ administration upregulated the levels of IL-27 (P = .001), TGF-β1 (P less than .001), and IL-10 (P less than .001), whereas levels of IL-17A (P = .024) and IL-6 (P less than .001) were downregulated.

Study details: The study assessed venous blood samples drawn from individuals with MS (n=25) and control participants including first-degree relative (n=25) and healthy participants (n=25) before and after vitamin D₃ supplementation of 50,000 IU.

Disclosures: Dr SR Arefhosseini received financial support from Nutrition Research Center and Tabriz University of Medical Sciences, Tabriz, Iran.

Citation: Hashemi R et al. PLoS One. 2020 Apr 6. doi: 10.1371/journal.pone.0231145.

Key clinical point: In patients with multiple sclerosis (MS), protein concentrations of inflammatory cytokines, interleukin (IL)-27, transforming growth factor beta-1 (TGF-β1), and IL-10 are upregulated after 8 weeks of vitamin D₃ supplementation.

Major finding: In patients with MS, 8 weeks of vitamin D₃ administration upregulated the levels of IL-27 (P = .001), TGF-β1 (P less than .001), and IL-10 (P less than .001), whereas levels of IL-17A (P = .024) and IL-6 (P less than .001) were downregulated.

Study details: The study assessed venous blood samples drawn from individuals with MS (n=25) and control participants including first-degree relative (n=25) and healthy participants (n=25) before and after vitamin D₃ supplementation of 50,000 IU.

Disclosures: Dr SR Arefhosseini received financial support from Nutrition Research Center and Tabriz University of Medical Sciences, Tabriz, Iran.

Citation: Hashemi R et al. PLoS One. 2020 Apr 6. doi: 10.1371/journal.pone.0231145.

Key clinical point: Study finds direct evidence of transient neurotoxicity immediately after immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for aggressive multiple sclerosis (MS).

Major finding: Three months post-IAHSCT, levels of serum markers of both neuroaxonal and glial cell injury (serum Neurofilament Light Chain [sNfL] and serum Glial Fibrillary Acidic Protein [sGFAP]) increased from baseline by 32.1% (P = .029) and 74.8% (P = .0004), respectively. sNfL increases correlated with the dose of busulfan administered during transplant conditioning (P = .034), Expanded Disability Status Scale score (P = .041), as well as brain volume loss (P = .044), attributed to gray matter loss (P = .0023).

Study details: sNfL and sGFAP levels were evaluated pre- and post-IAHSCT at 3, 6, 9, and 12 months in 22 patients with MS and 28 noninflammatory control participants.

Disclosures: The study was funded by the MS Society of Canada. The authors declared no conflict of interest.

Citation: Thebault S et al. Ann Clin Transl Neurol. 2020 Apr 18. doi: 10.1002/acn3.51045.

Key clinical point: Study finds direct evidence of transient neurotoxicity immediately after immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for aggressive multiple sclerosis (MS).

Major finding: Three months post-IAHSCT, levels of serum markers of both neuroaxonal and glial cell injury (serum Neurofilament Light Chain [sNfL] and serum Glial Fibrillary Acidic Protein [sGFAP]) increased from baseline by 32.1% (P = .029) and 74.8% (P = .0004), respectively. sNfL increases correlated with the dose of busulfan administered during transplant conditioning (P = .034), Expanded Disability Status Scale score (P = .041), as well as brain volume loss (P = .044), attributed to gray matter loss (P = .0023).

Study details: sNfL and sGFAP levels were evaluated pre- and post-IAHSCT at 3, 6, 9, and 12 months in 22 patients with MS and 28 noninflammatory control participants.

Disclosures: The study was funded by the MS Society of Canada. The authors declared no conflict of interest.

Citation: Thebault S et al. Ann Clin Transl Neurol. 2020 Apr 18. doi: 10.1002/acn3.51045.

Key clinical point: Study finds direct evidence of transient neurotoxicity immediately after immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for aggressive multiple sclerosis (MS).

Major finding: Three months post-IAHSCT, levels of serum markers of both neuroaxonal and glial cell injury (serum Neurofilament Light Chain [sNfL] and serum Glial Fibrillary Acidic Protein [sGFAP]) increased from baseline by 32.1% (P = .029) and 74.8% (P = .0004), respectively. sNfL increases correlated with the dose of busulfan administered during transplant conditioning (P = .034), Expanded Disability Status Scale score (P = .041), as well as brain volume loss (P = .044), attributed to gray matter loss (P = .0023).

Study details: sNfL and sGFAP levels were evaluated pre- and post-IAHSCT at 3, 6, 9, and 12 months in 22 patients with MS and 28 noninflammatory control participants.

Disclosures: The study was funded by the MS Society of Canada. The authors declared no conflict of interest.

Citation: Thebault S et al. Ann Clin Transl Neurol. 2020 Apr 18. doi: 10.1002/acn3.51045.

An official with the World Health Organization (WHO) has stated that it appears to be “rare” that an asymptomatic individual can pass SARS-CoV-2 to someone else.

“From the data we have, it still seems to be rare that an asymptomatic person actually transmits onward to a secondary individual,” Maria Van Kerkhove, PhD, WHO’s COVID-19 technical lead and an infectious disease epidemiologist, said June 8 at a news briefing from the agency’s Geneva headquarters.

This announcement came on the heels of the publication of an analysis in the Annals of Internal Medicine, which suggested that as many as 40-45% of COVID-19 cases may be asymptomatic. In this paper, the authors, Daniel P. Oran, AM, and Eric J. Topol, MD, of the Scripps Research Translational Institute in La Jolla, Calif stated: “The likelihood that approximately 40%-45% of those infected with SARS-CoV-2 will remain asymptomatic suggests that the virus might have greater potential than previously estimated to spread silently and deeply through human populations.”

"The early data that we have assembled on the prevalence of asymptomatic SARS-CoV-2 infection suggest that this is a significant factor in the rapid progression of the COVID-19 pandemic," the authors concluded.

Dr. Van Kerkhove also made comments suggesting otherwise on Twitter, citing a new summary by WHO: “@WHO recently published a summary of transmission of #COVID19, incl. symptomatic, pre-symptomatic and asymptomatic transmission.”

She also tweeted the following lines from the WHO summary: “Comprehensive studies on transmission from asymptomatic individuals are difficult to conduct, but the available evidence from contact tracing reported by Member States suggests that asymptomatically-infected individuals are much less likely to transmit the virus than those who develop symptoms.” 

In an additional post, Dr. Van Kerkhove added: “In these data, it is important to breakdown truly asymptomatic vs pre-symptomatic vs mildly symptomatic... also to note that the [percentage] reported or estimated to be ‘asymptomatic’ is not the same as the [percentage] that are asymptomatic that actually transmit.”

In the paper published in the Annals of Internal Medicine, Mr. Oran and Dr. Topol analyzed data of asymptomatic individuals from 16 cohorts between April 19 and May 26, 2020 – a wide-ranging group consisting of residents of cities, health care workers, individuals in homeless shelters, obstetric patients, residents of a nursing home, crew members of aircraft carriers, passengers on cruise ships, and inmates in correctional facilities. Each cohort had varying rates of asymptomatic or presymptomatic cases..

When residents of Iceland were tested, 43 of 100 individuals who tested positive for SARS-CoV-2 did not show symptoms. In Vo’, Italy, 30 of 73 people (41.1%) with positive SARS-CoV-2 test results did not have symptoms in a first round of testing, and 13 of 29 (44.8%) had no symptoms in a second round of testing. Over half of residents of San Francisco’s Mission District who received testing (39 of 74; 52.7%) did not have symptoms, while slightly less than half of Indiana residents tested showed no symptoms (35 of 78; 44.8%).

A majority of 41 individuals (65.9%) who were mostly health care workers at Rutgers University reported no symptoms of COVID-19 at the time of testing. Data from homeless shelters in Boston (129 of 147; 87.7%) and Los Angeles (27 of 43; 62.7%) also showed a high rate of individuals without symptoms. Among 33 obstetric patients in New York City who tested positive for SARS-CoV-2, 29 women (87.9%) were asymptomatic during a median 2-day length of stay. In a Washington state nursing facility, 12 of 23 individuals (52.1%) were positive for SARS-CoV-2 without showing symptoms in a first round of testing, with another 15 of 24 residents (62.5%) not showing symptoms in a second round of testing. Of these residents, 24 individuals (88.9%) later went on to show symptoms of COVID-19.

SOURCE: Oran DP, Topol EJ. Ann Intern Med. 2020 Jun 3. doi: 10.7326/M20-3012.

This article was updated 6/8/20.

An official with the World Health Organization (WHO) has stated that it appears to be “rare” that an asymptomatic individual can pass SARS-CoV-2 to someone else.

“From the data we have, it still seems to be rare that an asymptomatic person actually transmits onward to a secondary individual,” Maria Van Kerkhove, PhD, WHO’s COVID-19 technical lead and an infectious disease epidemiologist, said June 8 at a news briefing from the agency’s Geneva headquarters.

This announcement came on the heels of the publication of an analysis in the Annals of Internal Medicine, which suggested that as many as 40-45% of COVID-19 cases may be asymptomatic. In this paper, the authors, Daniel P. Oran, AM, and Eric J. Topol, MD, of the Scripps Research Translational Institute in La Jolla, Calif stated: “The likelihood that approximately 40%-45% of those infected with SARS-CoV-2 will remain asymptomatic suggests that the virus might have greater potential than previously estimated to spread silently and deeply through human populations.”

"The early data that we have assembled on the prevalence of asymptomatic SARS-CoV-2 infection suggest that this is a significant factor in the rapid progression of the COVID-19 pandemic," the authors concluded.

Dr. Van Kerkhove also made comments suggesting otherwise on Twitter, citing a new summary by WHO: “@WHO recently published a summary of transmission of #COVID19, incl. symptomatic, pre-symptomatic and asymptomatic transmission.”

She also tweeted the following lines from the WHO summary: “Comprehensive studies on transmission from asymptomatic individuals are difficult to conduct, but the available evidence from contact tracing reported by Member States suggests that asymptomatically-infected individuals are much less likely to transmit the virus than those who develop symptoms.” 

In an additional post, Dr. Van Kerkhove added: “In these data, it is important to breakdown truly asymptomatic vs pre-symptomatic vs mildly symptomatic... also to note that the [percentage] reported or estimated to be ‘asymptomatic’ is not the same as the [percentage] that are asymptomatic that actually transmit.”

In the paper published in the Annals of Internal Medicine, Mr. Oran and Dr. Topol analyzed data of asymptomatic individuals from 16 cohorts between April 19 and May 26, 2020 – a wide-ranging group consisting of residents of cities, health care workers, individuals in homeless shelters, obstetric patients, residents of a nursing home, crew members of aircraft carriers, passengers on cruise ships, and inmates in correctional facilities. Each cohort had varying rates of asymptomatic or presymptomatic cases..

When residents of Iceland were tested, 43 of 100 individuals who tested positive for SARS-CoV-2 did not show symptoms. In Vo’, Italy, 30 of 73 people (41.1%) with positive SARS-CoV-2 test results did not have symptoms in a first round of testing, and 13 of 29 (44.8%) had no symptoms in a second round of testing. Over half of residents of San Francisco’s Mission District who received testing (39 of 74; 52.7%) did not have symptoms, while slightly less than half of Indiana residents tested showed no symptoms (35 of 78; 44.8%).

A majority of 41 individuals (65.9%) who were mostly health care workers at Rutgers University reported no symptoms of COVID-19 at the time of testing. Data from homeless shelters in Boston (129 of 147; 87.7%) and Los Angeles (27 of 43; 62.7%) also showed a high rate of individuals without symptoms. Among 33 obstetric patients in New York City who tested positive for SARS-CoV-2, 29 women (87.9%) were asymptomatic during a median 2-day length of stay. In a Washington state nursing facility, 12 of 23 individuals (52.1%) were positive for SARS-CoV-2 without showing symptoms in a first round of testing, with another 15 of 24 residents (62.5%) not showing symptoms in a second round of testing. Of these residents, 24 individuals (88.9%) later went on to show symptoms of COVID-19.

SOURCE: Oran DP, Topol EJ. Ann Intern Med. 2020 Jun 3. doi: 10.7326/M20-3012.

This article was updated 6/8/20.

An official with the World Health Organization (WHO) has stated that it appears to be “rare” that an asymptomatic individual can pass SARS-CoV-2 to someone else.

“From the data we have, it still seems to be rare that an asymptomatic person actually transmits onward to a secondary individual,” Maria Van Kerkhove, PhD, WHO’s COVID-19 technical lead and an infectious disease epidemiologist, said June 8 at a news briefing from the agency’s Geneva headquarters.

This announcement came on the heels of the publication of an analysis in the Annals of Internal Medicine, which suggested that as many as 40-45% of COVID-19 cases may be asymptomatic. In this paper, the authors, Daniel P. Oran, AM, and Eric J. Topol, MD, of the Scripps Research Translational Institute in La Jolla, Calif stated: “The likelihood that approximately 40%-45% of those infected with SARS-CoV-2 will remain asymptomatic suggests that the virus might have greater potential than previously estimated to spread silently and deeply through human populations.”

"The early data that we have assembled on the prevalence of asymptomatic SARS-CoV-2 infection suggest that this is a significant factor in the rapid progression of the COVID-19 pandemic," the authors concluded.

Dr. Van Kerkhove also made comments suggesting otherwise on Twitter, citing a new summary by WHO: “@WHO recently published a summary of transmission of #COVID19, incl. symptomatic, pre-symptomatic and asymptomatic transmission.”

She also tweeted the following lines from the WHO summary: “Comprehensive studies on transmission from asymptomatic individuals are difficult to conduct, but the available evidence from contact tracing reported by Member States suggests that asymptomatically-infected individuals are much less likely to transmit the virus than those who develop symptoms.” 

In an additional post, Dr. Van Kerkhove added: “In these data, it is important to breakdown truly asymptomatic vs pre-symptomatic vs mildly symptomatic... also to note that the [percentage] reported or estimated to be ‘asymptomatic’ is not the same as the [percentage] that are asymptomatic that actually transmit.”

In the paper published in the Annals of Internal Medicine, Mr. Oran and Dr. Topol analyzed data of asymptomatic individuals from 16 cohorts between April 19 and May 26, 2020 – a wide-ranging group consisting of residents of cities, health care workers, individuals in homeless shelters, obstetric patients, residents of a nursing home, crew members of aircraft carriers, passengers on cruise ships, and inmates in correctional facilities. Each cohort had varying rates of asymptomatic or presymptomatic cases..

When residents of Iceland were tested, 43 of 100 individuals who tested positive for SARS-CoV-2 did not show symptoms. In Vo’, Italy, 30 of 73 people (41.1%) with positive SARS-CoV-2 test results did not have symptoms in a first round of testing, and 13 of 29 (44.8%) had no symptoms in a second round of testing. Over half of residents of San Francisco’s Mission District who received testing (39 of 74; 52.7%) did not have symptoms, while slightly less than half of Indiana residents tested showed no symptoms (35 of 78; 44.8%).

A majority of 41 individuals (65.9%) who were mostly health care workers at Rutgers University reported no symptoms of COVID-19 at the time of testing. Data from homeless shelters in Boston (129 of 147; 87.7%) and Los Angeles (27 of 43; 62.7%) also showed a high rate of individuals without symptoms. Among 33 obstetric patients in New York City who tested positive for SARS-CoV-2, 29 women (87.9%) were asymptomatic during a median 2-day length of stay. In a Washington state nursing facility, 12 of 23 individuals (52.1%) were positive for SARS-CoV-2 without showing symptoms in a first round of testing, with another 15 of 24 residents (62.5%) not showing symptoms in a second round of testing. Of these residents, 24 individuals (88.9%) later went on to show symptoms of COVID-19.

SOURCE: Oran DP, Topol EJ. Ann Intern Med. 2020 Jun 3. doi: 10.7326/M20-3012.

This article was updated 6/8/20.

Statins are one of the most common medications dispensed in the US and are associated with clinically significant drug interactions.^1,2 The most common adverse drug reaction (ADR) of statin drug interactions is muscle-related toxicities.² Despite technology advances to alert clinicians to drug interactions, updated statin manufacturer labeling, and guideline recommendations, inappropriate prescribing and dispensing of statin drug interactions continues to occur in health care systems.^2-10

The medical literature has demonstrated many opportunities for pharmacists to prevent and mitigate drug interactions. At the points of prescribing and dispensing, pharmacists can reduce the number of potential drug interactions for the patient.^11-13 Pharmacists also have identified and resolved drug interactions through quality assurance review after dispensing to a patient.^7,8

Regardless of the time point of an intervention, the most common method pharmacists used to resolve drug interactions was through recommendations to a prescriber. The recommendations were generated through academic detailing, clinical decision support algorithms, drug conversions, or the pharmacist’s expertise. Regardless of the method the pharmacist used, the prescriber had the final authority to accept or decline the recommendation.^7,8,11-13 Although these interventions were effective, pharmacists could further streamline the process by autonomously resolving drug interactions. However, these types of interventions are not well described in the medical literature.

Background

The US Department of Veterans Affairs (VA) Veterans Integrated Service Network (VISN), established the Safety Target of Polypharmacy (STOP) report in 2015. At each facility in the network, the report identified patients who were dispensed medications known to have drug interactions. The interactions were chosen by the VISN, and the severity of the interactions was based on coding parameters within the VA computerized order entry system, which uses a severity score based on First Databank data. At the Harry S. Truman Memorial Veterans’ Hospital (Truman VA) in Columbia, Missouri, > 500 drug interactions were initially active on the STOP report. The most common drug interactions were statins with gemfibrozil and statins with niacin.1^4-18 The Truman VA Pharmacy Service was charged with resolving the interactions for the facility.

The Truman VA employs 3 Patient Aligned Care Team (PACT) Clinical Pharmacy Specialists (CPS) practicing within primary care clinics. PACT is the patientcentered medical home model used by the VA. PACT CPS are ambulatory care pharmacists who assist providers in managing diseases using a scope of practice. Having a scope of practice would have allowed the PACT CPS to manage drug interactions with independent prescribing authority. However, due to the high volume of STOP report interactions and limited PACT CPS resources, the Pharmacy Service needed to develop an efficient, patient-centered method to resolve them. The intervention also needed to allow pharmacists, both with and without a scope of practice, to address the interactions.

Methods

The Truman VA Pharmacy Service developed protocols, approved by the Pharmacy and Therapeutics (P&T) Committee, to manage the specific gemfibrozil-statin and niacinstatin interactions chosen for the VISN 15 STOP report (Figures 1 and 2). The protocols were designed to identify patients who did not have a clear indication for gemfibrozil or niacin, were likely to maintain triglycerides (TGs) < 500 mg/dL without these medications, and would not likely require close monitoring after discontinuation^.19 The protocols allowed pharmacists to autonomously discontinue gemfibrozil or niacin if patients did not have a history of pancreatitis, TGs ≥ 400 mg/dL or a nonlipid indication for niacin (eg, pellagra) after establishing care at Truman VA. Additionally, both interacting medications had to be dispensed by the VA. When pharmacists discontinued a medication, it was documented in a note in the patient electronic health record. The prescriber was notified through the note and the patient received a notification letter. Follow-up laboratory monitoring was not required as part of the protocol.

If patients met any of the exclusion criteria for discontinuation, the primary care provider (PCP) was notified to place a consult to the PACT Pharmacy Clinic for individualized interventions and close monitoring. Patients prescribed niacin for nonlipid indications were allowed to continue with their current drug regimen. At each encounter, the PACT CPS assessed for ADRs, made individualized medication changes, and arranged follow-up appointments. Once the interaction was resolved and treatment goals met, the PCP resumed monitoring of the patient’s lipid therapy.

Following all pharmacist interventions, a retrospective quality improvement analysis was conducted. The primary outcome was to evaluate the impact of discontinuing gemfibrozil and niacin by protocol on patients’ laboratory results. The coprimary endpoints were to describe the change in TG levels and the percentage of patients with TGs ≥ 500 mg/dL at least 5 weeks following the pharmacist-directed discontinuation by protocol. Secondary outcomes included the time required to resolve the interactions and a description of the PACT CPS pharmacologic interventions. Additionally, a quality assurance peer review was used to ensure the pharmacists appropriately utilized the protocols.

Data were collected from August 2016 to September 2017 for patients prescribed gemfibrozil and from May 2017 to January 2018 for patients prescribed niacin. The time spent resolving interactions was quantified based on encounter data. Descriptive statistics were used to analyze demographic information and the endpoints associated with each outcome. The project was reviewed by the University of Missouri Institutional Review Board, Truman VA privacy and information security officers, and was determined to meet guidelines for quality improvement.

Results

The original STOP report included 397 drug interactions involving statins with gemfibrozil or niacin (Table 1). The majority of patients were white and male aged 60 to 79 years. Gemfibrozil was the most common drug involved in all interactions (79.8%). The most common statins were atorvastatin (40%) and simvastatin (36.5%).

Gemfibrozil-Statin Interactions

Pharmacists discontinued gemfibrozil by protocol for 94 patients (29.6%), and 107 patients (33.8%) were referred to the PACT Pharmacy Clinic (Figure 3). For the remaining 116 patients (36.6%), the drug interaction was addressed outside of the protocol for the following reasons: the drug interaction was resolved prior to pharmacist review; an interacting prescription was expired and not to be continued; the patient self-discontinued ≥ 1 interacting medications; the patient was deceased; the patient moved; the patient was receiving ≥ 1 interacting medications outside of the VA; or the prescriber resolved the interaction following notification by the pharmacist.

Ultimately, the interaction was resolved for all patients with a gemfibrozil-statin interaction on the STOP report. Following gemfibrozil discontinuation by protocol, 76 patients (80.9%) had TG laboratory results available and were included in the analysis. Sixty-two patients’ (82%) TG levels decreased or increased by < 100 mg/dL (Figure 4), and the TG levels of 1 patient (1.3%) increased above the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter was 6.5 (3.6) months (range, 1-17). The pharmacists spent a mean of 16 minutes per patient resolving each interaction.

Of the 107 patients referred to the PACT Pharmacy Clinic, 80 (74.8%) had TG laboratory results available and were included in the analysis. These patients were followed by the PACT CPS until the drug interaction was resolved and confirmed to have TG levels at goal (< 500 mg/dL). Gemfibrozil doses ranged from 300 mg daily to 600 mg twice daily, with 70% (n = 56) of patients taking 600 mg twice daily. The PACT CPS made 148 interventions (Table 2). Twenty-three (29%) patients required only gemfibrozil discontinuation. The remaining 57 patients (71%) required at least 2 medication interventions. The PACT CPS generated 213 encounters for resolving drug interactions with a median of 2 encounters per patient.

Quality assurance review identified 5 patients (5.3%) who underwent gemfibrozil discontinuation by protocol, despite having criteria that would have recommended against discontinuation. In accordance with the protocol criteria, these patients were later referred to the PACT Pharmacy Clinic. None of these patients experienced a TG increase at or above the threshold of 500 mg/dL after gemfibrozil was initially discontinued but were excluded from the earlier analysis.

Niacin-Statin Interactions

Pharmacists discontinued niacin by protocol for 48 patients (60.0%), and 22 patients (27.5%) were referred to the PACT Pharmacy Clinic (Figure 5). For the remaining 5 patients (6.3%), the interaction was either addressed outside the protocol prior to pharmacist review, or an interacting prescription was expired and not to be continued. Additionally, niacin was continued per prescriber preference in 5 patients (6.3%).

Thirty-six patients (75%) had TG laboratory results available following niacin discontinuation by protocol and were included in the analysis. Most patients’ (n = 33, 91.7%) TG levels decreased or increased by < 100 mg/dL. No patient had a TG level that increased higher than the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter, was 5.3 (2.5) months (range, 1.2-9.8). The pharmacists spent a mean of 15 minutes per patient resolving each interaction. The quality assurance review found no discrepancies in the pharmacists’ application of the protocol.

Of the 22 patients referred to the PACT Pharmacy Clinic, 16 (72.7%) patients had TG laboratory results available and were included in the analysis. As with the gemfibrozil interactions, these patients were followed by the PACT Pharmacy Clinic until the drug interaction was resolved and confirmed to have TGs at goal (< 500 mg/dL). Niacin doses ranged from 500 mg daily to 2,000 mg daily, with the majority of patients taking 1,000 mg daily. The PACT CPS made 23 interventions. The PACT CPS generated 46 encounters for resolving drug interactions with a median of 2 encounters per patient.

Discussion

Following gemfibrozil or niacin discontinuation by protocol, most patients with available laboratory results experienced either a decrease or modest TG elevation. The proportion of patients experiencing a decrease in TGs was unexpected but potentially multifactorial. Individual causes for the decrease in TGs were beyond the scope of this analysis. The retrospective design limited the ability to identify variables that could have impacted TG levels when gemfibrozil or niacin were started and discontinued. Although the treatment of TG levels is not indicated until it is ≥ 500 mg/dL, due to an increased risk of pancreatitis, both protocols excluded patients with a history of TGs ≥ 400 mg/dL.¹⁹ The lower threshold was set to compensate for anticipated increase in TG levels, following gemfibrozil or niacin discontinuation, and to minimize the number of patients with TG levels ≥ 500 mg/dL. The actual impact on patients’ TG levels supports the use of this lower threshold in the protocol.

When TG levels increased by 200 to 249 mg/dL after gemfibrozil or niacin discontinuation, patients were evaluated for possible underlying causes, which occurred for 4 gemfibrozil and 1 niacin patient. One patient started a β-blocker after gemfibrozil was initiated, and 3 patients were taking gemfibrozil prior to establishing care at the VA. The TG levels of the patient taking niacin correlated with an increased hemoglobin A1c. The TG level for only 1 patient taking gemfibrozil increased above the 500 mg/dL threshold. The patient had several comorbidities known to increase TG levels, but the comorbidities were previously well controlled. No additional medication changes were made at that time, and the TG levels on the next fasting lipid panel decreased to goal. The patient did not experience any negative clinical sequelae from the elevated TG levels.

Thirty-five patients (36%) who were referred to the PACT Pharmacy Clinic required only either gemfibrozil or niacin discontinuation. These patients were evaluated to identify whether adjustments to the protocols would have allowed for pharmacist discontinuation without referral to the PACT Pharmacy Clinic. Twenty-four of these patients (69%) had repeated TG levels ≥ 400 mg/dL prior to referral to the PACT Pharmacy Clinic. Additionally, there was no correlation between the gemfibrozil or niacin doses and the change in TG levels following discontinuation. These data indicate the protocols appropriately identified patients who did not have an indication for gemfibrozil or niacin.

In addition to drug interactions identified on the STOP report, the PACT CPS resolved 12 additional interactions involving simvastatin and gemfibrozil. Additionally, unnecessary lipid medications were deprescribed. The PACT CPS identified 13 patients who experienced myalgias, an ADR attributed to the gemfibrozil- statin interaction. Of those, 9 patients’ ADRs resolved after discontinuing gemfibrozil alone. For the remaining 4 patients, additional interventions to convert the patient to another statin were required to resolve the ADR.

Using pharmacists to address the drug interactions shifted workload from the prescribers and other primary care team members. The mean time spent to resolve both gemfibrozil and niacin interactions by protocol was 15.5 minutes. One hundred fortytwo patients (35.8%) had drug interactions resolved by protocol, saving the PACT CPS’ expertise for patients requiring individualized interventions. Drug interactions were resolved within 4 PACT CPS encounters for 93.8% of the patients taking gemfibrozil and within 3 PACT CPS encounters for 93.8% of the patients taking niacin.

The protocols allowed 12 additional pharmacists who did not have an ambulatory care scope of practice to assist the PACT CPS in mitigating the STOP drug interactions. These pharmacists otherwise would have been limited to making consultative recommendations. Simultaneously, the design allowed for the PACT pharmacists’ expertise to be allocated for patients most likely to require interventions beyond the protocols. This type of intraprofessional referral process is not well described in the medical literature. To the authors’ knowledge, the only studies described referrals from hospital pharmacists to community pharmacists during transitions of care on hospital discharge.^20,21

Limitations

The results of this study are derived from a retrospective chart review at a single VA facility. The autonomous nature of PACT CPS interventions may be difficult to replicate in other settings that do not permit pharmacists the same prescriptive authority. This analysis was designed to demonstrate the impact of the pharmacist in resolving major drug interactions. Patients referred to the PACT Pharmacy Clinic who also had their lipid medications adjusted by a nonpharmacist provider were excluded. However, this may have minimized the impact of the PACT CPS on the patient care provided. As postintervention laboratory results were not available for all patients, some patients’ TG levels could have increased above the 500 mg/dL threshold but were not identified. The time investment was extensive and likely underestimates the true cost of implementing the interventions.

Because notification letters were used to instruct patients to stop gemfibrozil or niacin, several considerations need to be addressed when interpreting the follow-up laboratory results. First, we cannot confirm whether the patients received the letter or the exact date the letter was received. Additionally, we cannot confirm whether the patients followed the instructions to stop the interacting medications or the date the medications were stopped. It is possible some patients were still taking the interacting medication when the first laboratory was drawn. Should a patient have continued the interacting medication, most would have run out and been unable to obtain a refill within 90 days of receiving the letter, as this is the maximum amount dispensed at one time. The mean time to the first laboratory result for both gemfibrozil and niacin was 6.5 and 5.3 months, respectively. Approximately 85% of patients completed the first laboratory test at least 3 months after the letter was mailed.

The protocols were designed to assess whether gemfibrozil or niacin was indicated and did not assess whether the statin was indicated. Therefore, discontinuing the statin also could have resolved the interaction appropriately. However, due to characteristics of the patient population and recommendations in current lipid guidelines, it was more likely the statin would be indicated.22,23 The protocols also assumed that patients eligible for gemfibrozil or niacin discontinuation would not need additional changes to their lipid medications. The medication changes made by the PACT CPS may have gone beyond those minimally necessary to resolve the drug interaction and maintain TG goals. Patients who had gemfibrozil or niacin discontinued by protocol also may have benefited from additional optimization of their lipid medications.

Conclusions

This quality improvement analysis supports further evaluation of the complementary use of protocols and PACT CPS prescriptive authority to resolve statin drug interactions. The gemfibrozil and niacin protocols appropriately identified patients who were less likely to experience an adverse change in TG laboratory results. Patients more likely to require additional medication interventions were appropriately referred to the PACT Pharmacy Clinics for individualized care. These data support expanded roles for pharmacists, across various settings, to mitigate select drug interactions at the Truman VA.

Acknowledgments
This quality improvement project is the result of work supported with resources and use of the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

Statins are one of the most common medications dispensed in the US and are associated with clinically significant drug interactions.^1,2 The most common adverse drug reaction (ADR) of statin drug interactions is muscle-related toxicities.² Despite technology advances to alert clinicians to drug interactions, updated statin manufacturer labeling, and guideline recommendations, inappropriate prescribing and dispensing of statin drug interactions continues to occur in health care systems.^2-10

The medical literature has demonstrated many opportunities for pharmacists to prevent and mitigate drug interactions. At the points of prescribing and dispensing, pharmacists can reduce the number of potential drug interactions for the patient.^11-13 Pharmacists also have identified and resolved drug interactions through quality assurance review after dispensing to a patient.^7,8

Regardless of the time point of an intervention, the most common method pharmacists used to resolve drug interactions was through recommendations to a prescriber. The recommendations were generated through academic detailing, clinical decision support algorithms, drug conversions, or the pharmacist’s expertise. Regardless of the method the pharmacist used, the prescriber had the final authority to accept or decline the recommendation.^7,8,11-13 Although these interventions were effective, pharmacists could further streamline the process by autonomously resolving drug interactions. However, these types of interventions are not well described in the medical literature.

Background

The US Department of Veterans Affairs (VA) Veterans Integrated Service Network (VISN), established the Safety Target of Polypharmacy (STOP) report in 2015. At each facility in the network, the report identified patients who were dispensed medications known to have drug interactions. The interactions were chosen by the VISN, and the severity of the interactions was based on coding parameters within the VA computerized order entry system, which uses a severity score based on First Databank data. At the Harry S. Truman Memorial Veterans’ Hospital (Truman VA) in Columbia, Missouri, > 500 drug interactions were initially active on the STOP report. The most common drug interactions were statins with gemfibrozil and statins with niacin.1^4-18 The Truman VA Pharmacy Service was charged with resolving the interactions for the facility.

The Truman VA employs 3 Patient Aligned Care Team (PACT) Clinical Pharmacy Specialists (CPS) practicing within primary care clinics. PACT is the patientcentered medical home model used by the VA. PACT CPS are ambulatory care pharmacists who assist providers in managing diseases using a scope of practice. Having a scope of practice would have allowed the PACT CPS to manage drug interactions with independent prescribing authority. However, due to the high volume of STOP report interactions and limited PACT CPS resources, the Pharmacy Service needed to develop an efficient, patient-centered method to resolve them. The intervention also needed to allow pharmacists, both with and without a scope of practice, to address the interactions.

Methods

The Truman VA Pharmacy Service developed protocols, approved by the Pharmacy and Therapeutics (P&T) Committee, to manage the specific gemfibrozil-statin and niacinstatin interactions chosen for the VISN 15 STOP report (Figures 1 and 2). The protocols were designed to identify patients who did not have a clear indication for gemfibrozil or niacin, were likely to maintain triglycerides (TGs) < 500 mg/dL without these medications, and would not likely require close monitoring after discontinuation^.19 The protocols allowed pharmacists to autonomously discontinue gemfibrozil or niacin if patients did not have a history of pancreatitis, TGs ≥ 400 mg/dL or a nonlipid indication for niacin (eg, pellagra) after establishing care at Truman VA. Additionally, both interacting medications had to be dispensed by the VA. When pharmacists discontinued a medication, it was documented in a note in the patient electronic health record. The prescriber was notified through the note and the patient received a notification letter. Follow-up laboratory monitoring was not required as part of the protocol.

If patients met any of the exclusion criteria for discontinuation, the primary care provider (PCP) was notified to place a consult to the PACT Pharmacy Clinic for individualized interventions and close monitoring. Patients prescribed niacin for nonlipid indications were allowed to continue with their current drug regimen. At each encounter, the PACT CPS assessed for ADRs, made individualized medication changes, and arranged follow-up appointments. Once the interaction was resolved and treatment goals met, the PCP resumed monitoring of the patient’s lipid therapy.

Following all pharmacist interventions, a retrospective quality improvement analysis was conducted. The primary outcome was to evaluate the impact of discontinuing gemfibrozil and niacin by protocol on patients’ laboratory results. The coprimary endpoints were to describe the change in TG levels and the percentage of patients with TGs ≥ 500 mg/dL at least 5 weeks following the pharmacist-directed discontinuation by protocol. Secondary outcomes included the time required to resolve the interactions and a description of the PACT CPS pharmacologic interventions. Additionally, a quality assurance peer review was used to ensure the pharmacists appropriately utilized the protocols.

Data were collected from August 2016 to September 2017 for patients prescribed gemfibrozil and from May 2017 to January 2018 for patients prescribed niacin. The time spent resolving interactions was quantified based on encounter data. Descriptive statistics were used to analyze demographic information and the endpoints associated with each outcome. The project was reviewed by the University of Missouri Institutional Review Board, Truman VA privacy and information security officers, and was determined to meet guidelines for quality improvement.

Results

The original STOP report included 397 drug interactions involving statins with gemfibrozil or niacin (Table 1). The majority of patients were white and male aged 60 to 79 years. Gemfibrozil was the most common drug involved in all interactions (79.8%). The most common statins were atorvastatin (40%) and simvastatin (36.5%).

Gemfibrozil-Statin Interactions

Pharmacists discontinued gemfibrozil by protocol for 94 patients (29.6%), and 107 patients (33.8%) were referred to the PACT Pharmacy Clinic (Figure 3). For the remaining 116 patients (36.6%), the drug interaction was addressed outside of the protocol for the following reasons: the drug interaction was resolved prior to pharmacist review; an interacting prescription was expired and not to be continued; the patient self-discontinued ≥ 1 interacting medications; the patient was deceased; the patient moved; the patient was receiving ≥ 1 interacting medications outside of the VA; or the prescriber resolved the interaction following notification by the pharmacist.

Ultimately, the interaction was resolved for all patients with a gemfibrozil-statin interaction on the STOP report. Following gemfibrozil discontinuation by protocol, 76 patients (80.9%) had TG laboratory results available and were included in the analysis. Sixty-two patients’ (82%) TG levels decreased or increased by < 100 mg/dL (Figure 4), and the TG levels of 1 patient (1.3%) increased above the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter was 6.5 (3.6) months (range, 1-17). The pharmacists spent a mean of 16 minutes per patient resolving each interaction.

Of the 107 patients referred to the PACT Pharmacy Clinic, 80 (74.8%) had TG laboratory results available and were included in the analysis. These patients were followed by the PACT CPS until the drug interaction was resolved and confirmed to have TG levels at goal (< 500 mg/dL). Gemfibrozil doses ranged from 300 mg daily to 600 mg twice daily, with 70% (n = 56) of patients taking 600 mg twice daily. The PACT CPS made 148 interventions (Table 2). Twenty-three (29%) patients required only gemfibrozil discontinuation. The remaining 57 patients (71%) required at least 2 medication interventions. The PACT CPS generated 213 encounters for resolving drug interactions with a median of 2 encounters per patient.

Quality assurance review identified 5 patients (5.3%) who underwent gemfibrozil discontinuation by protocol, despite having criteria that would have recommended against discontinuation. In accordance with the protocol criteria, these patients were later referred to the PACT Pharmacy Clinic. None of these patients experienced a TG increase at or above the threshold of 500 mg/dL after gemfibrozil was initially discontinued but were excluded from the earlier analysis.

Niacin-Statin Interactions

Pharmacists discontinued niacin by protocol for 48 patients (60.0%), and 22 patients (27.5%) were referred to the PACT Pharmacy Clinic (Figure 5). For the remaining 5 patients (6.3%), the interaction was either addressed outside the protocol prior to pharmacist review, or an interacting prescription was expired and not to be continued. Additionally, niacin was continued per prescriber preference in 5 patients (6.3%).

Thirty-six patients (75%) had TG laboratory results available following niacin discontinuation by protocol and were included in the analysis. Most patients’ (n = 33, 91.7%) TG levels decreased or increased by < 100 mg/dL. No patient had a TG level that increased higher than the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter, was 5.3 (2.5) months (range, 1.2-9.8). The pharmacists spent a mean of 15 minutes per patient resolving each interaction. The quality assurance review found no discrepancies in the pharmacists’ application of the protocol.

Of the 22 patients referred to the PACT Pharmacy Clinic, 16 (72.7%) patients had TG laboratory results available and were included in the analysis. As with the gemfibrozil interactions, these patients were followed by the PACT Pharmacy Clinic until the drug interaction was resolved and confirmed to have TGs at goal (< 500 mg/dL). Niacin doses ranged from 500 mg daily to 2,000 mg daily, with the majority of patients taking 1,000 mg daily. The PACT CPS made 23 interventions. The PACT CPS generated 46 encounters for resolving drug interactions with a median of 2 encounters per patient.

Discussion

Following gemfibrozil or niacin discontinuation by protocol, most patients with available laboratory results experienced either a decrease or modest TG elevation. The proportion of patients experiencing a decrease in TGs was unexpected but potentially multifactorial. Individual causes for the decrease in TGs were beyond the scope of this analysis. The retrospective design limited the ability to identify variables that could have impacted TG levels when gemfibrozil or niacin were started and discontinued. Although the treatment of TG levels is not indicated until it is ≥ 500 mg/dL, due to an increased risk of pancreatitis, both protocols excluded patients with a history of TGs ≥ 400 mg/dL.¹⁹ The lower threshold was set to compensate for anticipated increase in TG levels, following gemfibrozil or niacin discontinuation, and to minimize the number of patients with TG levels ≥ 500 mg/dL. The actual impact on patients’ TG levels supports the use of this lower threshold in the protocol.

When TG levels increased by 200 to 249 mg/dL after gemfibrozil or niacin discontinuation, patients were evaluated for possible underlying causes, which occurred for 4 gemfibrozil and 1 niacin patient. One patient started a β-blocker after gemfibrozil was initiated, and 3 patients were taking gemfibrozil prior to establishing care at the VA. The TG levels of the patient taking niacin correlated with an increased hemoglobin A1c. The TG level for only 1 patient taking gemfibrozil increased above the 500 mg/dL threshold. The patient had several comorbidities known to increase TG levels, but the comorbidities were previously well controlled. No additional medication changes were made at that time, and the TG levels on the next fasting lipid panel decreased to goal. The patient did not experience any negative clinical sequelae from the elevated TG levels.

Thirty-five patients (36%) who were referred to the PACT Pharmacy Clinic required only either gemfibrozil or niacin discontinuation. These patients were evaluated to identify whether adjustments to the protocols would have allowed for pharmacist discontinuation without referral to the PACT Pharmacy Clinic. Twenty-four of these patients (69%) had repeated TG levels ≥ 400 mg/dL prior to referral to the PACT Pharmacy Clinic. Additionally, there was no correlation between the gemfibrozil or niacin doses and the change in TG levels following discontinuation. These data indicate the protocols appropriately identified patients who did not have an indication for gemfibrozil or niacin.

In addition to drug interactions identified on the STOP report, the PACT CPS resolved 12 additional interactions involving simvastatin and gemfibrozil. Additionally, unnecessary lipid medications were deprescribed. The PACT CPS identified 13 patients who experienced myalgias, an ADR attributed to the gemfibrozil- statin interaction. Of those, 9 patients’ ADRs resolved after discontinuing gemfibrozil alone. For the remaining 4 patients, additional interventions to convert the patient to another statin were required to resolve the ADR.

Using pharmacists to address the drug interactions shifted workload from the prescribers and other primary care team members. The mean time spent to resolve both gemfibrozil and niacin interactions by protocol was 15.5 minutes. One hundred fortytwo patients (35.8%) had drug interactions resolved by protocol, saving the PACT CPS’ expertise for patients requiring individualized interventions. Drug interactions were resolved within 4 PACT CPS encounters for 93.8% of the patients taking gemfibrozil and within 3 PACT CPS encounters for 93.8% of the patients taking niacin.

The protocols allowed 12 additional pharmacists who did not have an ambulatory care scope of practice to assist the PACT CPS in mitigating the STOP drug interactions. These pharmacists otherwise would have been limited to making consultative recommendations. Simultaneously, the design allowed for the PACT pharmacists’ expertise to be allocated for patients most likely to require interventions beyond the protocols. This type of intraprofessional referral process is not well described in the medical literature. To the authors’ knowledge, the only studies described referrals from hospital pharmacists to community pharmacists during transitions of care on hospital discharge.^20,21

Limitations

The results of this study are derived from a retrospective chart review at a single VA facility. The autonomous nature of PACT CPS interventions may be difficult to replicate in other settings that do not permit pharmacists the same prescriptive authority. This analysis was designed to demonstrate the impact of the pharmacist in resolving major drug interactions. Patients referred to the PACT Pharmacy Clinic who also had their lipid medications adjusted by a nonpharmacist provider were excluded. However, this may have minimized the impact of the PACT CPS on the patient care provided. As postintervention laboratory results were not available for all patients, some patients’ TG levels could have increased above the 500 mg/dL threshold but were not identified. The time investment was extensive and likely underestimates the true cost of implementing the interventions.

Because notification letters were used to instruct patients to stop gemfibrozil or niacin, several considerations need to be addressed when interpreting the follow-up laboratory results. First, we cannot confirm whether the patients received the letter or the exact date the letter was received. Additionally, we cannot confirm whether the patients followed the instructions to stop the interacting medications or the date the medications were stopped. It is possible some patients were still taking the interacting medication when the first laboratory was drawn. Should a patient have continued the interacting medication, most would have run out and been unable to obtain a refill within 90 days of receiving the letter, as this is the maximum amount dispensed at one time. The mean time to the first laboratory result for both gemfibrozil and niacin was 6.5 and 5.3 months, respectively. Approximately 85% of patients completed the first laboratory test at least 3 months after the letter was mailed.

The protocols were designed to assess whether gemfibrozil or niacin was indicated and did not assess whether the statin was indicated. Therefore, discontinuing the statin also could have resolved the interaction appropriately. However, due to characteristics of the patient population and recommendations in current lipid guidelines, it was more likely the statin would be indicated.22,23 The protocols also assumed that patients eligible for gemfibrozil or niacin discontinuation would not need additional changes to their lipid medications. The medication changes made by the PACT CPS may have gone beyond those minimally necessary to resolve the drug interaction and maintain TG goals. Patients who had gemfibrozil or niacin discontinued by protocol also may have benefited from additional optimization of their lipid medications.

Conclusions

This quality improvement analysis supports further evaluation of the complementary use of protocols and PACT CPS prescriptive authority to resolve statin drug interactions. The gemfibrozil and niacin protocols appropriately identified patients who were less likely to experience an adverse change in TG laboratory results. Patients more likely to require additional medication interventions were appropriately referred to the PACT Pharmacy Clinics for individualized care. These data support expanded roles for pharmacists, across various settings, to mitigate select drug interactions at the Truman VA.

Acknowledgments
This quality improvement project is the result of work supported with resources and use of the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

Statins are one of the most common medications dispensed in the US and are associated with clinically significant drug interactions.^1,2 The most common adverse drug reaction (ADR) of statin drug interactions is muscle-related toxicities.² Despite technology advances to alert clinicians to drug interactions, updated statin manufacturer labeling, and guideline recommendations, inappropriate prescribing and dispensing of statin drug interactions continues to occur in health care systems.^2-10

The medical literature has demonstrated many opportunities for pharmacists to prevent and mitigate drug interactions. At the points of prescribing and dispensing, pharmacists can reduce the number of potential drug interactions for the patient.^11-13 Pharmacists also have identified and resolved drug interactions through quality assurance review after dispensing to a patient.^7,8

Regardless of the time point of an intervention, the most common method pharmacists used to resolve drug interactions was through recommendations to a prescriber. The recommendations were generated through academic detailing, clinical decision support algorithms, drug conversions, or the pharmacist’s expertise. Regardless of the method the pharmacist used, the prescriber had the final authority to accept or decline the recommendation.^7,8,11-13 Although these interventions were effective, pharmacists could further streamline the process by autonomously resolving drug interactions. However, these types of interventions are not well described in the medical literature.

Background

The US Department of Veterans Affairs (VA) Veterans Integrated Service Network (VISN), established the Safety Target of Polypharmacy (STOP) report in 2015. At each facility in the network, the report identified patients who were dispensed medications known to have drug interactions. The interactions were chosen by the VISN, and the severity of the interactions was based on coding parameters within the VA computerized order entry system, which uses a severity score based on First Databank data. At the Harry S. Truman Memorial Veterans’ Hospital (Truman VA) in Columbia, Missouri, > 500 drug interactions were initially active on the STOP report. The most common drug interactions were statins with gemfibrozil and statins with niacin.1^4-18 The Truman VA Pharmacy Service was charged with resolving the interactions for the facility.

The Truman VA employs 3 Patient Aligned Care Team (PACT) Clinical Pharmacy Specialists (CPS) practicing within primary care clinics. PACT is the patientcentered medical home model used by the VA. PACT CPS are ambulatory care pharmacists who assist providers in managing diseases using a scope of practice. Having a scope of practice would have allowed the PACT CPS to manage drug interactions with independent prescribing authority. However, due to the high volume of STOP report interactions and limited PACT CPS resources, the Pharmacy Service needed to develop an efficient, patient-centered method to resolve them. The intervention also needed to allow pharmacists, both with and without a scope of practice, to address the interactions.

Methods

The Truman VA Pharmacy Service developed protocols, approved by the Pharmacy and Therapeutics (P&T) Committee, to manage the specific gemfibrozil-statin and niacinstatin interactions chosen for the VISN 15 STOP report (Figures 1 and 2). The protocols were designed to identify patients who did not have a clear indication for gemfibrozil or niacin, were likely to maintain triglycerides (TGs) < 500 mg/dL without these medications, and would not likely require close monitoring after discontinuation^.19 The protocols allowed pharmacists to autonomously discontinue gemfibrozil or niacin if patients did not have a history of pancreatitis, TGs ≥ 400 mg/dL or a nonlipid indication for niacin (eg, pellagra) after establishing care at Truman VA. Additionally, both interacting medications had to be dispensed by the VA. When pharmacists discontinued a medication, it was documented in a note in the patient electronic health record. The prescriber was notified through the note and the patient received a notification letter. Follow-up laboratory monitoring was not required as part of the protocol.

If patients met any of the exclusion criteria for discontinuation, the primary care provider (PCP) was notified to place a consult to the PACT Pharmacy Clinic for individualized interventions and close monitoring. Patients prescribed niacin for nonlipid indications were allowed to continue with their current drug regimen. At each encounter, the PACT CPS assessed for ADRs, made individualized medication changes, and arranged follow-up appointments. Once the interaction was resolved and treatment goals met, the PCP resumed monitoring of the patient’s lipid therapy.

Following all pharmacist interventions, a retrospective quality improvement analysis was conducted. The primary outcome was to evaluate the impact of discontinuing gemfibrozil and niacin by protocol on patients’ laboratory results. The coprimary endpoints were to describe the change in TG levels and the percentage of patients with TGs ≥ 500 mg/dL at least 5 weeks following the pharmacist-directed discontinuation by protocol. Secondary outcomes included the time required to resolve the interactions and a description of the PACT CPS pharmacologic interventions. Additionally, a quality assurance peer review was used to ensure the pharmacists appropriately utilized the protocols.

Data were collected from August 2016 to September 2017 for patients prescribed gemfibrozil and from May 2017 to January 2018 for patients prescribed niacin. The time spent resolving interactions was quantified based on encounter data. Descriptive statistics were used to analyze demographic information and the endpoints associated with each outcome. The project was reviewed by the University of Missouri Institutional Review Board, Truman VA privacy and information security officers, and was determined to meet guidelines for quality improvement.

Results

The original STOP report included 397 drug interactions involving statins with gemfibrozil or niacin (Table 1). The majority of patients were white and male aged 60 to 79 years. Gemfibrozil was the most common drug involved in all interactions (79.8%). The most common statins were atorvastatin (40%) and simvastatin (36.5%).

Gemfibrozil-Statin Interactions

Pharmacists discontinued gemfibrozil by protocol for 94 patients (29.6%), and 107 patients (33.8%) were referred to the PACT Pharmacy Clinic (Figure 3). For the remaining 116 patients (36.6%), the drug interaction was addressed outside of the protocol for the following reasons: the drug interaction was resolved prior to pharmacist review; an interacting prescription was expired and not to be continued; the patient self-discontinued ≥ 1 interacting medications; the patient was deceased; the patient moved; the patient was receiving ≥ 1 interacting medications outside of the VA; or the prescriber resolved the interaction following notification by the pharmacist.

Ultimately, the interaction was resolved for all patients with a gemfibrozil-statin interaction on the STOP report. Following gemfibrozil discontinuation by protocol, 76 patients (80.9%) had TG laboratory results available and were included in the analysis. Sixty-two patients’ (82%) TG levels decreased or increased by < 100 mg/dL (Figure 4), and the TG levels of 1 patient (1.3%) increased above the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter was 6.5 (3.6) months (range, 1-17). The pharmacists spent a mean of 16 minutes per patient resolving each interaction.

Of the 107 patients referred to the PACT Pharmacy Clinic, 80 (74.8%) had TG laboratory results available and were included in the analysis. These patients were followed by the PACT CPS until the drug interaction was resolved and confirmed to have TG levels at goal (< 500 mg/dL). Gemfibrozil doses ranged from 300 mg daily to 600 mg twice daily, with 70% (n = 56) of patients taking 600 mg twice daily. The PACT CPS made 148 interventions (Table 2). Twenty-three (29%) patients required only gemfibrozil discontinuation. The remaining 57 patients (71%) required at least 2 medication interventions. The PACT CPS generated 213 encounters for resolving drug interactions with a median of 2 encounters per patient.

Quality assurance review identified 5 patients (5.3%) who underwent gemfibrozil discontinuation by protocol, despite having criteria that would have recommended against discontinuation. In accordance with the protocol criteria, these patients were later referred to the PACT Pharmacy Clinic. None of these patients experienced a TG increase at or above the threshold of 500 mg/dL after gemfibrozil was initially discontinued but were excluded from the earlier analysis.

Niacin-Statin Interactions

Pharmacists discontinued niacin by protocol for 48 patients (60.0%), and 22 patients (27.5%) were referred to the PACT Pharmacy Clinic (Figure 5). For the remaining 5 patients (6.3%), the interaction was either addressed outside the protocol prior to pharmacist review, or an interacting prescription was expired and not to be continued. Additionally, niacin was continued per prescriber preference in 5 patients (6.3%).

Thirty-six patients (75%) had TG laboratory results available following niacin discontinuation by protocol and were included in the analysis. Most patients’ (n = 33, 91.7%) TG levels decreased or increased by < 100 mg/dL. No patient had a TG level that increased higher than the threshold of 500 mg/dL. The mean (SD) time to the first laboratory result after the pharmacists mailed the notification letter, was 5.3 (2.5) months (range, 1.2-9.8). The pharmacists spent a mean of 15 minutes per patient resolving each interaction. The quality assurance review found no discrepancies in the pharmacists’ application of the protocol.

Of the 22 patients referred to the PACT Pharmacy Clinic, 16 (72.7%) patients had TG laboratory results available and were included in the analysis. As with the gemfibrozil interactions, these patients were followed by the PACT Pharmacy Clinic until the drug interaction was resolved and confirmed to have TGs at goal (< 500 mg/dL). Niacin doses ranged from 500 mg daily to 2,000 mg daily, with the majority of patients taking 1,000 mg daily. The PACT CPS made 23 interventions. The PACT CPS generated 46 encounters for resolving drug interactions with a median of 2 encounters per patient.

Discussion

Following gemfibrozil or niacin discontinuation by protocol, most patients with available laboratory results experienced either a decrease or modest TG elevation. The proportion of patients experiencing a decrease in TGs was unexpected but potentially multifactorial. Individual causes for the decrease in TGs were beyond the scope of this analysis. The retrospective design limited the ability to identify variables that could have impacted TG levels when gemfibrozil or niacin were started and discontinued. Although the treatment of TG levels is not indicated until it is ≥ 500 mg/dL, due to an increased risk of pancreatitis, both protocols excluded patients with a history of TGs ≥ 400 mg/dL.¹⁹ The lower threshold was set to compensate for anticipated increase in TG levels, following gemfibrozil or niacin discontinuation, and to minimize the number of patients with TG levels ≥ 500 mg/dL. The actual impact on patients’ TG levels supports the use of this lower threshold in the protocol.

When TG levels increased by 200 to 249 mg/dL after gemfibrozil or niacin discontinuation, patients were evaluated for possible underlying causes, which occurred for 4 gemfibrozil and 1 niacin patient. One patient started a β-blocker after gemfibrozil was initiated, and 3 patients were taking gemfibrozil prior to establishing care at the VA. The TG levels of the patient taking niacin correlated with an increased hemoglobin A1c. The TG level for only 1 patient taking gemfibrozil increased above the 500 mg/dL threshold. The patient had several comorbidities known to increase TG levels, but the comorbidities were previously well controlled. No additional medication changes were made at that time, and the TG levels on the next fasting lipid panel decreased to goal. The patient did not experience any negative clinical sequelae from the elevated TG levels.

Thirty-five patients (36%) who were referred to the PACT Pharmacy Clinic required only either gemfibrozil or niacin discontinuation. These patients were evaluated to identify whether adjustments to the protocols would have allowed for pharmacist discontinuation without referral to the PACT Pharmacy Clinic. Twenty-four of these patients (69%) had repeated TG levels ≥ 400 mg/dL prior to referral to the PACT Pharmacy Clinic. Additionally, there was no correlation between the gemfibrozil or niacin doses and the change in TG levels following discontinuation. These data indicate the protocols appropriately identified patients who did not have an indication for gemfibrozil or niacin.

In addition to drug interactions identified on the STOP report, the PACT CPS resolved 12 additional interactions involving simvastatin and gemfibrozil. Additionally, unnecessary lipid medications were deprescribed. The PACT CPS identified 13 patients who experienced myalgias, an ADR attributed to the gemfibrozil- statin interaction. Of those, 9 patients’ ADRs resolved after discontinuing gemfibrozil alone. For the remaining 4 patients, additional interventions to convert the patient to another statin were required to resolve the ADR.

Using pharmacists to address the drug interactions shifted workload from the prescribers and other primary care team members. The mean time spent to resolve both gemfibrozil and niacin interactions by protocol was 15.5 minutes. One hundred fortytwo patients (35.8%) had drug interactions resolved by protocol, saving the PACT CPS’ expertise for patients requiring individualized interventions. Drug interactions were resolved within 4 PACT CPS encounters for 93.8% of the patients taking gemfibrozil and within 3 PACT CPS encounters for 93.8% of the patients taking niacin.

The protocols allowed 12 additional pharmacists who did not have an ambulatory care scope of practice to assist the PACT CPS in mitigating the STOP drug interactions. These pharmacists otherwise would have been limited to making consultative recommendations. Simultaneously, the design allowed for the PACT pharmacists’ expertise to be allocated for patients most likely to require interventions beyond the protocols. This type of intraprofessional referral process is not well described in the medical literature. To the authors’ knowledge, the only studies described referrals from hospital pharmacists to community pharmacists during transitions of care on hospital discharge.^20,21

Limitations

The results of this study are derived from a retrospective chart review at a single VA facility. The autonomous nature of PACT CPS interventions may be difficult to replicate in other settings that do not permit pharmacists the same prescriptive authority. This analysis was designed to demonstrate the impact of the pharmacist in resolving major drug interactions. Patients referred to the PACT Pharmacy Clinic who also had their lipid medications adjusted by a nonpharmacist provider were excluded. However, this may have minimized the impact of the PACT CPS on the patient care provided. As postintervention laboratory results were not available for all patients, some patients’ TG levels could have increased above the 500 mg/dL threshold but were not identified. The time investment was extensive and likely underestimates the true cost of implementing the interventions.

Because notification letters were used to instruct patients to stop gemfibrozil or niacin, several considerations need to be addressed when interpreting the follow-up laboratory results. First, we cannot confirm whether the patients received the letter or the exact date the letter was received. Additionally, we cannot confirm whether the patients followed the instructions to stop the interacting medications or the date the medications were stopped. It is possible some patients were still taking the interacting medication when the first laboratory was drawn. Should a patient have continued the interacting medication, most would have run out and been unable to obtain a refill within 90 days of receiving the letter, as this is the maximum amount dispensed at one time. The mean time to the first laboratory result for both gemfibrozil and niacin was 6.5 and 5.3 months, respectively. Approximately 85% of patients completed the first laboratory test at least 3 months after the letter was mailed.

The protocols were designed to assess whether gemfibrozil or niacin was indicated and did not assess whether the statin was indicated. Therefore, discontinuing the statin also could have resolved the interaction appropriately. However, due to characteristics of the patient population and recommendations in current lipid guidelines, it was more likely the statin would be indicated.22,23 The protocols also assumed that patients eligible for gemfibrozil or niacin discontinuation would not need additional changes to their lipid medications. The medication changes made by the PACT CPS may have gone beyond those minimally necessary to resolve the drug interaction and maintain TG goals. Patients who had gemfibrozil or niacin discontinued by protocol also may have benefited from additional optimization of their lipid medications.

Conclusions

This quality improvement analysis supports further evaluation of the complementary use of protocols and PACT CPS prescriptive authority to resolve statin drug interactions. The gemfibrozil and niacin protocols appropriately identified patients who were less likely to experience an adverse change in TG laboratory results. Patients more likely to require additional medication interventions were appropriately referred to the PACT Pharmacy Clinics for individualized care. These data support expanded roles for pharmacists, across various settings, to mitigate select drug interactions at the Truman VA.

Acknowledgments
This quality improvement project is the result of work supported with resources and use of the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.